Progress in Neurobiology 70 (2003) 83–244

The neurobiology and control of anxious states

Mark J. Millan∗
Psychopharmacology Department, Centre de Rescherches de Croissy, Institut de Recherches (IDR) Servier,
125 Chemin de Ronde, 78290 Croissy-sur-Seine, Paris, France
Received 13 March 2003; accepted 21 May 2003

Abstract
Fear is an adaptive component of the acute “stress” response to potentially-dangerous (external and internal) stimuli which threaten to
perturb homeostasis. However, when disproportional in intensity, chronic and/or irreversible, or not associated with any genuine risk, it
may be symptomatic of a debilitating anxious state: for example, social phobia, panic attacks or generalized anxiety disorder. In view of
the importance of guaranteeing an appropriate emotional response to aversive events, it is not surprising that a diversity of mechanisms are
involved in the induction and inhibition of anxious states. Apart from conventional neurotransmitters, such as monoamines, ␥-amino-butyric
acid (GABA) and glutamate, many other modulators have been implicated, including: adenosine, cannabinoids, numerous neuropeptides,
hormones, neurotrophins, cytokines and several cellular mediators. Accordingly, though benzodiazepines (which reinforce transmission at
GABAA receptors), serotonin (5-HT)1A receptor agonists and 5-HT reuptake inhibitors are currently the principle drugs employed in the
management of anxiety disorders, there is considerable scope for the development of alternative therapies. In addition to cellular, anatomical
and neurochemical strategies, behavioral models are indispensable for the characterization of anxious states and their modulation. Amongst
diverse paradigms, conflict procedures—in which subjects experience opposing impulses of desire and fear—are of especial conceptual
and therapeutic pertinence. For example, in the Vogel Conflict Test (VCT), the ability of drugs to release punishment-suppressed drinking
behavior is evaluated. In reviewing the neurobiology of anxious states, the present article focuses in particular upon: the multifarious and
complex roles of individual modulators, often as a function of the specific receptor type and neuronal substrate involved in their actions;
novel targets for the management of anxiety disorders; the influence of neurotransmitters and other agents upon performance in the VCT;
data acquired from complementary pharmacological and genetic strategies and, finally, several open questions likely to orientate future
experimental- and clinical-research. In view of the recent proliferation of mechanisms implicated in the pathogenesis, modulation and,
potentially, treatment of anxiety disorders, this is an opportune moment to survey their functional and pathophysiological significance, and
to assess their influence upon performance in the VCT and other models of potential anxiolytic properties.
© 2003 Elsevier Ltd. All rights reserved.

Contents

1. General introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
1.1. Aims and scope of review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
1.2. Organization of review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
1.3. Anxiety disorders and experimental models: general considerations . . . . . . . . . . . . . . . . . . . 88
1.4. Conflict models for the detection of anxiolytic (or anxiogenic) activity . . . . . . . . . . . . . . . 88
1.4.1. Basic principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
1.4.2. Validity and clinical pertinence of the VCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Abbreviations: Ach, acetylcholine; ACPC, aminocyclopropylcarboxylic acid; ACTH, adrenocorticotropic hormone; AR, adrenoceptor; AMPA,
␣-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid; AR, adrenoceptor; BDNF, brain-derived neurotrophic factor; BZP, benzodiazepine; CART,
cocaine- and amphetamine-related transcript; CCK, cholecystokinin; CRF, corticotrophin releasing factor; DA, dopamine; DRN, dorsal raphe nucleus;
FCX, frontal cortex; GABA, ␥-amino-butyric acid; GAD, general anxiety disorder; GIRK, G-protein-coupled K+ -receptor; GR, glucocorticoid receptor;
5-HT, serotonin; LC, locus coeruleus; MAO, monoamine oxidase A; MCH, melanin concentrating hormone; mCPP, meta-chlorophenylpiperazine; MR,
mineralocorticoid receptor; MRN, median raphe nucleus; MSH, melanocyte-stimulating hormone; NA, noradrenaline; NGF, nerve growth factor; NK,
neurokinin; NMDA, N-methyl-d-aspartate; NO, nitric oxide; NPY, neuropeptide Y; OFQ, orphaninFQ; PACAP, pituitary adenylyl cyclase activating pep-
tide; PAG, periaqueductal gray; SP, substance P; SSRI, selective serotonin reuptake inhibitor; Trk, tropomyosin-related kinase; VCT, Vogel Conflict Test;
VDCC, voltage-dependent calcium channel; VTA, ventrotegmental area
∗ Tel.: +33-1-55-72-24-25; fax: +33-1-55-72-24-70.

E-mail address: mark.millan@fr.netgrs.com (M.J. Millan).

0301-0082/$ – see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0301-0082(03)00087-X
84 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

1.5. The integration and expression of anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

1.5.1. Adaptive and non-adaptive features of anxiety: basic pathological
mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
1.5.2. “Trait” and “state” anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
1.5.3. Cerebral circuits for the modulation of anxious states . . . . . . . . . . . . . . . . . . . . . . . . 91
2. GABA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
2.1. GABAergic pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
2.2. GABAA receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
2.2.1. Structure, localization and modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
2.2.2. Benzodiazepines and related ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
2.2.3. Neurosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
2.2.4. Propofol and other injectable general anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.2.5. Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.3. GABAB receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
2.3.1. Coupling and localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
2.3.2. Anxiolytic properties of GABAB receptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . 107
3. Excitatory amino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
3.1. Glutamatergic pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
3.2. NMDA receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
3.2.1. Cooperative operation of NMDA recognition and glycineB sites . . . . . . . . . . . . . 108
3.2.2. Anxiolytic actions of NMDA recognition site antagonists and open
channel blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
3.2.3. GlycineB site ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
3.2.4. Interaction with BZPs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
3.2.5. Modulatory sites on NR2B subunits: ifenprodil . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
3.3. AMPA receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
3.4. Kainate receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3.5. Metabotropic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
3.5.1. Multiple classes of functionally-heterogeneous metabotropic receptor . . . . . . . . 113
3.5.2. Anxiolytic profiles of ligands at metabotropic mGluR receptors . . . . . . . . . . . . . 113
3.6. Multiple glutamatergic mechanisms for anxiolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
4. Monoamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
4.1. Noradrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
4.1.1. Noradrenergic pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
4.1.2. α2 -AR agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
4.1.3. Significance of α2 -AR subtypes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
4.1.4. α2 -AR antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
4.1.5. Role of α1 -ARs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
4.1.6. Role of β-ARs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
4.2. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4.2.1. Dopaminergic pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4.2.2. Multiple classes of dopamine receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
4.2.3. Dopamine “D2 -like” receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
4.2.4. Dopamine “D1 -like” receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
4.3. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
4.3.1. Serotonergic pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
4.3.2. 5-HT1A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
4.3.3. 5-HT1B receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
4.3.4. Serotonin 5-HT2 receptor subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
4.3.5. 5-HT3 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
4.3.6. Other classes of 5-HT receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
4.4. Antidepressant agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
4.4.1. Clinical actions of antidepressant agents in the treatment of anxious states . . . 137
4.4.2. SSRIs and mixed 5-HT/NA reuptake inhibitors: long-term, adaptive actions . . 138
4.4.3. Selective NA reuptake inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4.4.4. Antidepressant agents possessing 5-HT2A/2C antagonist properties . . . . . . . . . . . 139
4.4.5. Monoamine oxidase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
4.5. Antipsychotic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
5. Histamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5.1. Coupling, localization and interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5.2. Control of anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 85

6. Acetylcholine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
6.1. Cholinergic pathways and their modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
6.2. Nicotinic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
6.2.1. Localization and interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
6.2.2. Influence upon anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
6.3. Muscarinic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
7. Adenosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
7.1. Generation, localization and coupling to multiple receptor subtypes . . . . . . . . . . . . . . . . . 143
7.2. Adenosine A1 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
7.3. Adenosine A2A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
7.4. Purinoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
8. Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
8.1. Generation and coupling to CB1 receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
8.2. Influence upon anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
9. Neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
9.1. Neuropeptides/receptors previously examined by use of the VCT . . . . . . . . . . . . . . . . . . . 146
9.1.1. Cholecystokinin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
9.1.2. Corticotropin releasing factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
9.1.3. Vasopressin and oxytocin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
9.1.4. Substance P and other tachykinins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
9.1.5. Neuropeptide Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
9.1.6. Glucagon-like peptide-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
9.1.7. Galanin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
9.1.8. Neurotensin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
9.1.9. Multiple opioid peptides and melanocortins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
9.1.10. Melanin Concentrating Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
9.1.11. Angiotensin/AT receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
9.2. Peptides/receptors as yet to be evaluated in the VCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
9.2.1. Vasoactive intestinal peptide and pituitary adenlyl cyclase activating peptide . . 158
9.2.2. Somatostatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
9.2.3. Natriuretic peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
9.2.4. Bombesin-related peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
10. Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
10.1. Coupling and localization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
10.2. Control of anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
11. Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
11.1. Genomic and non-genomic actions in the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
11.2. Interactions with neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
11.3. Control of anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
11.4. The complex role of glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
12. Estrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
12.1. Genomic and non-genomic actions in the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
12.2. Control of anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
12.3. Clinical pertinence: gender and anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
13. Ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
13.1. Calcium channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
13.1.1. Operation and localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
13.1.2. Control of anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
13.1.3. Actions of GABApentin and pregabalin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
13.2. Sodium channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
13.3. Potassium-channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
14. Nitric oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
15. Neurotrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
15.1. Actions of neurotrophins at “Trk” receptors: cerebral localization of BDNF . . . . . . . . 167
15.2. Role of BDNF in the control of anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
15.3. BDNF/TrkB receptors as a therapeutic target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
15.4. Other neurotrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
16. Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
17. Sigma1 and sigma2 sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
17.1. Sigma1 sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
17.2. Sigma2 sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
17.3. Perspectives for sigma ligands as anxiolytic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
86 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

18. General discussion: open questions, conceptual issues and future research directions . . . . . . . 171
18.1. Multiple substrates of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
18.2. Cellular mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
18.3. Long-term actions of anxiolytic agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
18.4. Detection of anxiogenic and anxiolytic properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
18.5. Comparing actions in the VCT to other models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
18.6. Complementary pharmacological and genetic strategies . . . . . . . . . . . . . . . . . . . . . . . . . . 175
18.7. Neuronal networks and anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
18.8. Anxious states and cognitive function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
18.9. Redundancy in the control of anxious states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
18.10. Clinical validation of hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
19. Concluding comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

1. General introduction
1.1. Aims and scope of review
Pharmacological studies, clinical investigations and, in
recent years, analyses of genetically-modified mice have
implicated a remarkable diversity of mechanisms in the
etiology, modulation and treatment of anxiety (Griebel,
1999a,b; Hood et al., 2000; Belzung and Griebel, 2001;
Blanchard et al., 2001a,b; Lesch, 2001; Moret and Briley,
2001; Wood and Toth, 2001; Clément et al., 2002; Kent
et al., 2002a,b). In this light, the major purpose of the
present article is to review the roles of specific neuro-
transmitters, their receptors and other modulators in the
control of anxious states. As a framework for discussion,
the following aspects are afforded particular emphasis.
First, their localization and actions in corticolimbic struc-
tures involved in the pathogenesis of anxiety disorders,
together with their influence upon intracellular transduc-
tion systems controlling neuronal excitability. Second, their
modulation by exposure to fear-inducing and other stress-
ful stimuli. Third, their interaction with ␥-amino-butyric
acid (GABA)-containing, serotonergic and noradrenergic
pathways, all of which play pivotal roles in the response to
stress and the control of mood. Fourth, where known, the
phenotype of genetically-manipulated mice in which the
functional status of specific neurotransmitters, receptors or
mediators has been disrupted. Finally, their relevance as tar-
gets (established or innovative) for the clinical management
of anxiety disorders.
In fact, studies of genetically-modified mice have (of-
ten serendipitously) revealed potentially interesting al-
terations in anxious behavior upon interference with a
plethora of different genes (see also Section 18.9). These
include protein kinases and intracellular messengers (Chen
et al., 1994; Rondi-Reig et al., 1997; Bowers et al., 2000;
Weeber et al., 2000), modulators of G-protein signaling
(Oliveira-Dos-Santos et al., 2000), serine proteases (Pawlak
et al., 2003) and regulators of development and neuronal
growth (Stork et al., 2000a,b). However, in these (and sev-
eral other) cases, little other compelling evidence is available
to suggest that such mechanisms directly and specifically
control anxious states. Further, in general, only a limited
range of models has been exploited in their behavioral
characterization, and the influence of genetic background
and developmental changes has not been systematically ad-
dressed. Such mechanisms were considered insufficiently
well characterized for inclusion herein, and these studies are
authoritatively discussed elsewhere (Picciotto, 1999; Weiss
et al., 2000; Belzung and Griebel, 2001; Holmes, 2001;
Stephens et al., 2002; Wood and Toth, 2001; Clément et al.,
2002; Rodgers et al., 2002a; Wolfer et al., 2002; Groenink
et al., 2003). The present review does not, thus, comprise
an all-inclusive inventory of every mechanism potentially
involved in the control and management of anxious states.
In the characterization of anxious states and their modu-
lation, behavioral tests for evaluation of potential anxiolytic
and anxiogenic properties are indispensable. Numerous ex-
perimental paradigms involving natural and trained behav-
iors (“unconditioned” and “conditioned” responses) have
been described (summarized in Table 1). Of particular in-
terest are procedures incorporating an element of “conflict”
whereby the subject experiences opposing and concomitant
tendencies of desire (for example, to obtain a reward) and
of fear (avoidance of a potentially aversive stimulus). One
instructive and well-established model is the Vogel Conflict
Test (VCT) in which water-deprived rodents are exposed to a
mild and intermittent electric shock via a water bottle (Vogel
et al., 1971; Treit, 1985; Pollard and Howard, 1989; Millan
and Brocco, 2003). To the best of the author’s knowledge,
no article has previously exploited this procedure as a vehi-
cle for a comprehensive survey of neuronal mechanisms in-
volved in the control of anxious behavior. Thus, the present
article focuses in particular upon the actions of agents in the
VCT. Indeed, in view of the enormous amount of ground
covered, it would be impossible to systematically present
detailed information from all behavioral procedures. Never-
theless, data from complementary models for the detection
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Table 1
Experimental models of anxiety widely used in rodents
I. “Trait”, long-term anxious states
(A) Rodent strains displaying high or low anxiety
(B) Inter-individual differences within a defined strain
(C) Chronic exposure to fear-provoking stimuli
(D) Genetic models: transgenic and knock-out mice
II. “State”, acute anxious states
(A) Unconditioned
(1) Exploration (avoidance, conflict)
(i) Light–dark box (light chambers vs. dark chambers)
(ii) Holeboard (nose pokes)
(iii) Elevated plus-maze (open arms vs. closed arms)
(iv) Open field (central squares vs. peripheral squares)
(v) Neophobia/emergence test (novel object)
(2) Interaction based
(i) Active social interaction (unfamiliar rat pairs)
(ii) Resident intruder
(iii) Ultrasonic vocalization (separation induced)
(3) Acute response to aversive stimuli (environment or brain
stimulation)
(i) Freezing
(ii) Ultrasonic vocalization
(iii) Startle
(iv) Autonomic-cardiovascular parameters (arterial pressure, heart
rate, endocrine secretion)
(4) Defensive behavior to threatening stimuli
(i) Fear/defence battery
(B) Conditioned
(1) Conflict procedures
(i) Geller–Seifter (operant, lever-pressing for reward)
(ii) Vogel Conflict Test
(iii) Conditioned suppression (no punishment during test session)
(iv) Safety-signal withdrawal (no punishment during test session)
(v) Conditioned place aversion
(2) Non-conflict procedures
(i) Fear-induced freezing, startle and ultrasonic vocalizations
(re-exposure to aversive environment)
(ii) Shock-probe (burying of aversive object)
(3) Drug-discrimination
(i) Anxiogenic agents
Note that “conflict” and “non-conflict” might also be employed as a
framework for classifying unconditioned models, e.g. exploration models
(conflict) vs. the acute response to aversive stimuli (non-conflict). Further,
actual exposure to aversive stimuli (usually punishment, as in the Vogel
Conflict Test) as compared to potential exposure (as in unconditioned, ex-
ploratory models) would also offer an appropriate categorization scheme.
Thus, no classification is definitive and all-inclusive (see text). Note also
that certain “state” models incorporate an element of chronicity inasmuch
as they are repeatedly performed in the same population of subjects. For
example, the Geller–Seifter conflict test and drug-discrimination models.
“State” models are, of course, invariably utilized in the characterization
of anxious behavior in “trait” paradigms.
of anxiolytic (or anxiogenic) properties, in particular other
conflict paradigms, are also carefully discussed.
1.2. Organization of review
The review is structured as follows:
Sections 1.3 and 1.4 summarize general features of the
VCT as compared to other procedures employed for the de-
87
tection of anxiolytic properties, while Section 1.5 considers
the adaptive significance of anxious states and outlines neu-
ronal circuits implicated in their integration and expression.
Section 2 focuses on the key inhibitory transmitter, GABA,
which exerts its actions via two major classes of ionotropic
(GABAA ) and metabotropic (GABAB ) receptors. GABAA
sites represent the molecular target of benzodiazepines
(BZP) such as diazepam (Valium® ) which are universally
employed in the clinical management of anxious states. On
the other hand, Section 3 focuses on the excitatory amino
acid, glutamate, which similarly acts via both ionotropic
and metabotropic receptors, yet which fulfils a radically
different role in the control of mood: drugs interacting with
glutamatergic mechanisms await therapeutic exploitation.
Section 4 is devoted to the monoamines. Serotonergic and
noradrenergic mechanisms have long been privileged in the
study and treatment (by antidepressant agents) of anxiety
disorders. However, with the exception of 5-HT1A recep-
tors, targeted by the agonist and anxiolytic agent, buspirone
(Buspar® ), the clinical significance of individual subtypes
of 5-HT receptor—of which 14 have been cloned—remains
nebulous. Likewise, the pathophysiological roles of specific
subtypes of adrenoceptor (AR), of which nine are known,
are poorly characterized. Moreover, though often neglected,
corticolimbic pools of dopamine, which acts via five sub-
types of receptor, are arguably of greater significance to
the induction and modulation of anxious states than gen-
erally appreciated. Sections 5 and 6 consider two further,
“conventional” transmitters, histamine and acetylcholine,
for which studies of multiple receptor subtypes are begin-
ning to provide insights into their complex roles in the
control of anxious states. Sections 7 and 8 deal with adeno-
sine and cannabinoids, respectively, both of which can be
ubiquitously generated in the CNS, and both of which play
major (but enigmatic) roles in the response to stress and
fear. Section 9 discusses an array of neuropeptides vari-
ously implicated in the suppression and/or enhancement
of anxious states. Though the significance of certain has
not, as yet, been evaluated employing the VCT, they all
comprise attractive potential targets for the development of
novel classes of anxiolytic agent. Section 10 focuses on
the pineal hormone, melatonin, while Sections 11 and 12,
respectively, draw attention to the pertinence of genomic
and non-genomic (cerebral) actions of the stress-sensitive
hormones, glucocorticoids and estrogen, in the modula-
tion of anxious states. Section 13 outlines the relevance
of voltage-dependent calcium—and, possibly, sodium and
potassium—channels as targets for the management of anx-
iety disorders. Conversely, actions of the intra- and intercel-
lular messenger, nitric oxide (NO) are evoked in Section 14.
Both rapid and longer-term actions of two further classes of
modulator implicated in the pathogenesis and treatment of
anxiety disorders, neurotrophins and cytokines, are outlined
in Sections 15 and 16, respectively. Section 17 focuses on
the still perplexing roles of sigma1 and sigma2 sites. Fi-
nally, Section 18 concludes with a discussion of several key
88 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
themes likely to orientate future research into mechanisms
involved in the etiology and (improved) management of
anxious states.
The text is accompanied by tables summarizing the ac-
tions of representative drugs in the VCT. In order to en-
hance readability and to obviate encumbering the test with
superfluous detail, most specific information concerning the
actions of individual drugs and endogenous modulators is
consigned to these tables. In addition, several figures are
provided in which the actions of certain key agents in the
VCT are illustrated, and in which their loci of action are
depicted. Though the accompanying citation list is by no
means exhaustive, it is comprehensive. Other reviews cov-
ering specific aspects of material discussed herein are gen-
erously cited, though primary references are, in principle,
prioritized. Emphasis is also afforded to recent publications
incorporating novel findings not as yet considered or ref-
erenced elsewhere. While the review attempts to minimize
unnecessary duplication, individual sections are generally
self-sufficient in material in order to avoid incessant con-
sultation of other parts. Numerous cross-references are also
made to sections in which supplementary information con-
cerning specific issues under discussion can be found.
1.3. Anxiety disorders and experimental models:
general considerations
One major difficulty confronted in the experimental study
of anxious disorders is the absence of concrete parame-
ters reflecting “anxiety” per se. Inasmuch as anxiety, like
other mood states, lies at the “interface” of neurobiology
and psychology, the approach is essentially inferential. By
analogy to depression and pain, and in contrast to hyper-
tension and diabetes, for example, no specific operational
measure of anxiety exists. “Surrogate” markers, such as an
increase in arterial pressure, tachycardia, hyperthermia and
excessive secretion of glucocorticoids into the systemic cir-
culation, can be instructive in the evaluation of anxiety.
However, these autonomic-somatic variables are generally
inappropriate—and impractical—for systematic characteri-
zation of the role of cerebral mechanisms in the modula-
tion of anxious states. Accordingly, behavioral end-points
reflecting the emotive component of anxiety are generally
preferred: avoidance, escape, freezing and so forth—despite
the fact that “a motor withdrawal” response is clearly not a
feature of chronic, maladaptive, debilitating anxious states
in man. In behavioral paradigms employed for the evaluation
of anxiolytic—and other classes of psychotropic—drugs, a
motor response is, then, considered to express a mood state.
In this respect, the VCT is no exception.
Partly for the above reasons, one must remain circum-
spect as concerns the exact “type” or “component” of anxi-
ety which is measured with the VCT and other experimental
models. Indeed, their precise relevance to the broad spec-
trum of anxiety disorders recognized in man is not easy to
decipher (Section 1.4.2). Correspondingly, as emphasized
throughout this review, the genuine, clinical pertinence of
the VCT can only realistically be gauged within the light
of controlled, therapeutic trials of mechanistically-diverse
agents—both active and inactive in this procedure—and it
is salutary to reflect just how little clinical feedback is cur-
rently available in this regard.
Table 1 offers a classification of models for the detection
of anxiolytic properties, axed around the criteria of “con-
ditioned versus unconditioned” behaviors. The criteria of
“punishment versus non-punishment” and of “conflict versus
non-conflict” provide alternative (and similarly valid) frame-
works for categorizing such models. In any case, this table
serves to emphasize that the VCT, while indubitably of im-
portance, is just one of many complementary models avail-
able for the characterization of anxiolytic agents (Section
18.5). Specific procedural features of the VCT (see in par-
ticular, Treit, 1985; Pollard and Howard, 1989; Millan and
Brocco, 2003) as compared to other experimental paradigms
(Bignami, 1998; Thiébot et al., 1991; Treit, 1994; Rodgers,
1997; Rodgers et al., 1997; Clément and Chapoutier, 1998;
Belzung and Griebel, 2001; Blanchard et al., 2001a,b, 2003;
Shekhar et al., 2001; Wall and Messier, 2001; Barros and
Tomaz, 2002; Bourin and Hascoët, 2003; De Boer and
Koolhaas, 2003; File and Seth, 2003; Prut and Belzung,
2003; Sanchez, 2003) employed for characterization of
anxiolytic drugs have been reviewed in detail elsewhere.
For individual models, these articles also provide additional
information concerning the actions of drug interacting with
mechanisms discussed herein.
1.4. Conflict models for the detection of anxiolytic (or
anxiogenic) activity
1.4.1. Basic principles
In conflict situations, the tendency of subjects to seek
out a positive stimulus is countered by an opposite impulse
of avoidance founded upon either spontaneous (unlearned)
or conditioned (learned) fear. For example, in a procedure
in which a natural (exploratory) behavior is monitored, the
plus-maze test (very much in vogue for the phenotyping of
transgenic mice), the urge to investigate an unfamiliar envi-
ronment is opposed by the fear associated with its novelty
(Rodgers and Johnson, 1995; Rodgers et al., 1997; Belzung
and Griebel, 2001). On the other hand, in the Geller and
Seifter (1960) conflict test, rats trained to respond for a
food reward are exposed to a modest electric shock dur-
ing a “conflict” component of the procedure: that is, the
response is both conditioned and punished. This original
conflict procedure remains of unquestionable value in the
evaluation of potential anxiolytic agents. Further, the inclu-
sion of both punished and non-punished sessions facilitates
the detection of specific anxiolytic properties of drugs as
compared to a generalized perturbation of motor function
resulting in an artifactual alteration in (punished) response
rates. However, the Geller–Seifter model requires a lengthy
and daily period of training, and one drug may potentially
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
interfere with the actions of a second drug tested at a later
date.
1.4.2. Validity and clinical pertinence of the VCT
By contrast, the VCT, in which water-deprived rats re-
ceive a mild shock from the spout of a test bottle, has
the advantage of circumventing a prolonged training period
and of avoiding potential drug interactions. Inasmuch as the
VCT does not incorporate a non-punished session, caution
must be exercised in uncoupling the anxiolytic actions of
drugs from their (potential) influence upon motor perfor-
mance: their possible modification of nociceptive thresholds
and water appetite must also be borne in mind (Treit, 1985;
Pollard and Howard, 1989; Millan and Brocco, 2003). As
regards the cognitive nature of the VCT, responding has
been variously considered as conditioned or unconditioned.
This somewhat disconcerting interpretational ambivalence
appears (as recently discussed in Millan and Brocco, 2003)
to reflect the precise experimental design. Though animals
are pre-exposed to the bottle in the absence of punishment
(that is, drinking behavior is learned), responding is punished
only during the (non-signaled) test session. That is, there is
no learned association of punishment with a response.
The VCT has significant “face validity” inasmuch as the
avoidance of an actual or threatened aversive stimulus, de-
spite a potential reward, clearly mimics human behavior—
though, as pointed out above (Section 1.3), avoidance is
not necessarily an inherent feature of pathological, anx-
ious states. As concerns “construct validity”, psychologi-
cal and biological processes underlying anxiety in the VCT
likely resemble those in man, though this is more chal-
lenging to demonstrate. Indeed, more generally, the extent
to which experimental models employed for the detection
of anxiolytic drugs mimic (heterogeneous classes of) clin-
ical anxiety disorder(s) remains a major question in need
of clarification. As intimated above (Section 1.3), the fun-
damental issue of predictive validity remains to be more
fully explored. Though the VCT is, for example, responsive
to BZPs (therapeutically-active) and refractory to cholecys-
tokinin (CCK)2 antagonists (essentially ineffective), insuffi-
cient clinical information is available from other drug classes
to permit an unambiguous statement concerning either false
positives or false negatives in the VCT. In this respect, of
course, the VCT is no different from the Geller–Seifter pro-
cedure, the plus-maze test or any other paradigm currently
employed for the detection of anxiolytic agents: sufficient
clinical evidence is simply not yet available (Section 18.10).
Moreover, for certain classes of drug (or individual agents),
experimental data from the VCT and other procedures re-
main limited, rendering generalized conclusions concern-
ing their pathophysiological roles and therapeutic pertinence
somewhat hazardous.
These uncertainties raise the interrelated question as to
which type of clinical anxiety is most effectively modeled by
the VCT. Likewise, in the absence of feedback from human
patients presenting diverse anxiety disorders, it is difficult to
89
afford a definitive response. Nevertheless, the VCT is of par-
ticular pertinence to generalized anxiety disorders (GAD)
(Barrett and Vanover, 1993; Shekhar et al., 2001) which are
characterized by excessive, persistent and unfounded anxi-
ety and an exaggerated response to acute, anxiogenic situ-
ations. GAD is an under-recognized yet incapacitating and
chronic disorder which often reveals co-morbidity with other
psychiatric and neurological conditions (Culpepper, 2002;
Grachev et al., 2002; Keller, 2002; Kessler and Wittchen,
2002; Sramek et al., 2002; Wittchen et al., 2002). Arguably,
positive actions of drugs in the VCT and other conflict
paradigms founded on conditioned fear are also relevant to
the therapy of social (and other) phobias, which similarly
encompass a component of conditioned fear (Hidalgo et al.,
2001). Their significance to other anxious states, such as
panic attacks and obsessive–compulsive disorders, is less
apparent (Gorman et al., 1989, 2000; Graeff and Deakin,
1991; Barrett and Vanover, 1993; Bourin, 1997; Bourin et al.,
1998; Blanchard et al., 2001a,b; Shekhar et al., 2001).
Though the VCT has been widely employed in rats,
the procedure has only recently been established in mice
(Umezu, 1999; Van Gaalen and Steckler, 2000). This is
an innovation to be welcomed inasmuch as transgenic and
knock-out mice should ideally be phenotyped with a vari-
ety of models reflecting different facets of clinical anxiety,
incorporating contrasting end-points, and reflecting both
conditioned and unconditioned behaviors (Tarantino and
Bucan, 2000; Weiss et al., 2000; Belzung and Griebel, 2001;
Wood and Toth, 2001; Clément et al., 2002; Van Gaalen
et al., 2002).
To summarize, then, the VCT is a particularly important,
rigorous and clinically-relevant model for pharmacological
and genetic studies of the role of endogenous modulators and
potential therapeutic agents in the control of anxious states.
1.5. The integration and expression of anxious states
1.5.1. Adaptive and non-adaptive features of anxiety:
basic pathological mechanisms
Fear and anxiety are crucial and adaptive components of
the overall behavioral and autonomic “stress” response to
dangerous situations which threaten to perturb homeosta-
sis (Rosen and Schulkin, 1998; Haller, 2001; Mineka and
Öhman, 2002). Transient anxiety proportional to the chal-
lenge encountered elicits an appropriate response (often es-
cape or avoidance) and is of fundamental importance as a
survival strategy for all higher animals, including man. Anx-
ious states are, thus, controlled by a highly complex sys-
tem of both inhibitory and facilitatory mechanisms: these
are reciprocally regulated in a highly-dynamic fashion and
display considerable redundancy. Indeed, a major message
of this article (see also Section 18.9) is the existence of
a hierarchy of interactive processes which either counter
or favor anxious states. The purpose of these homeostatic
controls is to: (1) maintain an appropriate degree of emo-
tionality (avoid pervasive anxiety) under non-threatening
90 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
circumstances; (2) efficiently respond to potential threats
with a (transient) “fear” proportional to the danger encoun-
tered; (3) permit adaptive behavioral responses, such as
escape or avoidance; and (4) rapidly restore a “normal” emo-
tional status once the threat has passed. The aberrant oper-
ation of mechanisms controlling mood and the response to
stress—due to genetic, developmental and/or environmen-
tal factors (Heim and Nemeroff, 1999; Holmes, 2001)—
can provoke a perturbation of equilibrium, an abrupt or
gradual shift to a new “stasis” (“set-point”) and, in patholog-
ical cases, a clinically-defined anxiety disorder. Correspond-
ingly, if the anxiety experienced is excessive with respect to
the trigger, persists following its withdrawal, is elicited in the
absence of potential threats, is associated with non-adaptive
behaviors, or is simply omnipresent for no apparent reason,
then an “anxiety disorder” is generally diagnosed and treat-
ment advocated.
Transient anxiety (fear) may, then, be compared to the
acute pain provoked by noxious (tissue-damaging) or po-
tentially noxious stimuli. However, by analogy to extreme
or chronic pain, when disproportional or prolonged (even
irreversible), anxiety is maladaptive and, generally, re-
flects an underlying pathology requiring treatment (Millan,
1999, 2002a). Pursuing the analogy to pain (Millan, 1999),
excessive anxiety may reflect the exaggerated (in terms of
duration or intensity) activation of mechanisms normally
fulfilling a physiological role in the induction of fear. How-
ever, this is not necessarily the case and, by analogy to
differences between chronic versus acute pain, mechanisms
underlying persistent, pathological anxious states may be
qualitatively as well as quantitatively distinct to those
involved in transitory (adaptive) anxious states. Several
conceptual examples of pathological mechanisms underly-
ing anxious states may be provided. First, anxiety may be
evoked by the failure of an endogenous anxiolytic mecha-
nism which either: (1) operates “constitutively” (tonically, in
the resting state); and/or (2) is recruited following cessation
of a fear-eliciting stimulus in order to restore equilibrium.
In the former instance, an enduring anxious state may arise
spontaneously and, in the latter, anxiety may be anoma-
lously protracted and severe relative to the transient threat
encountered. Second, a transmitter which normally exerts
no—or only a subliminal, positive—influence upon anxious
behavior may become a powerful inducer of anxious states
(“break-through”). This may occur, for example, following
the initiation of adaptive changes in the amygdala, hip-
pocampus or other corticolimbic structures upon chronic
exposure to fear-inducing situations or other stressors. This
comprises yet another analogy to “plastic” events underly-
ing pathological pain which permit normally sub-threshold
(innocuous) inputs to become intensely aversive (Millan,
1999). The influence of environmental events (stressors)
upon mechanisms inducing anxious states is discussed
throughout this article, while the significance of develop-
mental and genetic factors—which lie outside its scope—
has been considered elsewhere (Heim and Nemeroff, 1999;
Scherrer et al., 2000; Gratacos et al., 2001; Hettema et al.,
2001; Holmes, 2001; Stein et al., 2001a,b; Clément et al.,
2002; Freimer et al., 2002; Glatt and Freimer, 2002).
1.5.2. “Trait” and “state” anxiety
Certain authors distinguish personality-based (tempera-
ment), sustained, “trait” anxiety to ephemeral, fear-induced
“state” anxiety (see Table 1). Trait and state anxiety may,
in principle, be engendered by mechanisms outlined in
the preceding paragraph (Section 1.5.1) (Stewart et al.,
1993; Abadie et al., 1999; Kalin et al., 2001; Radu et al.,
2003). The VCT—like most other widely-used paradigms—
conforms to “state” anxiety (Herman et al., 1986; Rägo
et al., 1988; Molewijk et al., 1995a,b; Telch et al., 1996;
Liebsch et al., 1998; Davis and Shi, 1999; Belzung and
Griebel, 2001; Keogh and Cochrane, 2002; Ohl et al.,
2002). Experimentally, “trait” anxiety may be modeled
(Table 1) by: (1) genetically-modified lines of mice (see
Section 1.1 for references to reviews); (2) chronic stress ex-
posure (citations throughout this article); (3) highly-anxious
strains of mice and rats (Stewart et al., 1993; Tejani-Butt
et al., 1994; Kiaanman et al., 1995; Steimer et al., 1997;
Berton et al., 1998; Desousa et al., 1998; Dockstader and
Van Der Kooy, 2001; Sudakov et al., 2001; Bouwknecht
and Paylor, 2002; Pardon et al., 2002; Rodgers et al.,
2002a,b; Avgustinovich et al., 2003); and (4) inherent dif-
ferences in anxious behavior between individual animals
of a common strain (Colombo et al., 1985; Cools et al.,
1993; Rodgers, 1997; Ho et al., 2002; Wunderlich et al.,
2002).
In fact, considerable efforts have been valuably invested
(op. cit.) in the characterization of strains displaying differ-
ential responsiveness to stress and contrasting patterns of
anxious behavior. Nevertheless, it is somewhat disappoint-
ing that individual intra-strain differences have received so
little attention inasmuch as neither animal nor human popu-
lations are homogeneous in terms of “basal” levels of anxi-
ety and the response to anxiolytic agents. Indeed, individual
“disparities” between animals are of obvious heuristic per-
tinence to the striking differences seen amongst (“healthy”)
humans as concerns the response to stress and anxious be-
havior. Even bearing in mind the more complex cognitive
and emotional dimension of anxious states in man, appro-
priate analyses of inter-subject variability in experimental
studies should generate insights into those factors which
predispose to, or otherwise modify, anxious behavior in
man. Regrettably, then, for the majority of investigators,
heterogeneity within experimental groups is considered
as—at best—noise and, more seriously, as a profound
nuisance which can frustrate the inviolate objective of
statistically-significant inter-group comparisons. Few re-
ports in which variability is underlined have, therefore,
penetrated the literature and such enterprising studies, re-
quiring unusual analytical strategies, are to be encouraged.
Furthermore, of particular interest are studies of the in-
fluence of drugs upon performance in the VCT and other
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 91

models of “state” anxiety undertaken in “high-anxious” as
compared to “low-anxious” individuals or strains.
1.5.3. Cerebral circuits for the modulation of anxious
states
1.5.3.1. Corticolimbic integration of anxious states. It is
not unreasonabe to contend that the entire organism is in-
volved in the response to (and modulation of) stress and fear
inasmuch as anxious states impact upon, and are modified
by, virtually all major systems: motor, sensory, endocrine,
immune, cardiovascular and, of course, neural. Further, it
is important to acknowledge the therapeutic significance
of interventions which palliate non-emotional symptoms
known to provoke, aggravate or otherwise (reciprocally)
interact with anxious states, such as chronic pain, cardio-
vascular disease and any variety of somatic complaints
(Millan, 1999; Di Piero et al., 2001; Keogh and Cochrane,
2002; Rainville, 2002). Nevertheless, in the experimental
characterization of anxiety, its induction and alleviation,
we are generally concerned with cerebral circuits com-
mitted to the integration of its emotional (and cognitive)
components.
In this respect, numerous interconnected limbic and corti-
cal structures have been implicated in the emotional and/or
mnesic mechanisms which underlie and modulate anxious
states. A comprehensive discussion of their roles is beyond
the scope of the present paper (Fig. 1) (for reviews, see Gray,
1987; Gorman et al., 1989; Reiman et al., 1989; Deakin
and Graeff, 1991; Fanselow, 1991; Davis, 1992a,b;
Aggleton, 1993; Charney and Deutch, 1996; Risold and
Swanson, 1997; Davidson et al., 1999; Pikkarainen et al.,
1999; Groenewegen and Uylings, 2000; Lovick, 2000;
Grachev et al., 2002; Phan et al., 2002; File and Seth, 2003).
For a historical perspective on this issue, which can only
be briefly chronicled in the following paragraph, articles by
Pratt (1992) and LeDoux (2000), are recommended.
Broca (1878) originally coined the term “limbic” for
a series of phylogenetically-conserved structures, but
the first conscious and enduring attempt to provide a
neuroanatomically-circumscribed, physiological founda-
tion for the expression of emotion and fear was made by

Fig. 1. Schematic representation of the organization of structures involved in the integration and induction of anxious states: in particular conditioned
fear, an important characteristic of the Vogel Conflict Test. For simplicity, not all anatomical pathways are indicated: for example, those between various
regions of the cortex are not fully illustrated, and several other pathways of ascending nociceptive information are not shown. Note the central importance
of the amygdala which can be subdivided into essentially two sub-territories. First, the basolateral complex, the major region for direct (thalamus and
parabrachial nucleus (PBN)) and indirect (cortex) receipt of sensory and other modes of input. The basolateral complex displays reciprocal projections
with many structures from which it receives afferents. Second, the central nucleus, the principle region for projections to hindbrain regions coordinating
the behavioral, autonomic and endocrine response to fear, a role to which—according to the concept of an “extended amygdala”—the adjacent bed
nucleus of the stria terminals (not shown) also contributes. Other abbreviations are as follows (more or less clockwise). PF/F: prefrontal/frontal; ENT:
entorhinal; CX: cortex; MB (SMB): mammillary bodies (supramammillary bodies); CING: cingulate; ASSN: association; THAL: thalamus; INS: insular;
SS: somatosensory; STT: spinothalamic tract; DMV/NAMB—dorsal motor nucleus of the vagus/nucleus ambiguous; HR: heart rate; AP: arterial pressure;
LAT HYPOTH: lateral hypothalamus; PVN: paraventricular nucleus; ACTH: adrenocorticotropic hormone; NRPC: nucleus reticularis penduncocellularis;
PAG: periaqueductal gray; FMN: facial motor nucleus; VTA: ventrotegmental area; LC: locus coeruleus; DLTN: dorsolateral segmental nucleus; DA:
dopamine; NA: noradrenaline; ACh: acetylcholine and NACC: nucleus accumbens. This figure is to a large extent inspired by the work of Davis et al.
(1994) and LeDoux (2000). For further details, see text.
92 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Papez, 1937. His “Circle of Papez”’ embraces a projec-
tion (the fornix) from the hippocampus to the mammillary
bodies which are linked in turn to the anterior nucleus
of the thalamus: the anterior thalamus is connected to
the cingulate cortex which closes the circuit in transmit-
ting information back to the hippocampus. This nascent
limbic system matured in the work of MacLean (1949,
1952), who rectified the original omission of the amygdala
and elaborated a network encompassing the frontal cortex
(FCX) and other subcortical nuclei, such as the septum
and nucleus accumbens (Barili et al., 1998; Pralong et al.,
2002). The septum was subsequently incorporated into a
septo-hippocampal “behavioral inhibition system” subject
to modulation by cortical input (Gray, 1987; Gray and
McNaughton, 2000). Amongst several hypothalamic nu-
clei, the paraventricular nucleus deserves special mention
in view of its critical role in integrating the adrenocortical
response to stress (Yadin et al., 1993; Herman et al., 2002;
Carrasco and Van de Kar, 2003). In addition to the mam-
millary bodies themselves, the overlying supramammillary
nucleus, which is interlocked with the septo-hippocampal
system and amygdala, is likewise implicated in the control
of emotion—including fear-conditioning—and cognition
(Vertes, 1992; Kirk, 1998; Wirtshafter et al., 1998; Pan and
McNaughton, 2002). Moreover, together with the periaque-
ductal gray (PAG), amygdala and medial hypothalamus, an
important role has been ascribed to the inferior colliculus
in the assimilation of aversive input and the coordination of
anxious and defensive behaviors: the latter structure trig-
gers (conditioned and unconditioned) responses to auditory
stimuli via its projections to the amygdala (Graeff, 1990;
Brandao et al., 1994; Maisonnette et al., 2000; Macedo
et al., 2002; Brandao et al., 2003). Finally, virtually all
cortical regions (insular, orbital, entorhinal, temporal, as-
sociation, frontal, pre-frontal, cingulate and parietal) have
been shown to play significant, yet contrasting, roles in
the response to—and control of—fear and stress (Hurley
et al., 1991; Pratt, 1992; Bechara et al., 2000; Groenewegen
and Uylings, 2000; Grachev et al., 2002; Pralong et al.,
2002).
1.5.3.2. Key roles of the amygdala, the hippocampus and
the PAG. Over recent years, a burgeoning literature has fo-
cussed on the amygdala as an epicenter of events modulating
the response to fear in animals and in man, and as a major
site of action for anxiolytic agents (Fig. 1) (Pitkänen et al.,
1997; Swanson and Petrovich, 1998; Davis and Shi, 1999;
Van De Kar and Blair, 1999; LeDoux, 2000; Mineka and
Öhman, 2002; Weidenfeld et al., 2002). Indeed, the amyg-
dala possesses an extensive pattern of reciprocal connec-
tions with cortical, limbic, monoaminergic and other struc-
tures implicated in the emotional, cognitive, autonomic and
endocrine response to stress (Gray and Magnuson, 1992;
Swanson and Petrovich, 1998; LeDoux, 2000; Richter-Levin
and Akirav, 2000; Kjelstrup et al., 2002; McGaugh et al.,
2002; Carrasco and Van de Kar, 2003). Output pathways are
primarily derived from the central nucleus and the contigu-
ous bed nucleus of the stria terminals, whereas the basolat-
eral amygdaloid complex is principally responsible for the
receipt and filtering of cortical and subcortical (mostly tha-
lamic) sensory input (Fig. 1) (Gray and Magnuson, 1992;
Pitkänen et al., 1997; Davis and Shi, 1999; Richter-Levin
and Akirav, 2000; Kozicz, 2002; Saldivar-Gonzalez et al.,
2003; Walker et al., 2003).
Synaptic plasticity in the amygdala has been convinc-
ingly implicated in the induction, processing and extinction
of conditioned fear, in the generation of anticipatory anxiety
and in the coordination of the global response to threats.
Such phenomena are highly relevant to behavior in the VCT
and several other experimental models in rodents (Table 1),
as well as to GAD (and phobias) in man (Deakin and
Graeff, 1991; Davis, 1992a,b; Graeff et al., 1993, 2001;
Davis et al., 1994; Fanselow, 1994; Davis and Shi, 1999;
LeDoux, 2000; Blair et al., 2001; Kim et al., 2001;
Boshuisen et al., 2002; McGaugh et al., 2002). Both
the acquisition and extinction of conditioned fear repre-
sent forms of “learning” implying alterations in synaptic
strength. Moreover, extinction (the progressive dissipation
of the conditioned response upon repetitive exposure to the
initially-neutral, non-aversive conditioned stimulus), does
not merely reflect spontaneous recovery or passive decay
of events underlying conditioned fear, but rather active
inhibition by superimposition of novel adaptive processes
integrated at different synapses (LeDoux, 2000; Blair et al.,
2001; Myers and Davis, 2002; Vianna et al., 2003). In the
development of innovative anxiolytic agents it may, thus,
be possible to specifically target and strengthen processes
underlying the extinction of conditioned fear expressed in
the amygdala and other corticolimbic structures.
Lesion and stimulation studies have convincingly im-
plicated the amygdala in the control of behavior in the
VCT and other conflict models (Hodges et al., 1987; Yadin
et al., 1991; Kopchia et al., 1992; Möller et al., 1994, 1997;
Shibata et al., 1989; Yamashita et al., 1999)—though these
approaches have also unveiled roles for other structures,
such as the mammillary bodies, the septum, the frontal
cortex and raphe nuclei (Vogel et al., 1971; Thiébot et al.,
1983; Yamashita et al., 1989a,b; Pratt, 1992; Yadin et al.,
1993; Wieronska et al., 2001).
Curiously, comparable findings with the VCT do not ap-
pear to have been acquired for the hippocampus which bidi-
rectionally communicates with the amygdala and numerous
other corticolimbic structures. It has been proposed that the
hippocampus is specifically required for representation of
the context within which conditioning occurs: that is, the en-
vironment in which the conditioned and the unconditioned
stimulus are paired, but this concept remains somewhat
controversial (Kim and Fanselow, 1992; Fanselow, 2000;
Cahill and McGaugh, 1998; Gewirtz et al., 2000; LeDoux,
2000; Richter-Levin and Akirav, 2000; Burgess et al., 2002;
Grillon, 2002; Kjelstrup et al., 2002; Mineka and Öhman,
2002; Pralong et al., 2002).
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
A major component of cerebral circuits involved in co-
ordinating the defensive and aversive response to fear and
stress, the PAG, also justifies brief comment. In distinc-
tion to the amygdala (with which it is interlinked), several
authors have implicated the PAG in elaboration of the
stereotyped, reflexive, autonomic and behavioral fight/flight
response to unconditioned fear, a function related to clin-
ical panic attacks. Correspondingly, stimulation of the
PAG is aversive both in animals and in human subjects
(Deakin, 1988, 1991; Deakin and Graeff, 1991; Pratt, 1992;
Graeff et al., 1993, 2001; Lovick, 2000; Bandler et al., 2000;
Blanchard et al., 2001a,b). As discussed in Section 4.3.1,
these differential roles of the amygdala and the PAG have
been evoked in an attempt to reconcile a superficially
contradictory body of data indicating that 5-HT exerts a
complex and receptor-dependent inhibitory and facilitatory
influence upon specific anxious states.
Thus, numerous interlinked and interacting corticolimbic
centers orchestrate the overall response to fear and stress. As
indicated above for the amygdala, these regions are hetero-
geneous in that they incorporate functionally-distinct nuclei
(Graeff, 1990; Pratt, 1992; Pitkanen et al., 1997; Fanselow,
2000; Gray and McNaughton, 2000; LeDoux, 2000; Lovick,
2000; Levita et al., 2002). However, for the sake of sim-
plicity, and since studies aimed at the localization of drug
actions have often not differentiated specific sub-territories,
the present article usually adopts the “generic” term.
Finally, in light of the crucial role of corticolimbic no-
radrenergic, serotonergic and dopaminergic pathways in the
expression of anxious states, the significance of their cell
clusters of origin, the locus coeruleus (LC), the raphe nuclei
(of which the dorsal raphe nucleus (DRN) is embedded in
the ventral PAG), and the ventrotegmental area (VTA), re-
spectively, should also be emphasized (Sections 4.1.1, 4.3.1
and 4.2.1, respectively).
1.5.3.3. Diffuse neuronal circuits and anxious states. The
preceding paragraphs briefly evoked the key roles of several
corticolimbic structures in mechanisms integrating the re-
sponse to external (and internal) fear-inducing stimuli, and
in the induction and modulation of anxious states. Amongst
these, the amygdala has emerged as a nexus of primordial
importance in much the same way as the dorsal horn of the
spinal cord and the mediobasal hypothalamus fulfil pivotal
roles in the assimilation and processing of information con-
trolling nociception and endocrine secretion, respectively
(Millan, 1999, 2002a; Hermann et al., 2002; Carrasco and
Van de Kar, 2003).
Nonetheless, in referring to the amygdala (Section
1.5.3.2) and other—ostensibly—discrete structures men-
tioned above, it should not be forgotten that they exten-
sively and reciprocally interact via numerous classes of
neuronal pathway and transmitter. Thus, as encapsulated
by the historical concept that a “Circle of Papez” underlies
the expression of emotion (Section 1.5.3.1), the notion that
the generation, inhibition or experience of anxiety can be
93
attributed to any single locus is highly misleading, if not
frankly erroneous. In analogy to other higher functions,
such as pain and memory (see Damasio, 1989; Crick and
Koch, 1998; Millan, 1999, 2002a; Bechara et al., 2000;
Manns et al., 2003), extended and diffuse networks rather
than any well-defined entity, embody the experience of
anxiety and other emotions (Section 18.7).
Adding a further level of complexity, many neurotrans-
mitters and receptors fulfil multiple roles in the modulation
of anxious states, acting in contrasting or similar fashions as
a function of the precise cerebral circuits with which they
interact, and the precise timing and conditions of their en-
gagement (see ensuing sections).
The above points have important ramifications both for
studies of mechanisms underlying the induction and con-
trol of anxious states, and for the assignment of functions
to specific brain structures, neurotransmitters and receptors.
Indeed, it would be naı̈ve to impose a unitary function to any
of the structures, neurotransmitters or receptors discussed
in this review. This assertion has (as further discussed in
Section 18) evident implications for therapeutic strategies
designed to improve the management of anxiety disorders.
2. GABA
2.1. GABAergic pathways
GABAergic neurones constitute the major mode of in-
hibitory transmission throughout the CNS. Corticolimbic
structures involved in the modulation of anxious states,
such as the hippocampus, lateral septum, PAG and amyg-
dala, contain major networks of GABAergic interneurones
as well as, in certain cases, GABAergic projection neu-
rones (Scheel-Krüger and Petersen, 1982; Sanger, 1985;
Shephard, 1986, 1987; Cherubini and Conti, 2001; Mody,
2001).
GABAergic pathways exert an inhibitory influence upon
the release of many neurotransmitters known to mediate
anxiogenic actions (see below). Their suppressive influence
(expressed at both the cell body and terminal level) upon
corticolimbic noradrenergic and serotonergic projections,
of which a hyperactivity is implicated in the induction of
anxious states, should be accentuated in the present context
(Sections 4.1.1 and 4.3.1, respectively). Accordingly, condi-
tioned fear is accompanied by an activation of GABAergic
interneurones in both noradrenergic (LC) and serotonergic
(raphe nuclei) cell clusters, consistent with the notion that
their activity is subject to a GABAergic “brake” under condi-
tions of stress (Wang et al., 1992; Gobert et al., 2000; Millan
et al., 2000d; Somogyi and Llewellyn-Smith, 2001; Ishida
et al., 2002). Nevertheless, the degree to which a reduction
of noradrenergic and serotonergic transmission participates
in the anxiolytic properties of GABAergic agents—and the
extent to which an acceleration of NA and 5-HT release
mediates the anxiety precipitated by BZP withdrawal—is
94 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
still disputed (Scheel-Krüger and Petersen, 1982; Sanger,
1985; Shephard, 1986, 1987; Pan and Williams, 1989;
File et al., 1992; Plaznik et al., 1994a; Tao et al., 1996;
Dekeyne et al., 2000b; Millan et al., 2001a; Mohler et al.,
2002; Shekhar et al., 2002). Indeed, actions of GABAergic
neurones in the hippocampus and other limbic regions
postsynaptic to noradrenergic and serotonergic neurones
are likewise implicated in the expression of their anxiolytic
properties (Oleskewich and Lacaille, 1992; Söderpalm et al.,
1997; Nazar et al., 1999b). Further, GABAergic neurones
are inhibitory to the stress-induced release of dopamine
(DA), glutamate, CCK, corticotrophin-releasing factor
(CRF) and several other anxiogenic mediators discussed
in the present article (Owens et al., 1989, 1991; Karreman
and Moghaddam, 1996; Keim and Shekhar, 1996; Beaufour
et al., 2001a; Miklös and Kovacs, 2002). The global con-
trol of anxious states by GABAergic mechanisms entails
thus: (1) modulation of monoaminergic transmission; (2)
interactions with monoaminergic receptors postsynaptic to
monoaminergic projections; and (3) actions independent of
monoaminergic pathways (Sections 2.2.2.2 and 2.2.2.3).
There is curiously little functional evidence for a pertur-
bation in GABAergic transmission in patients with anxiety
disorders (Section 2.2.1) (Goddard et al., 2001, 2002). Nev-
ertheless, in line with neurochemical studies indicating that
interruption of GABAergic transmission can trigger anxiety
(Martijena et al., 2002; Stork et al., 2002a), mice deficient
in glutamate decarboxylase, the principle synthetic route to
GABA in the CNS (Millan, 2002b), show enhanced anxiety
(Kash et al., 1999; Stork et al., 2000a, 2003). On the con-
trary, anxiolytic actions of drugs which interfere with neu-
ronal GABA uptake have been demonstrated in the VCT and
other conflict models (Table 2) (Ågmo et al., 1991; Gadea
and Lopez-Colomé, 2001; Schmitt et al., 2002). Further,
though anxiolytic properties of inhibitors of GABA transam-
inase (a rate-limiting enzyme of GABA transformation—
ultimately—into glutamate (Millan, 2002b)) such as vi-
gabatrin have received scant attention, they have likewise
been documented in the VCT and several other procedures
(Liljequist and Engel, 1984a,b; Ågmo et al., 1991; Sherif
and Ahmad, 1995; Sherif and Oreland, 1995; Shors and
Oreland, 1995; Dalvi and Rodgers, 1996). Recently, in
small-scale clinical trials, vigabatrin was found to display
efficacy in the treatment of panic disorders (Zwanzger et al.,
2001a,b).
The inhibitory influence of GABA upon neuronal activ-
ity is expressed via chloride-permeable, ionotropic GABAA
receptors and via metabotropic GABAB receptors, both of
which, as outlined below (Sections 2.2 and 2.3, respectively),
are implicated in the control of anxious states (Barnard et al.,
1998; Bowery and Enna, 2000). Despite their occurrence in
the hippocampus and other limbic structures, heteromeric,
chloride-permeable “GABAC ” receptors are not discussed
further herein as information specifically pertaining to a role
in the modulation of anxious states has not been forwarded
(Zhang et al., 2001a; Möhler et al., 2002).
2.2. GABAA receptors
2.2.1. Structure, localization and modulation
Pentameric GABAA receptors are enriched throughout
corticolimbic structures and are well represented in raphe
nuclei, the LC and the VTA, the nuclei of origin of ascending
serotonergic, noradrenergic and mesocortical/mesolimbic
dopaminergic pathways, respectively. Accordingly, GABAA
receptors contribute to the inhibitory influence of GABA
upon serotonergic, noradrenergic and dopaminergic neu-
rones, actions exerted both at the level of their perikarya
and upon their terminals in the cortex, hippocampus, amyg-
dala and other limbic regions (Davis et al., 1994; Fritschy
and Möhler, 1995; Tao et al., 1996; Liu and Glowa, 1999;
Gobert et al., 2000; Millan et al., 2000d, 2001a; Pirker et al.,
2000; Celada et al., 2001; Shekhar et al., 2002). Of partic-
ular note in the present context is the suppressive influence
of GABAA receptors upon hypothalamic and corticolimbic
secretion of CRF (Section 9.1.2) (Cullinan, 2000; Skelton
et al., 2000).
Consistent with a role in the control of anxious states,
levels of GABAA receptors and their subunits are modified
by exposure to stress (Biggio et al., 1984; Giovannini et al.,
2001). Alterations in the binding properties and density
of GABAA receptors—principally, as monitored by stud-
ies with radioligands of BZP sites (Section 2.2.2)—have,
further, been specifically associated with: (1) experimental
models of anxiety; (2) rat strains displaying differential
sensitivity to stress; and (3) anxiety disorders in man (Rägo
et al., 1988; Harro et al., 1990; Kang et al., 1991; Kaschka
et al., 1995; Tiihonen et al., 1997b; Abadie et al., 1999;
Malizia, 2002). Long-term administration of BZPs them-
selves leads to changes in corticolimbic populations of
GABAA receptors which are related to the progressive de-
velopment of tolerance and dependence to their actions.
Similarly, abrupt discontinuation of treatment with BZPs or
other GABAergic modulators provokes marked alterations
in the relative densities of GABAA receptor subunits (Zhao
et al., 1994; Impagnatiello et al., 1996; Fahey et al., 1999;
Liu and Glowa, 1999; Nutt and Malizia, 2001; Tanay et al.,
2001; Malizia, 2002; Mascia et al., 2002).
GABAA receptors are assembled from several fami-
lies of subunit, of which at least 16 occur in the CNS
(Sieghart, 1995; Barnard et al., 1998; Rudolph et al., 1999;
Whiting et al., 1999; Kittler et al., 2002; Möhler et al.,
2002). Though their stoichiometry remains under discus-
sion, the majority of central sites appear to be “ternary”
associations of two ␣-subunits, two ␤-subunits and a single
(intervening) ␥-subunit, surrounding a central ion channel.
As concerns ␥2 sites, the ␥2S isoform predominates over
its—less BZP-responsive—␥2L homologue in the limbic
system and cortex. Individual ␣-subunits, which confer
specific functional properties to GABAA receptors, are dif-
ferentially distributed in the CNS. Notably ␣1 -, ␣2 - and
␣3 -subtypes are concentrated in the cortex, hippocampus
and various limbic structures, ␣4 - and ␣5 -subunits are
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 95

Table 2
Influence of drugs modulating GABA availability, and of GABAA receptor ligands, upon behavior in the Vogel Conflict Test
Drug Class Species Route Effect Active dose Maximum Reference
(strain) (structure) range change (%)
␥-Acetylene- GABA transaminase Rat (W) i.p. + 50 mg/kg +115 Ågmo et al. (1991)
GABA inhibitor
Valproate GABA transaminase Rat (W) i.p. IA 200–400 mg/kg IA Ågmo et al. (1991)
inhibitor Rat (SD) i.p. + 400 mg/kg +340 Liljequist and Engel
(1984a,b)
SKF 100330 GABA reuptake Rat (W) i.p. + 12 mg/kg +86 Ågmo et al. (1991)
inhibitor
Muscimol GABAA agonist Rat (SD) i.c. (lateral + 5 ng +170 Drugan et al. (1986)
septum)
Rat (LH) i.c. (DRN) + 5 and 10 ng +212 Higgins et al. (1988)
Rat (SD) i.c.v. + 150–300 ng +620 Canzani et al. (1980)
THIP GABAA agonist Rat (SD) i.c.v. + 2000 ng +340 Canzani et al. (1980)

Picrotoxin GABAA Ant Rat (W) i.p. − 2 mg/kg −95 Ågmo et al. (1991)
Isoniazide GABAA Ant Rat (W) i.p. − 200 mg/kg −87 Ågmo et al. (1991)
Drug actions are expressed as a percentage of control values (defined as 0%). Thus, +100%, for example, represents a two-fold increase in
punished responses; (+) significant increase in responses; (−) significant decrease in responses and IA, no significant change (inactive). THIP:
4,5,6,7-tetrahydroisoxyzolo [5,4-c]-pyridin-3-ol; W: Wistar; SD: Sprague–Dawley; LH: Lister Hooded; DRN: dorsal raphe nucleus; Ant: antagonist.

largely restricted to the hippocampus, and the ␣6 -subunit is
confined to the cerebellum (Wisden et al., 1992; Marksitzer
et al., 1993; Gutierrez et al., 1994; Fritschy and Möhler,
1995; Nusser et al., 1996; Bernard et al., 1998; Fritschy
et al., 1998; Pirker et al., 2000; Nyiri et al., 2001; Korpi
et al., 2002; Möhler et al., 2001, 2002).
Activation of GABAA receptors by GABA (which acts
at the ␣/␤-subunit interface) results in neuronal hyperpo-
larization via the opening of chloride-permeable ion chan-
nels. This action is modulated by a remarkable diversity
of allosteric sites differentially located on various subunits
(MacDonald and Olsen, 1994; Hevers and Lüddens, 1998;
Meadows et al., 1998; Rudolph et al., 1999; Whiting et al.,
1999; Kittler et al., 2002; Korpi et al., 2002; Stell and Mody,
2002). Of these, sites recognized by BZPs and related agents
(Rudolph et al., 1999; Sigel et al., 2001; Möhler et al.,
2002), by neurosteroids (Hevers and Lüddens, 1998;
Falkenstein et al., 2000), by barbiturates (Birnir et al.,
1997), by a further injectable anesthetic, propofol (Davis
et al., 1997; Krasowski et al., 1998), and by ethanol (Kittler
et al., 2002; Korpi et al., 2002; Miczek et al., 2002) are
of particular pertinence herein since they have been shown
to: (1) transduce the actions of drugs eliciting anxiolytic
actions in the VCT and other experimental models; and (2)
ameliorate anxious states in man.
Surprisingly, comparatively few data are available con-
cerning the anxiolytic and anxiogenic actions of GABAA
receptor agonists and antagonists, respectively, in the VCT
(Table 2). Nevertheless, anxiolytic properties of the proto-
typical agonist, muscimol, upon introduction either into the
lateral septum or into the DRN support a role of GABAA
sites both presynaptic (Tao et al., 1996; Celada et al., 2001;
Wirtshafter and Sheppard, 2001; Adell et al., 2002) and
postsynaptic to serotonergic pathways (Drugan et al., 1986;
Higgins et al., 1988; Dalvi and Rodgers, 1996) in the control
of anxious states. Further, upon intraventricular injection,
muscimol was also found to elicit anxiolytic actions in the
VCT, actions reproduced by its analogue, THIP (Cananzi
et al., 1980). In distinction to agonists, selective antagonists
at GABAA receptors manifest anxiogenic properties in the
VCT and related models (Getova et al., 1990; Ågmo et al.,
1991; Thiébot et al., 1991).
2.2.2. Benzodiazepines and related ligands
2.2.2.1. Influence upon anxious states: diverse classes of
ligand. In distinction to GABA, for which the recognition
site is located at the junction between ␣- and ␤-subunits,
BZPs act at the interface between ␣ and ␥2 -subunits of
GABA receptors. While inactive alone, they potentiate the
potency, duration and, at certain synapses, amplitude of the
actions of GABA (MacDonald and Olsen, 1994; Günther
et al., 1995; Sieghart, 1995; Hajos et al., 2000b; Walters
et al., 2000; Stell and Mody, 2002).
General features of the anxiolytic profiles of BZPs (Fig. 2)
do not necessitate detailed consideration herein inasmuch as
they are well-established both clinically and experimentally
(Sanger, 1985; Shephard, 1986, 1987; Pratt, 1992; Kasper
and Resinger, 2001; Blanchard et al., 2003; File and Seth,
2003; Prut and Belzung, 2003). Indeed, as for most other
models deemed predictive of therapeutic activity, the demon-
stration of responsiveness to BZPs was an ineluctable step
in the initial characterization of the VCT (Vogel et al., 1971;
Pollard and Howard, 1989). Thus, rather than a detailed
discussion, the reader is referred to Table 3 which com-
piles positive findings with a cohort of familiar (and several
96 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
750
LICKS/3 MIN
500
250
0
VEH
NO SHOCK
750
LICKS/3 MIN
500
250
0
VEH
NO SHOCK
Fig. 2. Actions of the benzodiazepine, clorazepate, and of the triazalo-benzodiazepine, triazolam, in the Vogel Conflict Test. Data are means ± S.E.M.s.
Star indicates significance of differences to corresponding vehicle values. ( ) P < 0.05. Data for clorazepate are from Millan et al. (1997) and for
triazolam from Brocco and Millan (unpublished observations).
lesser-known) agents. For example, the conventional (and
␣-subunit, non-selective) BZPs, diazepam, chlordiazepoxide
and clorazepate (Barrett and Gleeson, 1991; Griebel et al.,
1999a; Dekeyne et al., 2000b; Flores and Pellón, 2000);
the chemically-distinct and likewise, non-␣ subunit selec-
tive triazolo-BZPs, alprazolam and triazolam (Söderpalm
et al., 1989; Giusti et al., 1993; Millan et al., 1997, 2001a;
Nazar et al., 1997; Rowlett et al., 2001; Sanna et al., 2002;
Brocco, unpublished observations); the cyclopyrrolone, zo-
plicone (Ueki et al., 1987; Benavides et al., 1990; Carlson
et al., 2001), the preferential (full) ␣1 -subunit agonists and
hypnotics, zolpidem (an imidazopyridine) and zaleplon (a
pyrazolopyrimidine) (Depoortere et al., 1986; Hadingham
et al., 1993; Kleven and Koek, 1999; Sanger, 1995; Sanger
et al., 1996; Rush, 1998; Damgen and Lüddens, 1999;
Paconis et al., 2001; McLeod et al., 2002); abecarnil, a
preferential (full) agonist at ␣1 and ␣3 as compared to
␣2 -subunits (Stephens et al., 1990; Griebel et al., 1999a,c)
VEH 10.0 15.0 20.0 MG/KG, I.P.
CLORAZEPATE
SHOCK
VEH 0.16 0.63 1.25 2.5 MG/KG, I.P.
TRIAZOLAM
SHOCK
and the non-subtype-selective partial agonists, imidazenil,
bretazenil and pagoclone (Giusti et al., 1993; Griebel et al.,
1999a,c; Sorbera et al., 2001; Dubinsky et al., 2002).
In a fashion opposite to these positive modulators, neg-
ative modulators (or inverse agonists) at the BZP site on
GABAA receptors compromise operation of the associated
ion channel and, correspondingly, express anxiogenic prop-
erties (Dorow et al., 1983; Thiébot et al., 1988, 1991; Gentil
et al., 1989; Cole et al., 1995a,b; Sanger and Cohen, 1995;
Paronis et al., 2001; Sarter et al., 2001; Bourin and Hascoët,
2003; Prut and Belzung, 2003). Neutral antagonists (devoid
of intrinsic activity), such as flumazenil, interfere with the
actions of both positive and negative modulators but are
bereft of anxiolytic or anxiogenic activity in experimental
models (Corda et al., 1983; Liljequist and Engel, 1984a,b;
Mizoule et al., 1985; Paconis et al., 2001; Wieronska et al.,
2001; Dubinsky et al., 2002; Bourin and Hascoët, 2003; Prut
and Belzung, 2003). On the other hand, robust panicogenic
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 97

Table 3
Influence of benzodiazepines and related ligands upon behavior in the Vogel Conflict Test
Drug Class Species Route (structure) Effect Active dose Maximum Reference
(strain) range change (%)
Diazepam BZP agonist Rat (W) i.p. + 10 mg/kg +186 Dekeyne et al. (2000a,b)
Rat (SD) i.p. + 0.25–4.0 mg/kg +200 Söderpalm and Engel (1989)
Rat (LE) i.p. + 2–10 mg/kg +125 Carlson et al. (2001)
Rat (H) i.p. + 2–4 mg/kg +500 Vogel et al. (1980)
Rat (W) i.c. (amygdala) + 20 ␮g +255 Shibata et al. (1989)
Rat (SD) i.c. (hippocampus) + 40 ␮g/side +330 Kataoka et al. (1991)
Mouse s.c. + 1 mg/kg +133 Umezu et al. (1999)
Chlordiazepoxide BZP agonist Rat (W) i.p. + 10–20 mg/kg +370 Millan et al. (2001a)
Rat (H) i.p. + 6–8 mg/kg +667 Vogel et al. (1980)
Rat (SD) i.p. + 4–27 mg/kg +214 Vogel et al. (1980)
Lormetazepam BZP agonist Rat (W) i.c. (amygdala) + 1 ␮g +380 Shibata et al. (1989)
Flurazepam BZP agonist Rat (SD) i.p. + 4–27 mg/kg +214 Vogel et al. (1980)
Rat (H) i.p. + 6–8 mg/kg +667 Vogel et al. (1980)
Rat (W) i.c. (amygdala) + 40–80 ␮g +190 Shibata et al. (1989)
Rat (LH) i.c. (amygdala) + 5 ␮g +154 Higgins et al. (1991)
Alprazolam Triazolo-BZP Rat (SD) i.p. + 0.5–16 mg/kg +220 Söderpalm and Engel (1989)
agonist Rat (LE) i.p. + 2–5 mg/kg +125 Carlson et al. (2001)
Triazolam Triazolo-BZP Rat (SD) i.p. + 0.01 and 0.1 mg/kg +220 Depoortere et al. (1986)
agonist Rat (W) i.p. + 1.25 mg/kg +380 Brocco (unpublished
observations)
Midazolam Triazolo-BZP Rat (W) i.p. + 1–4 mg/kg +94 Stefanski et al. (1992)
agonist Rat (W) i.c. (hippocampus) + 10 and 20 ␮g +180 Nazar et al. (1999b)
Rat (W) i.c. (hippocampus) + 10 and 20 ␮g +300 Stefanski et al. (1993a)
Rat (W) i.c. (N. accumbens) IA 5–20 ␮g IA Stefanski et al. (1993a)
Rat (?) i.c. (amygdala) + 1 ␮g +1000 Schell-Krüger and Petersen
(1982)
Zolpidem ␣1 > ␣2 ,␣3 -agonist Rat (SD) i.p. + 1.0–10.0 mg/kg +200 Depoortere et al. (1986)
Rat (W) i.c. (hippocampus) IA 0.1–10 ␮g IA Nazar et al. (1999b)
Abecarnil ␣1 > ␣2 ,␣3 -agonist Rat (W) i.p. + 0.3–10.0 mg/kg +825 Stephens et al. (1990)
Rat (W) i.p. + 30.0 mg/kg +250 Griebel et al. (1999c)
Zopiclone ␣1 ,␣2 ,␣3 -agonist Rat (W) i.p. + 10 mg/kg +282 Shibata et al. (1989)
Rat (W) i.c. (amygdala) + 1 ␮g +185 Shibata et al. (1989)
SL 651,498 ␣2 ,␣3 > ␣1 -agonist Rat (W i.p. + 10 mg/kg +122 Griebel et al. (2001b)
and SD)
Bretazenil BZP partial agonist Rat (W) i.p. + 1 and 10 mg/kg +310 Griebel et al. (1999c)
Rat (W) i.c. (hippocampus) IA 0.1–10 ␮g/site IA Nazar et al. (1999b)
Imidazenil BZP partial agonist Rat (W) i.p. + 30.0 mg/kg +225 Griebel et al. (1999c)
RWJ-51204 BZP partial agonist Rat (LE) p.o. + 0.1–10 mg/kg NI Dubinsky et al. (2002)
Flumazenil BZP Ant Rat (W) i.p. IA >10 mg/kg IA Wieroñska et al. (2001)
Rat (SD) p.o. IA 10–50 mg/kg IA Liljequist and Engel (1984a,b)
Ethyl-␤-carboline BZP inv. agonist Rat (W) i.p. − 10 mg/kg −50 Mizoule et al. (1985)
Methyl-␤-carboline BZP inv. agonist Rat (SD) i.v. − 0.15 mg/kg −60 Corda et al. (1983)
FG 7142 BZP inv. agonist Rat (W) i.p. − 5 mg/kg −50 Mizoule et al. (1985)
Rat (SD) i.v. − 4 mg/kg −55 Corda et al. (1983)
Abbreviations—N. accumbens: nucleus accumbens; LE: Long–Evans; H: Holtzman; BZP: benzodiazepine; IA: no significant change (inactive) and NI:
not indicated. For other abbreviations, see Table 2. For ␣-subunits, relative activities refers to efficacies rather than affinities.

effects of flumanezil have been documented in man (Nutt,
1996).
2.2.2.2. Influence upon anxious states: multiple mechanisms
of action. BZPs exert their actions at multiple supraspinal
loci and, as a function of the structure involved, their actions
are probably expressed upon different components of anx-
ious states. This involvement of diverse sites of action may
underlie the distinctively powerful and broad-based anxi-
olytic profile of BZPs—though also contributing to their
panoply of side-effects (Section 18.1) (Petersen et al., 1985;
Pratt, 1992; Menard and Treit, 1999; Sramek et al., 2002).
Employing the VCT, anxiolytic actions of diazepam and
other BZPs were seen upon their application into the dorsal
hippocampus (Katoaka et al., 1991; Stefański et al., 1993a;
Plaznik et al., 1994a), observations mimicked by studies
98 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

of exploratory behavior in a novel environment (Stefański
et al., 1993a) though, curiously, few other data are available
for this structure. By analogy, only a single study (Katoaka
et al., 1982), employing a Geller conflict procedure, has lo-
calized anxiolytic actions of BZPs to the mammillary bod-
ies. On the other hand, by use of the VCT (Scheel-Kruger
and Petersen, 1982; Petersen et al., 1985; Shibata et al.,
1989) and other conflict procedures, numerous investiga-
tors have pinpointed the amygdala as a crucial structure for
anxiolytic actions of BZPs, a conclusion underscored by
models involving untrained behaviors (Menard and Treit,
1999). The majority of these studies suggest that the ba-
solateral complex of the amygdala is a more prominent
locus of action for BZPs than the central nucleus, pos-
sibly reflecting the greater concentration of BZP sites in
the former region. However, as implied above, it is possi-
ble that these two sub-territories fulfil complementary roles
in mediating different elements of the anxiolytic profile of
BZPs (Scheel-Kruger and Petersen, 1982; Menard and Treit,
1999). The lateral septum has also been identified as an im-
portant structure for expression of the anxiolytic properties
of BZPs, though its role differs to that of amygdalar nuclei
(Menard and Treit, 1999). While data for actions of BZPs in
conflict procedures appear to be unavailable for this struc-
ture, evidence for anxiolytic actions of GABAA agonists is
available (Drugan et al., 1986). There is, finally, evidence
for a role of the dorsal PAG in mediating the anxiolytic
actions of BZPs in the open-field procedure (Menard and
Treit, 1999). Thus, contrasting neuronal substrates are im-
plicated in (various components) of the anxiolytic actions of
BZPs, of which several regions, notably the amygdala and
the hippocampus, are involved in their effects in the VCT
(Fig. 3).
2.2.2.3. Influence upon anxious states: monoaminergic and
non-monoaminergic mechanisms. The anxiolytic actions
of BZPs in limbic structures involve both pre- and post-
synaptic interactions with serotonergic terminals (Section
4.3.1) (Pratt, 1992; Tao et al., 1996; Dekeyne et al., 2000b;
Millan et al., 2001b; Olivier et al., 2001; Adell et al., 2002).
There is also evidence that actions of BZPs upon serotoner-
gic perikarya participate in their anxiolytic actions (Fig. 4).
Unambiguous evidence that BZPs act at sites in raphe nu-
clei to enhance responding in conventional conflict models
has not, in fact, been presented but, employing a modified
conflict procedure (Section 18.5), a role for the DRN was
deduced (Thiébot et al., 1980, 1982). Moreover, employ-
ing models of unconditioned behaviors, both the DRN and
the MRN have been identified as substrates for anxiolytic
actions of BZPs (Costall et al., 1989; Menard and Treit,
1999).
An interruption of the stress-induced activation of nora-
drenergic neurones by actions in the LC also contributes to
the anxiolytic properties of BZPs (Fig. 4) (Owens et al.,
1989, 1991; Shekhar et al., 2002). In addition, the ability of
BZPs to brake the engagement of mesolimbic-mesocortical
dopaminergic projections originating in the VTA may par-
ticipate in their relief of anxious states (Fig. 4) (Millan et al.,
2000d; Morrow et al., 2000; Beaufour et al., 2001a; Dazzi
et al., 2001; Gifkins et al., 2002).
Notwithstanding the significance of this generalized,
inhibitory influence of BZPs upon the response of cor-
ticolimbic monoaminergic pathways to fear and stress, a
reduction of monoamine release is neither necessary nor
sufficient to account for their anxiolytic actions under all
conditions—an axiom applicable to other classes of anxi-
olytic agent (see Section 18.1). Indeed, as explained below

Fig. 3. Schematic illustration of the sites of action of agents interacting with GABA receptors, NMDA receptors and metabotropic glutamatergic receptors
in the Vogel Conflict Test. The loci of action indicated are based upon results published for the Vogel Conflict Test (see tables). Additional sites of
anxiolytic action, revealed by other procedures, should be borne in mind. Abbreviations—BZP: benzodiazepine; T-BZP: triazolo-benzodiazepine; GlyB:
glycine B; mGlu: metabotropic glutamatergic; BARB: barbiturate; AGO: agonist; ANT: antagonist; D/MRN: dorsal/median raphe nucleus and PAG,
periaqueductal gray.
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 99

Fig. 4. Influence of the benzodiazepines, diazepam and chlordiapoxide, upon extracellular levels of monoamines in the frontal cortex of freely-moving
rats. Drugs were administered at doses which elicit robust increases in punished responses in the Vogel Conflict Test. Data are means ± S.E.M.s. Dialysis
levels are expressed as a percentage of baseline, pre-injection values. Data are from Millan et al. (1997, 2001a). For the Vogel Conflict Test, ( ) P < 0.05
to vehicle values and, for dialysis data, ( ) P < 0.05 to basal pre-injection values.

(Section 2.2.2.3), one component of the anxiolytic pro-
file of BZPs may be exerted via populations of GABAA
receptors which do not interact (at least presynaptically at
the perikarya level) with monoaminergic pathways. Fur-
ther, in contrast to traditional BZPs (such as diazepam),
which exert a pronounced, dose-dependent and robust in-
hibitory influence upon hippocampal and frontocortical
release of 5-HT, NA and DA at anxiolytic doses (Fig. 4),
triazolo-BZPs (such as alprazolam) display a complex pat-
tern of structure-dependent increases and decreases in ex-
tracellular levels of monoamines (Section 18.1) (Lima et al.,
1995; Broderick, 1997; Broderick et al., 1998; Millan et al.,
2000b,d; Bentué-Ferrer et al., 2001). Fig. 5 exemplifies the
marked anxiolytic properties of alprazolam at a dose which,
in distinction to conventional BZPs (Fig. 4), decreases
dialysis levels of 5-HT but not NA or DA in the FCX.
Indeed, preservation of catecholaminergic transmission
may account for the utility of triazolo-BZPs—as compared
to conventional BZPs—in the management of depressive
states (Jonas and Cohon, 1993; Petty et al., 1995; Broderick
et al., 1998; Broderick, 1997; Srisurapanon and
Boonyanaruthee, 1997; Millan et al., 2000d, 2001b;
Beaufour et al., 2001a).
It is, therefore, critical to recognize that BZPs exert their
distinctive anxiolytic (and undesirable) properties in ex-
perimental models—and, presumably, in man—via actions
at a diversity of loci involving both monoaminergic and
non-monoaminergic mechanisms.
2.2.2.4. Functional roles of GABAA receptor subunits.
Genetic disruption of individual isoforms of the ␣-subunit
of GABAA receptors by point mutations at position 101
(substitution of a histidine by an arginine residue) suggests
that ␣1 -, ␣2 -, ␣3 - and ␣5 -subunits may each be associated
with contrasting facets of the functional profile of BZPs
(Table 4) (Sieghart, 1995; Möhler et al., 2002). In interpret-
ing the results discussed below, however, it should be borne
in mind that the deletion of one individual subunit may
result in adaptive changes of others (Sur et al., 2001; Korpi
et al., 2002; Kralic et al., 2002a,b; Thompson et al., 2002).
Though mice overexpressing ␥2S -subunits are virtually in-
distinguishable from wild-type conspecifics, populations de-
100 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Fig. 5. Influence of the triazolo-benzodiazepines, triazolam and alprazolam, upon extracellular levels of monoamines in the frontal cortex of freely-moving
rats. Drugs were administered at doses which elicit robust increase in punished responses in the Vogel Conflict Test. Data are means ± S.E.M.s.
Dialysis levels are expressed as a percentage of baseline, pre-injection values. Data are from Millan et al. (2001d), and Gobert and Millan (unpublished
observations). ( ) P < 0.05 to vehicle values for the Vogel Conflict Test and, for dialysis data, ( ) P < 0.05 to basal pre-injection values.

ficient in ␥2S -subunits are refractory to BZPs (Günther et al.,
1995; Wick et al., 2000). Further, heterozygous (±) ␥2S mice
present an anxiogenic phenotype (Crestani et al., 1999). As
mentioned above (Section 2.2.2.1), BZPs act at the interface
between ␣ and ␥2 -subunits. The probable explanation for the
anxious phenotype of ␥2S (±) mice is a reduction in the clus-
tering of GABAA receptors in somatic and dendritic regions
of neurones in the hippocampus, amygdala and/or cortex,
structures in which ␥2S -subunits are concentrated (Gutierrez
et al., 1994; Crestani et al., 1999; Pirker et al., 2000; Nyiri
et al., 2001). By analogy to the ␥2S -isoform, mice overex-
pressing ␥2L -subunits are unremarkable, while populations
with deleted ␥2L -sites are anxiogenic (Günther et al., 1995;
Homanics et al., 1999; Wick et al., 2000). Intriguingly, mice
lacking ␥2L -subunits are more sensitive to BZPs due to sub-
stitution of absent ␥2L -subunits by their ␥2S counterparts
which favor an “agonist-preferring”, BZP-responsive con-
figuration of GABAA receptors (Quinlan et al., 2000).
Introduction of a point mutation into the ␣2 -subunit,
which is enriched in corticolimbic structures, rendered mice
resistant to the anxiolytic actions of diazepam. This effect
was specific inasmuch as pentobarbital was still effective,
consistent with its action at a separate site on GABAA
receptors (Section 2.2.4) (Löw et al., 2000). A similar ap-
proach suggested that the myorelaxant actions of diazepam
are mediated by ␣2 -subunits, presumably reflecting their ex-
pression in spinal motoneurones (Löw et al., 2000; Crestani
et al., 2001; Möhler et al., 2001, 2002).
␣1 -Subunits are found in GABAergic neurones them-
selves and are highly expressed in the cerebellum, basal
ganglia, thalamus and cortex (Section 2.2.1). In distinc-
tion to ␣2 -subunits, inactivation of ␣1 -subunits eliminated
the sedative and amnesic actions of diazepam whereas its
anxiolytic (and myorelexant) properties were maintained.
The sedative actions of zolpidem were also abolished in
mice lacking ␣1 -subunits, and these effects were selective
inasmuch as pentobarbital continued to compromise motor
function (Gao et al., 1993; Rudolph et al., 1999; Crestani
et al., 2000, 2002a; McKernan et al., 2000; Reynolds
et al., 2001; Kralic et al., 2002a). (These observations con-
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Table 4
Differential functional roles of GABAA receptor ␣-subunits as evaluated
by genetic studies in mice
Activity ␣1 ␣2 ␣3 ␣5
Anxiolytic No Yes (Yes) No
Amnesic Yes ? ? Yes
Myorelaxant No Yes Yesa No
Hypnotic (EEG) No Yes Yes No
Sedative Yes No No No
Anticonvulsant Yes Yes?b Yes?b Yes?b
Yes: involved; No: not involved; (Yes): to be confirmed as data cur-
rently inconsistent and EEG: electroencephalography; a At high doses of
diazepam; b Though the role of ␣1 -subunits in anticonvulsant properties
is confirmed, it remains to be elucidated which additional site(s) are in-
volved. Note that the indication “No” should be considered as provisional
since the involvement of specific subunits is dependent upon experimental
conditions, including the choice of benzodiazepine employed to validate
function. Further, pharmacological studies of selective agents at specific
␣-subunits have, in certain cases, generated data indicating roles which
have not, as yet, been clearly revealed by studies of genetically-modified
mice. See text for further details. Data summarized from Crestani et al.
(1999, 2000, 2001, 2002a,b), Rudoph et al. (1999), Löw et al. (2000),
McKernan et al. (2000), Kralic et al. (2002a,b), McKernan (2002) and
Möhler et al. (2002).
form, incidentally, to the somewhat anachronistic notion
that GABAA receptors incorporating ␣1 -subunits may be
equated with pharmacologically-defined “GABAA /BZ1 ”
sites thought to transduce the sedative and hypnotic actions
of BZPs, as compared to “GABA/BZ2 ” sites—containing
other subunits—which mediate their anxiolytic properties
(Dennis et al., 1988; McLeod et al., 2002).) In complemen-
tary studies, the use of ␣1 -subunit preferring antagonists
has similarly suggested that ␣1 -subunits—and other (as yet
unidentified) mechanisms—mediate the sedative actions
of BZPs in primates (Platt et al., 2002). Nevertheless, a
possible incoherence between genetic and pharmacologi-
cal approaches is provided by findings that a preferential
␣1 -subunit antagonist, ␣-carboline-3-carboxylate-t-butyl
ester, did interfere with the anxiolytic (and myorelax-
ant) effects of BZPs in rodents (Griebel et al., 1999a,c;
Belzung, 2001). Interestingly, further, on the basis of
pharmacological studies, ␣1 -subunits were implicated in
the “interoceptive” (discriminative stimulus), subjective—
though not anxiolytic—effects of BZPs in primates (Lelas
et al., 2002; Rowlett et al., 2002, 2003).
Counterintuitively, in view of the fact that serotonergic
cell bodies express ␣3 but not ␣1 - (or ␣2 ) subunits, it was re-
ported that deletion of ␣3 -subunits did not interfere with the
anxiolytic actions of diazepam (Gao et al., 1993; Fritschy
and Möhler, 1995; Pirker et al., 2000; Möhler et al., 2001,
2002). However, ␣2 -subunits exist on afferent terminals in
raphe nuclei (Pirker et al., 2000), and several other GABAA
receptor subunits occur both in the DRN and in the LC
(Moragues et al., 2002). Thus, subunits other than ␣3 may
modify monoaminergic transmission. Further, no informa-
tion from conflict models is available, and studies with other
drugs and/or anxiolytic procedures may have yielded con-
101
trasting patterns of data as concerns the phenotype of mice
with dysfunctional ␣3 -subunits. In line with this supposition,
in an independent series of studies adopting a similar genetic
approach but different experimental conditions, it was re-
cently found that selective elimination of ␣3 -subunits did ab-
rogate the anxiolytic properties of BZPs (McKernan, 2002).
␣3 -Subunits, which are localized on noradrenergic neurones
facilitatory to motor function (Crestani et al., 2001), may
also play a role complementary to ␣1 -subunits in mediating
the myorelaxant properties of (high doses of) BZPs (Möhler
et al., 2002).
Targeted disruption of ␣5 -subunits, which are principally
found at extrasynaptic sites in the hippocampus (Section
2.2.1), failed to impair the anxiolytic actions of diazepam.
This result questions a major role of ␣5 -subunits in the
control of anxious states by BZPs despite reports that in-
verse agonists at ␣5 -subunits manifest anxiogenic properties
(Crestani et al., 2002b; Garcia et al., 2002; McKernan, 2002;
Navarro et al., 2002). Interestingly, cognitive performance—
including association learning and fear conditioning—was
improved in mice lacking ␣5 -subunits (Collinson et al., 2002;
Crestani et al., 2002b; Garcia et al., 2002) though equivalent
findings with selective inverse agonists at ␣5 -subunits await
confirmation (McKernan, 2002).
Recombinant GABAA receptors incorporating ␣4 -subunits
are essentially refractory to the actions of BZPs. Accord-
ingly, it has been posited that an up-regulation of hip-
pocampal ␣4 -subunits by sudden termination of long-term
BZP administration participates in the negative emotional
symptoms of the accompanying withdrawal syndrome—
though this hypothesis implicitly assumes the existence
of tonically-active, endogenous BZP-like ligands (Follesa
et al., 2001, 2002).
It should, finally, be noted that substitution of ␥-subunits
by ␦-subunits (present in the hippocampus, but not the
amygdala), ε-subunits (enriched in the hypothalamus)
or ␪-subunits (confined to peripheral tissues) generates
GABAA receptors insensitive to BZPs (Barnard et al., 1998;
Möhler et al., 2002).
2.2.2.5. Functional profiles of subunit-selective agents.
Notwithstanding the need for more extensive analysis, these
elegant studies of the functional consequences of point
mutations in specific ␣-subunits of GABAA receptors pro-
vide an instructive framework for improved interpretation
of the actions of drugs differentially recognizing ␣1 -, ␣2 -
and ␣3 -subunits. (That is, drugs which display contrasting
efficacies at individual subunits inasmuch as the synthe-
sis of agents possessing absolute selectively—in terms of
affinity—has not, to date, proven feasible.) Thus, the novel
pyridoindole derivative, SL651,498, which behaves as a
full agonist at ␣2 - and ␣3 as compared to ␣1 -subunits,
displays robust anxiolytic actions in the VCT and other
models in the absence of sedative (and amnesic) properties
(Griebel et al., 2001b). Moreover, the recently-described
ligand, L838,417, reveals potent anxiolytic properties in
102 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
the relative absence of motor disruption, a profile which
may be ascribed to its combined agonist actions at ␣2 - and
␣3 -subunits as compared to ␣1 -subunits (McKernan et al.,
2000). Contrariwise, the potent hypnotic versus anxiolytic
actions of zolpidem and zaleplon are congruent with their
preferential (high efficacy) activation of ␣1 versus ␣2 , ␣3
and (even less potently) ␣5 -subunits (Benavides et al., 1990;
Meadows et al., 1998; Damgen and Lüddens, 1999; Doble,
1999; Rush et al., 1999; Platt et al., 2002; Sanna et al.,
2002). Finally, the relatively modest myorelexant effects
of abecarnil are consistent with lower efficacy at ␣2 as
compared to ␣1 -subunits (Pribilla et al., 1993).
2.2.2.6. Clinical relevance of subunit-selective drugs: open
questions. Clearly, then, the assignment of specific func-
tional correlates to distinct subunits of GABAA receptors
offers the perspective of novel classes of anxiolytic agent
possessing an improved therapeutic window between doses
exerting beneficial actions as compared to those provoking
deleterious side-effects. However, there remain several ques-
tions and caveats.
First, inasmuch as myorelaxant properties are primarily
mediated by the same ␣2 -subunit as that which transduces
the anxiolytic actions of BZPs, drugs exerting a “pure” anx-
iolytic profile may be difficult to obtain—though the clini-
cal benefits of myorelaxation in the management of anxious
states should not be neglected, notably in patients suffering
from discomfort of muscular origin (Millan, 1999).
Second, development of tolerance and dependence upon
protracted administration of agents acting exclusively (as ag-
onists or antagonists) at specific ␣-subunits warrants careful
examination.
Third, as intimated above, employing diverse drugs and
experimental approaches, it will be important to corroborate
and amplify insights provided by genetic studies into the
roles of specific GABAA receptor subunits (Reynolds et al.,
2001).
Fourth, possibly reflecting species differences, though
partial BZP agonists display functional profiles distinct
from those of conventional (full agonist) BZPs in many
experimental models (Stephens et al., 1990; Martin et al.,
1993; Potokar and Nutt, 1994; Nazar et al., 1997; Dubinsky
et al., 2002; Platt et al., 2002; McMahon and France, 2003),
they have not proven to be markedly different in the clinic
in terms of their therapeutic index between anxiolytic and
adverse effects (Haefely et al., 1992; Busto et al., 1994;
Guldner et al., 1995; Aufdembrinke, 1998; Rush, 1998;
Sandford et al., 2001). Thus, clinical studies will be decisive
in assessing the advantages of subunit-selective anxiolytic
agents as compared to traditional drugs which interact
indiscriminately with all ␣-subunits of GABAA receptors.
Fifth, the precise relationship between discrete ␣-subunits
and the heterogeneity of anxious disorders in man remains
to be established. It should not, for example, be assumed
on the basis of extant data that the selective recruitment of
␣2 -subunits will suffice for effective relief of all forms of
anxiety responsive to currently-available BZPs in the ab-
sence of sedative and cognitive side-effects.
Sixth, it has become almost a platitude to cite the amnesic
properties of BZPs as a troubling complication of their uti-
lization. It should not, however, be ignored that for certain
categories of anxiety disorder, an inability to forget is a car-
dinal and diagnostic feature. Correspondingly, caution is im-
perative in the exploitation of drugs possessing, for example,
inverse agonist properties at ␣5 -subunits, and consequently
anticipated to “improve” mnesic function (Section 18.8).
Seventh, though elimination of sedative properties may, at
first sight, also appear to represent a major advantage, this
supposition does not fully reflect the reality of therapeutic
trials and common clinical usage. Indeed, introduction of
the 5-HT1A receptor agonist, buspirone (Section 4.3.2.3),
encountered major difficulties precisely due to its lack of
sedative properties in patients accustomed to BZPs.
Eighth, as for all neuropsychiatric indications, a consid-
eration of paramount importance in the treatment of anxi-
ety disorders is the influence of drugs upon sleep (Benca,
1994a,b; Roth, 2001; Smith et al., 2002a). Sleep is almost
invariably disturbed in anxious patients—while, recipro-
cally, patients with primary insomnia frequently reveal
high state anxiety (Benca, 1994a; Roth, 2001; Smith et al.,
2002a,b). Indeed, patients suffering from panic attacks or
GAD are characterized by a decline of sleep continuity, re-
duced total time and efficiency of sleep, high sleep latency
and early morning waking. These features are often encoun-
tered in depressive subjects though, in contrast to the latter,
anxious patients reveal a suppression of “REM” sleep dura-
tion and no change “in REM” latency (Papadimitriou et al.,
1988a; Haurie et al., 1989; Mellman and Uhde, 1989a;
Benca, 1994a,b). Thus, successful (subunit-selective and
other) anxiolytic agents should favor high-quality, regular
and prolonged sleep without provoking a deterioration of
“morning-after” activities (Haefely et al., 1992; Gieschke
et al., 1994; Patat et al., 1994; Borbély, 1995; Ashton,
1994; Noble et al., 1998; Mitler, 2000; Mailliet et al., 2001;
Platt et al., 2002; Smith et al., 2002a,b). In this light, it has
been suggested that the hypnotic qualities of BZPs involve
␣2 - and ␣3 -subunits, though this awaits confirmation (Platt
et al., 2002)
2.2.3. Neurosteroids
2.2.3.1. Multiple central actions. The term “neurosteroids”
(a contraction of neuroactive steroids) refers to a range
of steroids synthesized in glial cells and neurones from
cholesterol and other precursors. Neurosteroids exert rapid
(non-genomic) actions in the brain leading to alterations
in neuronal excitability (Lambert et al., 1995; Beaulieu,
1997; Maurice et al., 1999; Rupprecht and Holsboer, 1999;
Falkenstein et al., 2000; Rupprecht et al., 2001; Miksys and
Tyndale, 2002; Van Broekhoven and Verkes, 2003). In this
regard, innumerable central actions of neurosteroids have
been described, including effects at the following sites:
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
5-HT3 receptors, glycineA receptors, nicotinic and mus-
carinic receptors, oxytocin receptors, N-methyl-d-aspartate
(NMDA), kainate and ␣-amino-2,3-dihydro-5-methyl-3-
oxo-4-isoxazolepropanoic acid (AMPA) receptors, and
sigma1 binding sites (Section 17). All might, in theory, be
involved in the influence of neurosteroids upon anxious
states though little if any concrete information is available
in this regard (Park-Chung et al., 1997; Maurice et al., 1999;
Zinder and Dar, 1999; Falkenstein et al., 2000; Meyer et al.,
2002; Van Broekhoven and Verkes, 2003). Indeed, the prin-
ciple mode of action implicated in the anxiolytic properties
of neurosteroids is their positive, allosteric modulation of
GABAA receptors. The term “epalon” has been specifically
applied to (endogenous and synthetic) steroids which exert
such actions (Lan and Gee, 1997), but it is not employed in
the present article.
2.2.3.2. Generation and modulation. Cholesterol in the
brain is sequentially converted (primarily in the mito-
chondria of glial cells) via pregnenolone and progesterone
into reduced metabolites of the latter: allopregnanolone
(or 3␣-hydroxy-5␣-pregnan-20-one) and pregnanolone (or
3␣-hydroxy-5␤-pregnan-20-one), respectively (Lambert
et al., 1995; Beaulieu, 1997; Maurice et al., 1999; Rupprecht
and Holsboer, 1999; Falkenstein et al., 2000; Rupprecht
et al., 2001; Miksys and Tyndale, 2002; Van Broekhoven and
Verkes, 2003). Circulating sources of progesterone are also
(peripherally and centrally) converted into allopregnanolone.
These neurosteroids enhance the frequency and duration
of opening of GABAA receptor-coupled chloride channels,
properties shared by: (1) the deoxycorticosterone deriva-
tives, 3␣,5␣- and 3␣,5␤-tetrahydrodeoxycorticosterone
(3␣,5␣- and 3␣,5␤-THDOC) and (2) the testosterone
metabolites, androsterone and 3␣-androstanediol, which
may also be derived from circulating, endocrine sources
(Section 12) (Lambert et al., 1995; Beaulieu, 1997; Maurice
et al., 1999; Rupprecht and Holsboer, 1999; Falkenstein
et al., 2000; Rupprecht et al., 2001; Miksys and Tyndale,
2002; Van Broekhoven and Verkes, 2003). In contrast to
these reduced steroids, other products of cholesterol trans-
formation may act as antagonists at GABAA sites, includ-
ing progesterone itself, pregnenolone sulfate—which can
also activate NMDA receptors—and its processing product,
dehydroepiandrosterone sulfate (op. cit.).
The first synthetic drug shown to enhance activity at
GABAA receptors via an action at “neurosteroid” sites was
the general anaesthetic, alphaxalone. Numerous other exoge-
nous neurosteroids have since been proposed as therapeutic
agents for the treatment of BZP-sensitive anxiety disorders
in the hope of achieving improved efficacy while avoiding
motor and cognitive side-effects, though this remain to be
proven clinically (Lan and Gee, 1997; Gasior et al., 1999;
Vanover et al., 2000; Visser et al., 2002).
The synthesis of neurosteroids is accelerated by stress
(Purdy et al., 1991; Steimer et al., 1997; Rupprecht and
Holsboer, 1999) and, intriguingly, an elevation in circulat-
103
ing levels of allopregnanolone has been detected in patients
with GAD (Semeniuk et al., 2001), as well as patients suf-
fering from panic disorders and other anxious states (Purdy
et al., 1991; Steimer et al., 1997; Rupprecht and Holsboer,
1999; Vallee et al., 2000; Girdler et al., 2001; Ströhle et al.,
2002, 2003). This may represent a negative-feedback re-
sponse counteracting the accompanying anxiety, though a
very recent report suggested that neurosteroid levels may ac-
tually be transiently reduced during a panic attack (Ströhle
et al., 2003).
It has been hypothesized that the anxiolytic effects
of (long-term) administration of SSRIs (Section 4.4) re-
flect (independently of 5-HT transporters), the progres-
sive (5␣-reductase and 3␣-hydroxysteroid oxidoreductase-
catalysed) formation of allopregnanolone (Uzunov et al.,
1996; Guidotti and Costa, 1998; Uzunova et al., 1998;
Ströhle et al., 1999; Griffin and Mellon, 1999; Serra et al.,
2001; Roca et al., 2002). Clinical support for this con-
tention is provided by observations that cerebral levels of
neurosteroids—and GABA—are elevated by fluoxetine in
premenstrual females, in parallel with an alleviation of their
emotional symptoms (Halbreich et al., 1996; Uzunov et al.,
1996; Wang et al., 1996a; Bixo et al., 1997; Dimmock et al.,
2000; Girdler et al., 2001; Epperson et al., 2002; Sanacora
et al., 2002). However, there are also indications for a rapid
facilitatory influence of fluoxetine upon neurosteroid levels
in rodents (Griffin and Mellon, 1999; Serra et al., 2001),
despite its anxiogenic properties upon acute administration
(Section 4.4.2). Thus, the temporal and causal relationship
between the influence of SSRIs and other antidepressant
agents upon corticolimbic generation of neurosteroids as
compared to their control of anxious states requires further
clarification (Van Broekhoven and Verkes, 2003). Moreover,
it was recently found that fluoxetine can directly facilitate
the actions of GABA at GABAA receptors, further compli-
cating analysis of the role of GABAergic transmission in
its influence upon anxious states (Robinson et al., 2003).
2.2.3.3. Anxiolytic properties: roles of GABAA subunits.
Synthetic and endogenous neurosteroids (positive modula-
tors) suppress the anxiogenic actions and gene expression
of corticotrophin-releasing factor (CRF) (Section 9.1.2)
(Britton et al., 1992; Patchev et al., 1994) and evoke an
impressive spectrum of anxiolytic actions at non-sedative
doses in diverse experimental models (Britton et al., 1991;
Wieland et al., 1995, 1997; Akwa et al., 1999; Gasior et al.,
1999; Rupprecht and Holsboer, 1999; Gomez et al., 2002;
Van Broekhoven and Verkes, 2003; De Boer and Koolhaas,
2003). Correspondingly, central administration of neuros-
teroids is associated with anxiolytic properties in the VCT
and other conflict paradigms (Table 5) (Crawley et al., 1986;
Wieland et al., 1991; Carboni et al., 1996; Czlonkowska
et al., 1999). Concordant with studies of BZP receptor
ligands (Section 2.2.2.2), the amygdala has been identi-
fied as an important locus for expression of the anxiolytic
properties of neurosteroids possibly in interaction with neu-
104 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Table 5
Influence of neurosteroids, of injectable anesthetics and of ethanol upon behavior in the Vogel Conflict Test
Drug Class Species Route Effect Active dose Maximum Reference
(strain) (structure) range change (%)
Allopregnanolone GABAA NST agonist Mouse (SW) i.p. + 20 mg/kg +140 Wieland et al. (1991)
Rat (W) i.c.v. + 10 ␮g +290 Czlonkowska et al. (1999)
Rat (SD) i.c.v. + 2.5 and 10 ␮g +430 Carboni et al. (1999)
3␣,5␣-THDOC GABAA NST agonist Rat (SD) i.p. + 10 mg/kg +1000 Crawley et al. (1986)
Rat (W) i.c.v. + 10–30 ␮g +200 Czlonkowska et al. (1999)
3␣,5␤-THDOC GABAA NST agonist Rat (W) i.c.v. + 20 and 30 ␮g +250 Czlonkowska et al. (1999)
3␣,5␤-P-20-one GABAA NST agonist Rat (SD) i.c.v. + 2.5–20 ␮g +200 Carboni et al. (1999)
3␣,5␣-P-20␣-diol GABAA NST agonist Rat (SD) i.c.v. + 10–20 ␮g +275 Carboni et al. (1999)
3␣,5␣-P-20␤-diol GABAA NST agonist Rat (SD) i.c.v. + 60 ␮g +160 Carboni et al. (1999)
3␣,5␤-P-20␣-diol GABAA NST agonist Rat (SD) i.c.v. + 10 and 20 ␮g +620 Carboni et al. (1999)
Pregnenolone GABAA NST Ant Rat (W) i.c.v. IA 10–30 ␮g IA Czlonkowska et al. (1999)
3␤,5␣-P-20-one GABAA NST Ant Rat (SD) i.c.v. IA 2.5–5 ␮g IA Carboni et al. (1999)
Phenobarbital Barbiturate Rat (?) i.p. + 15 mg/kg +41 Getova et al. (1990)
Anesthetic Rat (W) i.c. (amygdala) + 40 ␮g +220 Shibata et al. (1989)
Pentobarbital Barbiturate Rat (H) i.p. + 5 and 10 mg/kg +450 Vogel et al. (1980)
Anesthetic Mouse (ICR) s.c. + 20 mg/kg +51 Umezu (1999)
Propofol Anesthetic Rat (W) i.p. + 20 and 40 mg/kg +340 Matsuo et al. (1997)
4-I-Pro Anesthetic Rat (SD) i.p. + 60 mg/kg +330 Sanna et al. (1999)
Ethanol Modulator Rat (SD) i.p. + 2000 mg/kg +290 Liljequist and Engel (1984a,b)
Abbreviations—H: Holtzman; SW: Swiss; ICR: Swiss CD; NST: neurosteroid; IA: no significant change (inactive); 3␣,5␣- and 3␣,5␤-THDOC: 3␣,5␣- and
3␣,5␤-tetrahydrodeoxycorticosterone; P: pregnan and 4-I-Pro: 4-iodo-2,6-diisopropylphenone (propofol analogue). For other abbreviations, see Table 2.

ropeptides Y (NPY) (Section 9.1.5)—though the septum
and hippocampus may likewise be implicated (Akwa et al.,
1999; Bitran et al., 1999; Ferrara et al., 2001). Negative
modulators at neurosteroid sites are generally devoid of ac-
tivity though anxiogenic (and even anxiolytic) actions have
been detected under certain conditions (Purdy et al., 1992;
Picazo and Fernandez-Guasti, 1995; Akwa et al., 1999).
The significance of individual GABAA receptor subunits
to the actions of neurosteroids is less apparent than for
their BZP counterparts, though it is well-established that
␤-subunits are of comparatively minor significance in this
regard (Section 2.2.2.4) (Lambert et al., 1995; Smith et al.,
1998b; Gulinello et al., 2001; Belelli et al., 2002; Bianchi
et al., 2002). Interestingly, in contrast to BZPs, genetic
disruption of ␦-subunits, which are well represented in
the hippocampus and nucleus accumbens, interfered with
the anxiolytic and sedative (though not cognitive) actions
of neurosteroids. This finding coincides with studies in
recombinant systems of GABAA receptors incorporating
␦-subunits which are highly sensitive to neurosteroids
(Laurie et al., 1992; Wisden et al., 1992; Zhu et al., 1996;
Mihalek et al., 1999; Adkins et al., 2001; Belelli et al.,
2002; Vicini et al., 2002; Wohlfarth et al., 2002).
The above observations underscore the notion that neu-
rosteroids act at sites different to those recognized by
BZPs (Section 2.2.2.4). In support of contrasting (and com-
plementary) mechanisms of action of neurosteroids and
BZPs, they exert their anxiolytic actions synergistically in
a flumazenil-resistant and flumazenil-sensitive manner, re-
spectively (Van Broekhoven and Verkes, 2003). Moreover,
various subunits of GABAA receptors are subject to modu-
lation by protein kinase-mediated phosphorylation (Hodges
et al., 1991, 2002; Krishek et al., 1994; Lin et al., 1996;
McDonald et al., 1998; Millan, 1999; Bowers et al., 2000)
and, in this regard, the actions of neurosteroids are differ-
entially modified as compared to those of BZPs and GABA
itself. Of particular interest, mice lacking the “ε” isoform
of protein kinase C (which indirectly targets GABAA re-
ceptors) displayed both behavioral and endocrine—low
adrenocorticotropic hormone (ACTH) release—signs of
blunted anxiety, together with an enhanced sensitivity to
neurosteroids. In line with these findings, the actions of
neurosteroids in wild-type populations could be mimicked
by specific inhibitors of protein kinase C-ε (Hodges et al.,
1999, 2002).
Following prolonged exposure to neurosteroids, precipi-
tation of withdrawal is accompanied by a complex pattern
of regionally-specific alterations in GABAA receptor sub-
unit expression—these effects are partially mediated ge-
nomically by oxidized derivatives of neurosteroids acting at
estrogen receptors (Section 12) (Biggio et al., 2001). The ac-
companying behavioral syndrome, which includes rebound
anxiety may—by analogy to BZPs themselves (Section
2.2.2.4)—be partly attributable to an up-regulation of hip-
pocampal GABAA receptors incorporating ␣4 -subunits
(Smith et al., 1998b; Follesa et al., 2001, 2002; Gulinello
et al., 2001, 2002; Mascia et al., 2002; Möhler et al., 2002;
Hsu and Smith, 2003).
2.2.3.4. Other properties of neurosteroids. Notwithstand-
ing the above observations, much remains to be learned
concerning the interrelationship between neurosteroids,
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
GABAA receptors and anxious states. Notably, mechanisms
controlling the local synthesis, release and accumulation of
neurosteroids still elude identification. Further, processes
regulating the balance between positive allosteric modula-
tors, such as pregnanolone, as compared to negative modu-
lators, such as pregnenolone, remain to be clarified, and the
precise contribution of GABAA receptors to the global in-
fluence of neurosteroids upon anxious states requires further
evaluation (Falkenstein et al., 2000; Van Broekhoven and
Verkes, 2003). From a therapeutic perspective, the potential
advantages (and disadvantages) of neurosteroids as alterna-
tive (or adjunctive) agents to BZPs in the treatment of anxi-
ety disorders should become clearer as results from clinical
trials begin to be disclosed (see also comments in Section
2.2.2.6). This is a crucial issue since it cannot, a priori, be
guaranteed that neurosteroids will be devoid of the detrimen-
tal effects of BZPs. For example, recent studies have revealed
reinforcing properties of allopregnanolone in rats, while
neurosteroids substitute for BZPs in drug-discrimination
procedures. These data raise the possibility of a similar sus-
ceptibility for abuse in man (Engel et al., 2001; McMahon
et al., 2001; Fish et al., 2002; Miczek et al., 2002; Sinnott
et al., 2002; McMahon and France, 2003).
2.2.4. Propofol and other injectable general anesthetics
Injectable general anesthetics such as propofol and the
barbiturate, pentobarbital, both potentiate responsiveness
to GABA and directly activate GABAA receptors in its
absence. Mutational analyses of specific GABAA recep-
tor subunits have shown that, in contrast to BZPs, the
␣2 -subunit is not critical for expression of the anxiolytic
properties of pentobarbitol (Löw et al., 2000) which—like
other barbiturates—displays robust activity in the rat and
mouse VCT (Table 5) (Vogel et al., 1980; Shibata et al.,
1989; Getova et al., 1990; Umezu, 1999; Prut and Belzung,
2003). Further, the GABAA receptor subunits recognized
by this and other intravenous anesthetics differ to those
engaged by their volatile counterparts, such as isoflurane
(Puia et al., 1991; Harris et al., 1995; Birnir et al., 1997;
Krasowski et al., 1998; Amin, 1999; Chen et al., 1999;
Haseneder et al., 2002; Jenkins et al., 2002). Binding to ␤-
(but not ␥-) subunits appears to be of particular importance
for the functional actions of pentobarbital and propofol,
though this remains to be corroborated (Concas et al., 1991;
Hara et al., 1993; Cestari et al., 1996; Hevers and Lüddens,
1998; Krasowski et al., 1998; Sanna et al., 1999; Haseneder
et al., 2002; Korpi et al., 2002; Williams and Akabas, 2002).
In analogy to BZPs, it has been shown that barbiturates,
propofol and propofol derivatives all exert pronounced anx-
iolytic activity in the VCT in parallel with a reduction in the
accompanying induction of 5-HT release (Table 5) (Matsuo
et al., 1996, 1997; Chen et al., 1999; Sanna et al., 1999).
General anesthetics also exert a complex pattern of (in gen-
eral, inhibitory) effects upon corticolimbic noradrenergic,
dopaminergic and, probably, glutamatergic transmission: it
is plausible that these effects contribute to their modulation
105
of anxious states, though the mechanistic bases remain un-
clear (MacIver, 1997; Schulte et al., 2000; Pain et al., 2002;
Pashkov and Hemmings, 2002; Westphalen and Hemmings,
2003).
A recent report raised the possibility that potentiation of
transmission at GABAB receptors (Section 2.3) participates
in the anxiolytic (and other functional) actions of propofol
(Schweiler et al., 2003).
2.2.5. Ethanol
2.2.5.1. Anxiolytic properties. It has long been held (the
“tension reduction hypothesis”) that a predisposition to
voluntary ethanol consumption reflects its anxiolytic prop-
erties: that is, anxious patients are both more sensitive to
the reinforcing effects of ethanol and more vulnerable to
its pernicious, long-term addictive potential (Cappell and
Herman, 1972; Altman et al., 1996; Silvestre et al., 2002)
(see also Section 4.2.1). as regards the implication of
dopaminergic mechanisms in coping strategies in response
to anxiety and stress. Though a causal relationship be-
tween “trait” anxiety (tension reduction) and ethanol abuse
has been vigorously repudiated—and alcoholic patients
are clearly a heterogeneous population (Cloninger, 1987;
Schuckit and Hesselbrock, 1994; Stephens et al., 2002;
Van Erp et al., 2001)—both epidemiological and experimen-
tal support for this hypothesis has been advanced. For exam-
ple, anxiety (and stress in general) is predictive of recidivism
in ethanol addicts and provokes reinstatement of ethanol-
seeking behavior in rodents (Lê et al., 1998; Brady and
Sonne, 1999). Intriguingly, the amygdala appears to fulfil
a critical role both in the self-administration of ethanol and
in the expression of its anxiolytic properties (Stewart et al.,
1993; Colombo et al., 1995; Hyytia and Koob, 1995; Spa-
nagel et al., 1995; Roberts et al., 1996; Möller et al., 1997).
Thus, in the amygdala and, possibly, other limbic struc-
tures, the facilitatory influence of ethanol upon GABA
receptor-mediated ionic currents likely accounts for its
broad influence upon emotion and cognitive function
(Pohorecky, 1990; Mihic, 1999; Korpi et al., 2002; Miczek
et al., 2002) including its anxiolytic properties in the VCT
and other procedures—though anti-conflict actions are best
demonstrated where parameters are adjusted to yield modest
response suppression (Vogel et al., 1971; Petersen and Buus
Lassen, 1981; Liljequist and Engel, 1984a,b; Criswell and
Breese, 1989; Koob et al., 1987; Möller et al., 1997; Silvestre
et al., 2002; De Boer and Koolhaas, 2003). Though recurrent
ethanol administration elicits tissue-dependent alterations
in the gene expression of various ␣-, ␤- and ␥-GABAA
receptor subunits (Grobin et al., 2000), its binding domain
remains ill-defined. The contention that ␥2 -subunits (the
long splice variant) are a prerequisite for its behavioral and
other actions remains controversial (Wafford and Whiting,
1992; Homanics et al., 1999; Cagetti et al., 2003). Fur-
ther, though certain actions of ethanol may, like those of
neurosteroids, be dependent on the integrity of ␦-subunits,
106 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
their genetic elimination did not modify the anxiolytic prop-
erties of ethanol (Mihalek et al., 2001; Sundstrom-Poromaa
et al., 2002). On the other hand, ␣1 - and ␤2 -subunits are
implicated in the hypnotic effects of ethanol (Blednov
et al., 2003). Further, ␣4 -subunits are of particular signif-
icance to the GABAA receptor-mediated enhancement of
chloride-currents by low concentrations of ethanol (Korpi
et al., 2002; Sundstrom-Poromaa et al., 2002), and hip-
pocampal (extrasynaptic) populations of ␣4 -subunits play
a prominent role in its influence upon mood, including its
anxiolytic and stress-attenuating properties (Smith et al.,
1998b; Sundstrom-Poromaa et al., 2002). Mimicking re-
sults obtained both with BZPs themselves (Section 2.2.2.4)
and with neurosteroids (Section 2.2.3.2), discontinuation of
protracted ethanol treatment elicits an up-regulation of hyp-
pocampal ␣4 -subunits. In view of their resistance to BPZs,
this surfeit of ␣4 -subunits may contribute to the accompa-
nying withdrawal syndrome (Devaud et al., 1997; Papadeas
et al., 2001; Möhler et al., 2002; Cagetti et al., 2003).
A further parallel to neurosteroids—which may be in-
volved in the actions of ethanol (Mihalek et al., 2001;
Morrow et al., 2001; Cagetti et al., 2003; Tokunaga et al.,
2003)—is provided by the supersensitivity to its motor ac-
tions in mice genetically deficient in protein kinase C-ε,
reproducing cellular findings that inhibitors of protein ki-
nase C-ε potentiate actions of ethanol at GABAA receptors
(Hodges et al., 1999; Olive et al., 2000; Choi et al., 2002).
In mice lacking this enzyme, functional “rescue” of pro-
tein kinase C-ε by conditioned induction of its expression
in the amygdala and other forebrain structures normalized
responsiveness to ethanol (Choi et al., 2002). It would be
informative to undertake comparable studies specifically
focussing on the anxiolytic properties of ethanol in light of
the implication of GABAA receptors in the amygdala in the
control of anxious states (Section 2.2) and in the functional
actions of ethanol (see above).
2.2.5.2. Other actions of ethanol. It is convenient to evoke
here several other mechanisms by which ethanol may mod-
ulate anxious states—though they are not necessarily ex-
pressed via its allosteric interaction with GABAA receptors.
Protein kinase C-ε (see Section 2.2.5.1) modulates the
induction by ethanol of DA release in the amygdala and
other limbic structures, though the precise underlying mech-
anisms remain obscure and actions of ethanol independent of
GABAA receptors may also be involved (Olive et al., 2000;
Sher, 2003). Indeed, while the marked influence of ethanol
upon corticolimbic release of monoamines is clearly related
to its modulation of emotionality, the precise significance for
its control of anxious states awaits clarification (Campbell
and McBride, 1995; Kiianman et al., 1995; Carboni et al.,
2000; Köhnke et al., 2002).
It has also been suggested that alterations in the release of
glutamate contribute to the influence of ethanol upon anx-
ious states. Thus, ethanol has been shown to diminish gluta-
matergic transmission in the hippocampus and other limbic
tissues, while abrupt suspension of its long-term administra-
tion elicits a opposite elevation in limbic glutamate release
together with a negative affective state characterized by
pronounced anxiety (Rossetti and Carboni, 1995; Shimuzu
et al., 1998; Yan et al., 1998; Piepponen et al., 2002). Direct
(inhibitory) interactions of ethanol with NMDA and, possi-
bly, kainate receptors may also participate in its functional
actions, such as (vide supra) an enhancement of mesolim-
bic dopaminergic transmission (Allgaier et al., 1999;
Woodward, 2000; Crowder et al., 2002). In this light, evi-
dence has been forwarded that a component of the anxiolytic
properties of ethanol is mediated via its (non-competitive)
antagonist properties at NMDA receptors, though the pre-
cise locus of action of ethanol remains unclear. NR1/NR2B
receptor complexes, which are enriched in the forebrain,
may be particularly sensitive to inhibition by ethanol
(Section 3.2.2) (Moraes-Ferreira and Morato, 1997; Harrison
et al., 1998; Wirkner et al., 1999; Woodward, 2000; Criswell
et al., 2003).
In view of the above-discussed (Section 2.2.5.1) concor-
dance of experimental and clinical evidence in favor of a
close interrelationship amongst stress, anxiety and ethanol
abuse in man, many studies have focussed on the facilitatory
influence of acute ethanol administration upon the activ-
ity of the hypothalamo-corticotropic axis. The transitory
pulse of ACTH release provoked by ethanol is accompa-
nied by an enhancement in hypothalamic gene expression
of CRF. Contrariwise, it was recently shown that repeti-
tive exposure to ethanol is characterized by a reversible
(restored upon withdrawal) depression in CRF production
in the hypothalamic paraventicular nucleus (Spencer and
McEwen, 1990; Madeira and Paula-Barbosa, 1999; Silva
et al., 2002). Extrapolating from these results, one may rea-
sonably conjecture that ethanol treatment (irrespective of
its duration) should have marked effects on corticolimbic
CRF-containing pathways and, underpinning this asser-
tion, CRF-deficient mice revealed excessive ingestion of
ethanol, apparently due to the blunting of its rewarding and
motor-stimulant properties (Olive et al., 2003) It is, thus,
likely that both endocrine and neuronal actions of CRF
contribute to the influence of ethanol upon anxious states,
an issue awaiting experimental confirmation by use of the
VCT and other paradigms.
Finally, the facilitation of 5-HT3 receptor function by et-
hanol via an increase of channel activation may also contr-
ibute to its influence upon anxious states (Yang et al., 2003).
Thus, though ethanol is considered here under the rubric
of GABAA receptors, it exemplifies the principle that mul-
tiple mechanisms are often involved in the (generally com-
plex) influence of specific drug classes upon anxious states.
2.3. GABAB receptors
2.3.1. Coupling and localization
In contrast to the rapid actions of GABA trans-
duced by ionotropic GABAA receptors, metabotropic, G
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
protein-coupled GABAB receptors are responsible for its
slower component of neuronal inhibition. Though they
modulate the activity of adenylyl cyclase, a suppression
of Ca2+ -conductance (P/Q and N-type voltage-dependent
calcium channels (VDCCs)) is implicated in the autorecep-
tor/heteroceptor actions of GABAB sites at GABAergic/
non-GABAergic classes of terminal, respectively (Section
13.1). In addition, engagement of K+ -channels (“GIRKs”)
underlies their postsynaptic, hyperpolarizing properties at
both soma and dendrites (Section 13.3) (Kaupmann et al.,
1997; Bowery and Enna, 2000; Billinton et al., 2001;
Bowery et al., 2002; Murakami et al., 2002).
Virtually all GABAB receptors are heterodimers of
two proteins termed GABAB1 and GABAB2 . Though
the GABAB1 subunit is primarily responsible for ligand
recognition, the GABAB2 component is essential for cell
surface insertion of the receptor and its appropriate func-
tional operation (Kuner et al., 1999; Bowery and Enna,
2000; Devi, 2001; Galvez et al., 2001; Bowery et al.,
2002; Kniazeff et al., 2002). Several splice variants of
GABAB1 and GABAB2 proteins are known. N-terminal
GABAB1␣ and GABAB1␤ isoforms of the former are the
most prominent, possibly predominating as post and presy-
naptic sites, respectively, in relationship to GABAergic
neurones in the hippocampus, though their neuronal local-
ization varies in a tissue-dependent fashion (Benke et al.,
1999; Billinton et al., 1999; Bischoff et al., 1999; Lu
et al., 1999; Margeta-Mitrovic et al., 1999; Ng et al., 2001;
Bowery et al., 2002). Despite the tendency of GABAB1 and
GABAB2 subunits to associate with alien proteins (see also
Section 18.2), no GABAB receptor “subtypes” as such are
currently accepted (Bowery and Enna, 2000).
GABAB receptors are broadly distributed throughout cor-
ticolimbic structures, and GABAB1␣ and GABAB1␤ proteins
show distinctive and complementary patterns of localization.
Both are enriched in the hippocampus, the hypothalamus and
the amygdala. On the other hand, GABAB1␤ sites predomi-
nate in the septum and nucleus accumbens, while GABAB1␣
sites are more conspicuously expressed in the PAG, mam-
millary bodies, LC and raphe nuclei (Benke et al., 1999;
Bischoff et al., 1999; Lu et al., 1999; Margeta-Mitrovic et al.,
1999; Liang et al., 2000). In line with their anatomical lo-
calization, the moderating influence of GABAB receptors
upon corticolimbic release of noradrenaline (NA) and gluta-
Table 6
Influence of GABAB receptor ligands upon behavior in the Vogel Conflict Test
Drug Class Species Route
(strain) (structure)
Baclofen GABAB agonist Rat (W) i.p.
Rat (W) i.p.
Rat (SD) i.p.
Mouse (ICR) s.c.
␦-Amino-valeric acid GABAB Ant Rat (SD) i.p.
Abbreviations—ICR: Swiss CD and IA: no significant change (inactive). For other abbreviations, see Table 2.
107
mate, as well as CRF, CCK and other neuropeptides, likely
participates in their control of anxious states (Bonanno and
Raiteri, 1994; Waldmeier et al., 1994; Tanaka et al., 2003).
Furthermore, the high density of GABAB sites in the dor-
sal and medial raphe nuclei suggests a role synergistic to
GABAA receptors in modulating the activity of serotonergic
pathways. However, in raphe nuclei, the presence of GABAB
sites on GABAergic interneurones themselves, as well as on
afferent terminals, should not be neglected. Consequently,
it would be simplistic to assume that all functional effects
of GABAB agonists introduced into raphe nuclei can be at-
tributed to a direct suppression of serotonergic transmission
(Wirtshafter et al., 1993; Tao et al., 1996; Abellan et al.,
2000; Wirtshafter and Sheppard, 2001; Adell et al., 2002;
Varga et al., 2002; Serrats et al., 2003).
2.3.2. Anxiolytic properties of GABAB receptor
agonists
Mice lacking GABAB receptors have not been reported
to display alterations in anxiety (Schuler et al., 2001) and,
rather surprisingly, the GABAB receptor agonist, baclofen,
has not invariably elicited anxiolytic actions in rodents,
though it blocks the anxiety elicited by stress, attenuates the
withdrawal syndrome provoked by discontinuation of BZP
administration, and was reported to decrease state anxiety
in alcohol-dependent patients (Andrews and File, 1993;
Sanders and Shekhar, 1995; Dalvi and Rodgers, 1996;
Addolorato et al., 2002). One possible explanation for the
variable influence of baclofen upon anxious states appeals
to its actions at GABAB autoreceptors. Thus, occasional re-
ports of anxiogenic actions of baclofen—and an isolated re-
port of anxiolytic properties of the antagonist, CGP35348—
may reflect an indirect, GABAB autoreceptor-mediated
suppression—enhancement—of GABA release onto post-
synaptic, anxiolytic GABAA receptors (Dalvi and Rodgers,
1996; Zarrindast et al., 2001). It is also conceivable that
(postsynaptic) anxiolytic GABAB receptors are saturated
under certain conditions of high stress, so agonists would
achieve little if any further stimulation. In any event, while
baclofen (like several other classes of putative anxiolytic
agent) was inactive in the mouse VCT, it generally elic-
its robust increases in punished responses in the rat VCT
(Table 6) (Ketelaars et al., 1988; Shephard et al., 1992;
Umezu, 1999).
Effect Active dose Maximum Reference
range (mg/kg) change (%)
IA 1.25–2.5 IA Ågmo et al. (1991)
+ 0.46 and 1.0 +185 Ketelaars et al. (1988)
+ 0.5–2.0 +190 Shephard et al. (1992)
IA 0.1–3.0 IA Umezu (1999)
IA >10 IA Shephard et al. (1992)
108 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
As discussed elsewhere in this article (Section 13.1.3),
GABApentin, which directly binds to ␣2␦ subunits of
VDCCs, displays pronounced anxiolytic actions. Activ-
ity at P/Q-type (␣2␦ , ␤1 , ␣1A ) and N-type (␣2␦ , ␤1 , ␣1B )
VDCCs controlling transmitter release can be indirectly
suppressed by engagement of presynaptic GABAB recep-
tors (Wu and Saggau, 1997; Bowery and Enna, 2000),
while activation of postsynaptic GABAB sites coupled
to GIRKs elicits neuronal hyperpolarization in the hip-
pocampus and other structures (Section 2.3.1). Intriguingly,
then, GABApentin was claimed to behave as an agonist
at cloned and postsynaptic (hippocampal) populations of
GABAB1␣ /GABAB2 heterodimers positively and nega-
tively coupled to GIRKs and VDCCs, respectively (Taylor
et al., 1998; Bertrand et al., 2001; Ng et al., 2001). This
action was postulated to be involved in its anti-epileptic
actions and, inasmuch as GABApentin did not affect
presynaptic GABAB1␤ /GABAB2 heterodimers, postsynaptic
GABAB1␣ /GABAB2 heterodimers might also be involved
in its anxiolytic properties (Ng et al., 2001; Patel et al.,
2001). However, the contention that GABApentin displays
agonist properties at GABAB receptors has been vigorously
challenged (Stringer and Lorenzo, 1999; Lanneau et al.,
2001; Bowery et al., 2002).
Irrespective of the potential role of GABAB receptors in
the anxiolytic actions of gabapentin, allosteric modulators
acting at the N-terminal of the GABAB2 protein were re-
cently disclosed. Such ligands may, by analogy to the ac-
tions of BZPs at GABAA receptors, provide a route towards
novel classes of anxiolytic agent (Pin et al., 2001; Urwyler
et al., 2001; Kerr et al., 2002).
3. Excitatory amino acids
3.1. Glutamatergic pathways
Glutamate, the major excitatory neurotransmitter in the
mammalian CNS, fulfils a virtually universal role in in-
formation transfer and synaptic plasticity. Prior to its exo-
cytotic release, it is loaded into vesicles by brain-specific,
Na+ -dependent “vesicular glutamate transporters”, of which
types I and II display complementary patterns of distribution
in the brain: both have a predeliction for vesicles forming
asymmetrical synapses, a hallmark of glutamatergic termi-
nals (Herzog et al., 2001; Varoqui et al., 2002). In light of
the omnipresence of glutamatergic pathways in corticolim-
bic regions, it is hardly surprising that they fulfil—in inter-
action with GABAergic and monoaminergic networks—a
plurality of roles in the emotional and cognitive response
to fear. Correspondingly, psychological stress and exposure
to aversive stimuli is characterized by a pronounced in-
crease in extracellular levels of glutamate derived, at least
partially, from neuronal sources (Lowy et al., 1993, 1995;
Moghaddam et al., 1994; Saulskaya and Marsden, 1995;
Karreman and Moghaddam, 1996; Timmerman et al.,
1999). Moreover, a perturbation of glutamatergic transmis-
sion is implicated in the affective and mnesic symptoms
of several neurological and psychiatric disorders, includ-
ing anxious states (Carlsson and Carlsson, 1990; Shors
et al., 1997; Schwendt and Jezová, 2000; Millan, 2002b;
Moghaddam, 2002). Extracellular pools of glutamate are
rapidly sequestered by at least five classes of transporter,
including the key glial subtypes, “EAAT1” and “EAAT2”.
These transporters play a vital role in the highly complex
pattern of communication amongst glutamatergic terminals
and astrocytes (Danbolt, 2001; Amara and Fontana, 2002;
Millan, 2002b; Nedergaard et al., 2002).
A fascinating new angle on the role of glutamate in
cerebral neurotransmission and—it may be deduced—
the control of anxious states was recently unveiled by
the discovery of a third vesicular glutamate transporter
in “non-glutamatergic” neurones, including VTA-derived
dopaminergic projections, raphe-localized serotonergic
fibers, striatal cholinergic interneurones and, quite extraor-
dinarily, a subset of hippocampal and cortical GABAergic
interneurones (Takamori et al., 2001; Fremeau et al., 2002;
Gras et al., 2002). By extrapolation from studies of types I
and II transporters, it may be inferred that glutamate can be
released from these pathways. Though this remains to be
formally proven, in line with this assertion, previous studies
have shown that glutamate is liberated by monoaminergic
neurones (Bezzi et al., 1998; Sulzer et al., 1998). An addi-
tional and distinctive feature of the type III transporter is its
localization in soma and dendrites (raising the possibility of
retrograde glutamatergic transmission), as well as in astro-
cytes, consistent with glial release of glutamate (Danbolt,
2001; Alger, 2002; Millan, 2002b).
Glutamate (together with other excitatory amino acids,
such as aspartate) exerts its actions via several classes of
ionotropic and metabotropic receptor. Though ligands at glu-
tamate transporters have to date attracted little attention,
drugs acting at ionotropic and metabotropic receptors have
been extensively examined in the VCT and other models of
potential anxiolytic activity.
3.2. NMDA receptors
3.2.1. Cooperative operation of NMDA recognition and
glycineB sites
Of the three classes of ionotropic receptor which mediate
glutamatergic transmission, cation-permeable, heteromeric
NMDA receptors are unique inasmuch as both glutamate
itself (or an alternative, excitatory amino acid) and a
“co-agonist”, glycine (or d-serine), are mandatory for their
operation. The NMDA receptor complex is a tetramer (or
pentamer) assembled from two NR1 subunits (of which
eight splice variants exist) and two (or three) NR2 subunits
(of which four members, A, B, C and D, are known) (Danysz
and Parsons, 1998; Ozawa et al., 1998; Dingledine et al.,
1999; Millan, 2002b). The precise subunit composition con-
fers specific properties upon NMDA receptors, including
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
kinetics, ligand recognition profiles, modulation and cerebral
distribution. NR1 and NR2 subunits are broadly-distributed
throughout the brain, including the cortex, amygdala and
hippocampus, wherein NR2B and, to a much lesser degree,
NR2C and NR2D subunits are also located (Danysz and
Parsons, 1998; Ozawa et al., 1998; Dingledine et al., 1999;
Millan et al., 2002). Incorporation of a more recently-dis-
covered and developmentally-regulated NR3A subunit, lo-
calized to adult hippocampus, cortex and PAG, suppresses
Ca2+ -permeability leading to a reduction in channel func-
tionality (Al-Hallaq et al., 2002; Millan, 2002b). (Their as-
sociation with NR1 sites only generates excitatory channels
sensitive to glycine (Chatterton et al., 2002)).
Glutamate and glycine (d-serine) act at the NMDA recog-
nition site and glycineB site, respectively, which are situated
on different subunits—NR2 and NR1, respectively (Danysz
and Parsons, 1998; Ozawa et al., 1998; Dingledine et al.,
1999; Mothet et al., 2000; De Miranda et al., 2002; Millan,
2002b). In addition to antagonists at NMDA recognition and
glycineB sites, agents acting within the cation-permeable
channel itself (“open channel blockers”) comprise poten-
tial anxiolytic agents. Furthermore, degradation of trypto-
phan by the “kynurenine pathway” generates the NMDA
recognition site agonist, quinolinic acid, and the antago-
nist, kynurenic acid. Drugs targeting enzymes of this path-
way also represent potential therapeutic agents (Stone, 2001;
Millan, 2002b; Schwarcz and Pellicciari, 2002; Stone and
Darlington, 2002).
In addition to their high density throughout corticol-
imbic structures, interest in the role of NMDA/glycineB
receptors in the control of anxious states is encouraged by
numerous observations including: (1) the role of NMDA re-
ceptors in the amygdala—in association with metabotropic
receptors (Section 3.5.2)—in cognitive processes underly-
ing fear-conditioning, a paradigm highly pertinent to the
VCT (Tang et al., 1999; Walker and Davis, 2000; Bauer
et al., 2002); (2) the pronounced, modulatory influence
of NMDA receptors upon the activity of monoaminergic
pathways (Takahata and Moghaddam, 1998; Morrow et al.,
2000; Babar et al., 2001; Del Arco and Mora, 2001; Adell
et al., 2002; Millan, 2002b); (3) the facilitatory influence
of NMDA receptors upon limbic release of the anxiogenic
(Section 9.1.2) neuropeptide, CRF (Cratty and Birkle,
1999); (4) similarities in the behavioral effects of NMDA
receptor antagonists and GABAergic agonists (Willetts
et al., 1990) and (5) evidence for reciprocal, short and
long-term functional interactions amongst NMDA receptors
and BZPs in the modulation of anxious states (Sharma and
Kulkarni, 1993; Smith and Dudek, 1996; De Souza et al.,
1998; Przegaliński et al., 2000; Allison and Pratt, 2003).
3.2.2. Anxiolytic actions of NMDA recognition site
antagonists and open channel blockers
Unlike certain other drug classes, conflict paradigms have
been privileged in the characterization of potential anxiolytic
properties of agents which interrupt transmission at NMDA
109
receptors. Studies effected in rats and in pigeons have gen-
erally revealed anxiolytic profiles of recognition site antag-
onists, though open channel blockers are less consistently
active, and primates have proven relatively irresponsive to
both these classes of NMDA receptor antagonist (Bennett
and Amrick, 1986; Dunn et al., 1989; Corbett and Dunn,
1991, 1993; Koek and Colpaert, 1991; Willetts et al., 1991,
1993; Wiley et al., 1992, 1998; Wiley and Balster, 1992; Xu
and Commissaris, 1992). Microinjection studies have pro-
vided evidence that NMDA receptors located in the PAG
and the hippocampus are involved in the anxiolytic actions
of recognition site antagonists and open channel blockers
in the VCT, though other structures such as the nucleus ac-
cumbens and amygdala are also implicated (Table 7 and
Fig. 3) (Bennett and Amrick, 1986; Falls et al., 1992; Plaznik
et al., 1994a; Jessa et al., 1995, 1996b; Przegaliński et al.,
1996; Sajdyk and Shekhar, 1997; Menard and Treit, 2000;
Carobrez et al., 2001; Martinez et al., 2002; Molchanov and
Guimarães, 2002; Pilc et al., 2002a). Though few studies of
long-term administration have been performed, anxiolytic
actions of recognition site antagonists and, probably, open
channel blockers are maintained in the VCT and other con-
flict procedures upon chronic administration (Wiley et al.,
1992; Xie et al., 1995a; Jessa et al., 1996a).
Anxiolytic actions of NMDA receptor antagonists in con-
flict tests are expressed independently of their analgesic
properties and several studies have emphasized the speci-
ficity of their actions in the VCT (Plaznik et al., 1994b,c;
Przegaliński et al., 1996; Molchanov and Guimarães, 2002;
Pilc et al., 2002a). Investigations employing other conflict
procedures underline the discrete influence of NMDA re-
ceptor antagonists upon punished responses as compared to
other behaviors (Plaznik et al., 1994b,c; Jessa et al., 1995,
1996b; Przegaliński et al., 1996; Danysz and Parsons, 1998;
Wiley et al., 1998; Pilc et al., 2002a). Nevertheless, the
therapeutic margin of recognition site antagonists and, in
particular, open channel blockers, for expression of their
anxiolytic versus undesirable actions (perturbation of motor
performance, psychiatric side-effects, etc.) is unimpressive
(Plaznik et al., 1994c; Jessa et al., 1996b; Przegaliński et al.,
1996; Danysz and Parsons, 1998; Wiley et al., 1998; Krystal
et al., 1999; Millan, 2002b; Pilc et al., 2002a). Much interest
has, thus, been directed towards the hypothesis that drugs
(partial agonists and antagonists) acting at the glycineB site
may behave as anxiolytic agents with a superior therapeutic
window.
3.2.3. GlycineB site ligands
3.2.3.1. Anxiolytic profiles. In fact, conflict procedures
and other paradigms have yielded a rather ambivalent
body of data concerning the potential anxiolytic properties
of partial agonists, such as aminocyclopropyl carboxylic
acid (ACPC) and d-cycloserine, at glycineB sites. Overall,
however, it appears that they express modest anxiolytic ef-
fects in the virtual absence of a generalized disruption of
110 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Table 7
Influence of ligands acting at ionotropic glutamatergic receptors upon behavior in the Vogel Conflict Test
Drug Class Species Route (structure) Effect Active dose range Maximum Reference
(strain) change (%)
AP-7 NMDA (RS Ant) Rat (W) i.c.v. + 0.5 ␮g +94 Plaznik et al. (1994c)
Rat (W) i.c. (PAG) + 0.4 ␮g +60 Molchanov and Guimarães
(2002)
Rat (W) i.c. (hippocampus) + 0.5 ␮g +460 Jessa et al. (1995)
CGP37849 NMDA (RS Ant) Rat (W) i.p. + 1.25–5.0 mg/kg +171 Przegaliński et al. (1996)
Rat (W) i.p. + 2.5 mg/kg +220 Jessa et al. (1996a)
Rat (W) i.p. + 1.0 and 2.5 mg/kg +165 Plaznik et al. (1994c)
Rat (W) i.c. (hippocampus) IA 0.01–1.0 ␮g IA Przegaliński et al. (1996)
CGP39551 NMDA (RS Ant) Rat (W) i.p. + 5 and 20 mg/kg +100 Plaznik et al. (1994c)
Dizocilpine NMDA (OCB) Rat (W) i.p. + 0.0025 mg/kg +320 Jessa et al. (1996a)
Rat (W) i.p. + 0.005 and 0.01 mg/kg +450 Plaznik et al. (1994c)
Rat (W) i.c. (hippocampus) + 0.1 and 1.0 ␮g +110 Jessa et al. (1995)
Glycine Glycine B agonist Rat (W) i.p. IA >800 mg/kg IA Chojnacka-Wójcik et al.
(1996a)
ACPC Glycine B (PAGO) Rat (W) i.p. + 200 mg/kg +200 Przegaliński et al. (1996)
Rat (W) i.p. + 200 mg/kg +260 Chojnacka-Wójcik et al.
(1996a)
Rat (W) i.c. (hippocampus) + 3–30 ␮g +302 Przegaliński et al. (1996)
d-Cycloserine Glycine B (PAGO) Rat (W) i.p. + 200 and 300 mg/kg +337 Klodzińska and
Chojnacka-Wójcik (2000)
5,7-Dichloro- Glycine B Ant Rat (W) i.c.v. + 5 ␮g +104 Plaznik et al. (1994c)
kynurenate
L701,324 Glycine B Ant Rat (SD) i.p. IA 0.1–10 mg/kg IA Karcz-Kubiscka et al. (1997)
MRZ 21576 Glycine B Ant Rat (SD) i.p. IA 2.5–10 mg/kg IA Karcz-Kubiscka et al. (1997)

CNQX AMPA Ant Rat (W) i.p. IA 0.05–5 mg/kg IA Czlonkowska et al. (1997)
NBQX AMPA Ant Rat (W) i.p. IA 0.1–5 mg/kg IA Czlonkowska et al. (1997)
LY326,325 AMPA Ant Rat (SD) i.p. + 2.5–5.0 mg/kg +100 Kotlinska and Liljequist (1998b)
Piracetam AMPA positive Rat (W) p.o. + 500 mg/kg per day +95 Bhattacharyya et al. (1996)
modulator (14 days)
Abbreviations—AP-7: DL-2-amino-7-phosphonoheptanoic acid; ACPC: 1-aminocyclopropanecarboxylic acid; CNQX: 6-cyano-7-nitroquinoxaline-2,3-
dione; NBQX: 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-quinoxaline; RS: recognition site; OCB: open channel blocker; PAGO: partial agonist; PAG:
periaqueductal gray and IA: no significant change (inactive). For other abbreviations, see Table 2.

behavior (Corbett and Dunn, 1991, 1993; Koek and Colpaert,
1991; Trullas et al., 1991; Dunn et al., 1992; Anthony
and Nevins, 1993; Danysz and Parsons, 1998; Dunn et al.,
1998; Wiley et al., 1998). Correspondingly, selective anx-
iolytic effects of glycineB ligands have been documented
for the VCT at doses which do not markedly modify motor
function, nociception or other relevant parameters (Table 7)
(Chojnacka-Wójcik et al., 1996a; Przegaliński et al., 1996;
Klodzińska and Chojnacka-Wójcik, 2000). Of special note
is the observation that anxiolytic actions of glycineB partial
agonists persist following their prolonged administration,
in line with findings in other models (Skolnick et al., 1992;
Przegaliński et al., 1999). Likewise in accordance with re-
sults acquired with recognition site antagonists and open
channel blockers (Section 3.2.2), it has been shown that
glycineB sites in the hippocampus participate in the anxi-
olytic actions of the partial agonist, ACPC, in the VCT, while
observations with other paradigms suggest a prominent role
for glycineB sites in the PAG (Table 7 and Fig. 3) (Matheus
et al., 1994; Przegaliński et al., 1996; De Souza et al., 1998).
3.2.3.2. Significance of antagonist properties at glycineB
sites. It is necessary to address the question of whether the
anxiolytic actions of glycineB partial agonists reflect rein-
forcement or suppression of transmission at NMDA recep-
tors. Several arguments lend credence to the latter possibil-
ity.
First, though there are circumstances under which spe-
cific populations of glycineB sites are not saturated, their
degree of occupation by endogenous ligands in vivo is
pronounced. It is likely to be particularly high under con-
ditions of stress owing to the enhanced availability of
glycine and d-serine, both of which behave as full ago-
nists (Danysz and Parsons, 1998; Dingledine et al., 1999;
Millan, 2002b). The higher the concentration of these
endogenous ligand(s) at glycineB sites, the greater the
likelihood that exogenous partial agonists will act as an-
tagonists in opposing their actions. Second, the relatively
high doses of d-cycloserine and ACPC required for anx-
iolytic actions in the VCT and other models are com-
mensurate with those exerting antagonist actions in other
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
functional paradigms (Millan, 2002b; Danysz and Parsons,
1998). Third, glycine itself and NMDA (upon systemic or
intracerebral administration) do not elicit anxiolytic proper-
ties in the VCT and other procedures (Table 7) (Anthony and
Nevins, 1993; Schmitt et al., 1995; Chojnacka-Wójcik et al.,
1996a; De Souza et al., 1998). Moreover, glycine and/or
NMDA have been reported to interfere with the anxiolytic
actions of ACPC and d-cycloserine (Chojnacka-Wójcik
et al., 1996a; Teixeira and Carobrez, 1999; Klodzińska
and Chojnacka-Wójcik, 2000). Fourth, paralleling the ac-
tions of glycineB partial agonists, recognition site antag-
onists and open channel blockers, in the VCT, anxiolytic
effects have been documented upon i.c.v. administra-
tion of the poorly brain-penetrant glycineB antagonist,
5,7-dichlorokynurenate, and of the systemically-active, po-
tent and selective antagonist, L701,324 (Table 7) (Kotlinska
and Liljequist, 1998a). Curiously, and possibly reflect-
ing procedural variables, (Karcz-Kubicka et al., 1997)
failed to demonstrate anxiolytic actions of L701,324 or a
further antagonist, MRZ 21576, in the VCT, suggesting
the need for further studies of pure antagonists in this
paradigm (Table 7). Nevertheless, 5,7-dichlorokynurenate
and the chemically-distinct glycineB receptor antagonists,
(+)HA-966 (a pyrrolidinone derivative) and ACEA-1021
(a quinoxalinedione derivative), have proven active in a
variety of models of anxiolytic properties, including other
conflict procedures (Corbett and Dunn, 1991, 1993; Kehne
et al., 1991; Dunn et al., 1992; Anthony and Nevins, 1993;
Wiley et al., 1995; Baron et al., 1997; Carobrez et al.,
2001; Pilc et al., 2002a). Microinjection studies indicate
(in line with observations mentioned in Section 3.2.3.1)
that at least one locus of action is the PAG (Matheus
et al., 1994). A fifth and final argument supporting the
notion that a decrease in activity at glycineB sites is as-
sociated with anxiolytic properties is provided by the
finding that mice with genetically-disturbed function at
glycineB receptors show a reduction in anxiety (Kew et al.,
2000).
Despite these arguments, it still remains to be convinc-
ingly demonstrated that glycineB antagonists do, indeed,
elicit robust, clinically-relevant anxiolytic actions with a suf-
ficiently wide margin relative to doses provoking undesir-
able actions (Pilc et al., 2002b).
3.2.4. Interaction with BZPs
As mentioned above (Section 3.2.1), there is functional
evidence for short-term and long-term interactions between
glutamatergic and GABAergic systems in the control of
anxious states. In line with such observations, the BZP antag-
onist, flumazenil, attenuated anxiolytic actions of the recog-
nition site antagonist, CGP37849, and of the glycineB partial
agonist, ACPC, in the VCT and other procedures (Kuribara
et al., 1990; Sharma and Kulkarni, 1993; Klodzińska and
Chojnacka-Wójcik, 2000; Przegaliński et al., 2000). The pre-
cise substrates and mechanisms underlying such interactions
remain to be ascertained.
111
3.2.5. Modulatory sites on NR2B subunits: ifenprodil
As mentioned above (Section 3.2.1), NMDA receptors
containing NR2B subunits are concentrated in corticolim-
bic structures of the forebrain. This raises the possibility
that, by analogy to glycineB ligands, an alternative route
towards anxiolytic agents with improved separation of
beneficial properties to side-effects might be obtained by
selectively targeting NR2B subunits (Danysz and Parsons,
1998; Dingledine et al., 1999; Chizh et al., 2001; Millan,
2002b; Loftis and Janowsky, 2003). The neuroleptic,
haloperidol (Section 4.5) has high affinity for NR2B sites
and the phenylethanolamine, ifenprodil, has long been
known to preferentially interact with this subunit. Though
its actions at ␣1 -ARs, sigma1 receptors and other sites
compromise its utility as a pharmacological tool, several
highly-selective agents for NR2B subunits have now been
described (Williams, 1993, 2001; Chizh et al., 2001; Millan,
2002b; Higgins et al., 2003; Loftis and Janowsky, 2003).
In comparison to subunit non-selective antagonists, these
chemically-diverse NR2B subunit-selective antagonists
show an improved therapeutic window between doses ex-
erting, for example, analgesic actions (reflecting blockade
of NR2B sites in the dorsal horn as well as the forebrain)
as compared to motor disruption and psychomimetic prop-
erties (Millan, 1999; Chizh et al., 2001; Narita et al., 2001;
Higgins et al., 2003; Loftis and Janowsky, 2003).
Long-term administration of BZPs modulates the corti-
colimbic density of NR2B sites (Van Sickle et al., 2002).
Further, it appears that they are involved in the acceleration
of cortical 5-HT release by NMDA receptors (Fink et al.,
1995), though they may not contribute to the induction of
mesolimbic DA release by stress (Serrano et al., 1989).
Hippocampal populations of NR2B receptors have been
implicated in the control of cognitive function under fear
conditioning Tang et al. (2001) and they contribute to the
anxious behavior which accompanies withdrawal from
chronic alcohol administration (Stork et al., 2002b). How-
ever, ifenprodil was, in contrast to competitive NMDA
receptor antagonists, ineffective in a pigeon conflict proce-
dure (Koek and Colpaert, 1991) and in a rat Geiler–Seifter
paradigm (Wiley et al., 1998). Further, it did not display a
coherent pattern of specific anxiolytic actions in a murine
open-field procedure (Fraser et al., 1996; Pilc et al., 2002b).
It will, thus, be of importance to characterize the influence
of novel, highly-selective NR2B antagonists in the VCT
and other paradigms to establish whether such agents in-
deed promise to be anxiolytic agents of improved tolerance
relative to drugs which indiscriminately interact with all
isoforms of NR2B subunits.
3.3. AMPA receptors
Ionotropic, heteromeric, cation-permeable AMPA recep-
tors are composed of four subunits (GluR1–4), of which
their “flop” as compared to their alternatively-spliced
“flip” isoforms predominate in adult CNS (Sommer
112 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
et al., 1990; Bleakman and Lodge, 1998). The pre-
cise composition of AMPA receptor subunits determines
their Ca2+ -permeability and other biophysical proper-
ties. In addition to the recognition site for glutamate,
AMPA receptors bear multiple allosteric site(s) responsive
to chemically-diverse positive and negative modulators
(Hollmann and Heinemann, 1994; Miu et al., 2001; Arai
et al., 2002; Quirk and Nisenbaum, 2002; Ruel et al.,
2002). These sites control the kinetics of desensitization
and (following removal of AMPA) deactivation.
AMPA receptors play a ubiquitous role in the CNS in me-
diating fast excitatory transmission. In line with a role in
the control of anxious states, AMPA receptors have been vi-
sualized in high concentrations in monoaminergic cell clus-
ters, and in the PAG, amygdala, septum and hippocampus
(Ozawa et al., 1998; Lees, 2000). Acute and prolonged stress
(including social stress) have been shown to elicit both im-
mediate and more sustained (delayed) alterations in AMPA
receptor expression in the hippocampus and cortex, though
no consensus has as yet been reached as concerns the precise
nature of these changes. Indeed, there appears to be a com-
plex pattern of alterations in individual subunits and their
flip–flop isoforms, with an increase in the relative propor-
tion of the former suggestive of enhanced permeability to
calcium (Krugers et al., 1993; Bartanusz et al., 1995; Geiger
et al., 1995; Schwendt and Jezová, 2000; Rosa et al., 2002).
If corroborated, this finding would be of importance since
excessive stimulation of AMPA receptors is implicated in
the ultrastructural, molecular and other detrimental changes
associated with long-term exposure to stress (Magarinos and
McEwen, 1995; Rosa et al., 2002). It is possible that corti-
costeroids, which are likewise incriminated in these events,
contribute to the recruitment of AMPA receptors: further,
they may exert their deleterious actions cooperatively with
those of glutamate at AMPA sites (Section 11) (Magarinos
and McEwen, 1995).
The above observations provide a framework for partic-
ipation of AMPA receptors in the emotional and cognitive
changes elicited by fear and stress. Though remarkably few
studies have addressed this question, activation of AMPA re-
ceptors is involved in the induction of dependence to BZPs,
as well as the rebound anxiety and other symptoms pro-
voked by their abrupt withdrawal (Steppuhn and Turski,
1993; Jackson et al., 2000; Izzo et al., 2001; Van Sickle
and Tietz, 2002). In line with these findings, Kotlinska and
Liljequist (1998b) reported a significant increase in punished
response in the VCT with the highly-selective antagonist,
LY326,325, at doses which failed to modify locomotor func-
tion or to elicit other non-specific actions (Table 7). Paradox-
ically, then, Czlonkowska et al. (1997) failed to demonstrate
anxiolytic actions of the first generation antagonist, NBQX,
in a VCT, but the conditions of study may not have been
optimal for their detection (Table 7). Indeed, anxiolytic ac-
tions of these and chemically-distinct AMPA antagonists in
conflict (and other) procedures in mice and pigeons under-
pin the utility of the VCT for evaluation of their anxiolytic
potential (Turski et al., 1992; Kim et al., 1993; Benvenga
et al., 1995; Tizzano, 2002).
Corticolimbic regions responsible for integrating the
anxiolytic actions of AMPA antagonists remain to be defini-
tively identified, but the hippocampus, PAG, septum and
amygdala are likely candidates (Kim et al., 1993; Matheus
and Guimaraes, 1997; Sajdyk and Shekhar, 1997; Menard
and Treit, 2000; Martinez et al., 2002). The precise neuronal
substrates subserving the anxiolytic properties of AMPA
receptor antagonists also remain to be delineated. How-
ever, congruent with anatomical findings evoked above,
together with a suppression of the stress-induced activation
of raphe-derived serotonergic projections, VTA-derived
dopaminergic neurones and LC-derived noradrenergic
pathways, a (postsynaptic?) reinforcement of GABAergic
transmission in limbic structures is probably of signifi-
cance (Jedema and Moghaddam, 1996; Rasmussen et al.,
1996; Fedele et al., 1997; Tao et al., 1997; Adell et al.,
2002; Wu et al., 2002).
In light of the above observations, it is curious that the
potential anxiolytic actions of negative modulators at al-
losteric sites on AMPA receptors do not appear to have been
described. On the other hand, it has been reported that the
pyrrolidinone derivative and positive modulator, piracetam,
possesses anxiolytic properties in the VCT and certain
other paradigms (Table 7) (File et al., 1979; Bhattacharyya
et al., 1996, 1993) while the chemically-related anirac-
etam revealed anxiolytic properties in mice (Nakamura and
Kurasawa, 2001). Since there is no obvious mechanistic
interpretation for these observations, they would merit sub-
stantiation (or refutation) with other classes (benzamide and
benzodiathiazine) of more selective, positive modulators at
AMPA receptors (Arai et al., 2002; Quirk and Nisenbaum,
2002).
3.4. Kainate receptors
Ionotropic, neuronal kainate receptors are, like their
AMPA counterparts, composed of various combinations of
subunits (KA-1, KA-2 and GluR5–7). GluR5–7 subunits
can assemble into functional homo- and heteromeric re-
ceptors, but KA-1 and KA-2 cannot and appear to confer
specific pharmacological properties upon associations of
GluR5–7 subunits (Bleakman, 1999; Dingledine et al., 1999;
Lerma et al., 2001; Swanson et al., 2002). Though gating
properties of kainate receptors differ from those of AMPA
receptors, structure-activity relationships for glutamatergic
ligands have proven similar. This has complicated the dis-
covery of selective agents permitting dissociation of their
functional roles (Bleakman, 1999; Dingledine et al., 1999).
Moreover, though novel drugs interacting selectively at
kainate subunits, such as the GluR5 antagonist, LY382,884,
have recently been disclosed, data concerning their actions
in the VCT or other models of anxiolytic activity are not,
as yet, available (Conti et al., 2002). Such studies would be
of considerable interest in light of: (1) the above-discussed
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
roles of AMPA and NMDA receptors in the control of
anxious states; (2) evidence for functionally-active, post-
and presynaptic (on glutamatergic fibers) kainate receptors
in the hippocampus and amygdala and (3) a complex pat-
tern of influence of kainate receptors upon corticolimbic
GABAergic and monoaminergic transmission (Bleakman,
1999; Kathmann et al., 1999; Frerking and Nicoll, 2000;
Van Bockstaele, 2000; Lerma et al., 2001; Szabo and Blier,
2001; Braga et al., 2003; Ghersi et al., 2003).
3.5. Metabotropic receptors
3.5.1. Multiple classes of functionally-heterogeneous
metabotropic receptor
Metabotropic (mGlu) receptors are functional homod-
imers (Kunishima et al., 2000) which can be divided into
three classes. Group I (mGluR1 and 5) receptors are posi-
tively coupled via Gq to phospholipase C. Their activation
promotes the activity of colocalized NMDA receptors via
are a complex interplay of mechanisms ultimately involv-
ing (for GluR5 receptors) their protein kinase C-mediated
tyrosine phosphorylation. In contrast, group II (mGluR2
and mGluR3) and group III (mGluR4 and mGluR6–8)
receptors are negatively coupled via Gi/o to adenylyl cy-
clase (Conn and Pin, 1997; Bordi and Ugolini, 1999; Pin
et al., 1999, 2001; Schoepp et al., 1999; Bräuner-Osborne
et al., 2000; Schoepp, 2001; Benquet et al., 2002). Inas-
much as inhibitory classes II and III receptors are localized
both pre- and postsynaptically with respect to glutamater-
gic pathways, agonists at these sites functionally counter
actions mediated by excitatory postsynaptic, ionotropic re-
ceptors both directly and indirectly—by suppressing the
(stress-induced) release of glutamate. On the other hand,
antagonists at excitatory group I receptors postsynaptic
and (possibly) presynaptic to glutamatergic pathways may
likewise oppose actions elicited by their ionotropic coun-
terparts (Karreman and Moghaddam, 1996; Stefani et al.,
1998b; Cartmell and Schoepp, 2000; Thomas et al., 2001;
Corti et al., 2002; Xi et al., 2002; De Novellis et al., 2003).
All three classes of metabotropic receptor are enriched in
the hippocampus (Pin and Duvoisin, 1995; Blumcke et al.,
1996; Shigemoto et al., 1997; Pin et al., 1999, 2001). Further
group I mGluR5 receptors, as well as group II mGluR2 and 3
receptors, are well-represented in the cortex, nucleus accum-
bens and amygdala (Fotuhi et al., 1994; Bordi and Ugolini,
1999; Spooren et al., 2001; Schoepp and Marek, 2002). Of
particular note, engagement of group II mGluR receptors
attenuates the anxiety-associated activation of LC-derived
noradrenergic neurones and blunts the induction of corti-
cal release of NA by stress (Vandergriff and Rasmussen,
1999; Schoepp, 2001; Schoepp and Marek, 2002). On the
other hand, though conflicting data have been documented,
a majority of studies suggest that group II mGluR receptors
moderate hippocampal release of GABA, an action incon-
sistent with the expression of anxiolytic properties (Cartmell
and Schoepp, 2000; Ferris et al., 2001; Schoepp and Marek,
113
2002). Correspondingly, while the influence of group II
mGluR receptors upon 5-HT release in the hippocampus
and amygdala remains to be described, their induction of
5-HT release in the FCX may reflect a disinhibitory action
effected via a reduction in tonic, GABAergic tone (Lee and
Croucher, 2003). The induction of 5-HT release by group
II/III mGluR agonists in the PAG may likewise reflect re-
lief of GABAergic inhibition of serotonergic neurones, and
this action may be related to their suppression of uncon-
ditioned, aversive (panic-like) states (Sections 1.5.3.2 and
4.3.4.4) (Graeff et al., 1993; Maione et al., 1998; Cartmell
and Schoepp, 2000). In contrast to group II mGluR recep-
tors, no evidence has, as yet, been forwarded for a role of
group I mGluR receptors in the modulation of 5-HT re-
lease (Maione et al., 1998; Lee and Croucher, 2003), though
their facilitatory influence upon GABA and glutamate re-
lease likely affects anxious states (De Novellis et al., 2003).
Finally, the suppressive influence of group II mGluR re-
ceptors upon hippocampal release of CCK (Section 9.1.1)
(Breukel et al., 1998; Hu et al., 1999) is consistent with anx-
iolytic actions in behavioral models (Section 3.5.2.1).
3.5.2. Anxiolytic profiles of ligands at metabotropic
mGluR receptors
3.5.2.1. Group II/III mGluR agonists. The preceding re-
marks provide a framework for observations that group II/III
mGluR agonists display, like NMDA and AMPA antago-
nists (Sections 3.2.2 and 3.3, respectively), anxiolytic prop-
erties in conflict and other models (Chojnacka-Wójcik et al.,
1996a,b; Helton et al., 1998; Benvenga et al., 1999; Sporeen
et al., 2000; Tatarczyńska et al., 2001b; Collado et al., 2002;
Tizzano et al., 2002) including a paradigm of panic-like be-
havior (Shekhar and Keim, 2002). In exerting its anxiolytic
actions, the group II (mGluR2/3) agonist, LY354,740, ap-
pears to interrupt glutamatergic transmission in the amyg-
dala via pre- and postsynaptic actions—and to act without
modifying cognitive performance (Stanek et al., 2000;
Tizzano et al., 2002). LY354,740 is active in the rat VCT
both upon systemic administration and (in analogy to ag-
onists which fail to penetrate the blood-brain barrier) upon
introduction into the CA1 region of the dorsal hippocampus
(Table 8 and Fig. 3) (Tatarczyńska et al., 2001b). Though the
amygdala has not to date been examined by use of the VCT,
this structure represents a substrate for anxiolytic properties
of group II agonists in a fear-potentiated startle paradigm
(Walker et al., 2002). A group III mGluR agonist, “l-SOP”,
was likewise active in a rat VCT upon injection into the hip-
pocampus, but this result would benefit from corroboration
with more selective ligands inasmuch as a further serine ana-
logue which behaves as an antagonist at group III mGluR
sites, MSOP, likewise showed anxiolytic properties (Table 8
and Fig. 3) (Chojnacka-Wójcik et al., 1997; Tatarczyńska
et al., 2001b). It is currently controversial as to whether
GABAergic mechanisms participate in the expression of
anxiolytic actions of group II and III mGluR agonists (Ferris
114 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Table 8
Influence of ligands acting at metabotropic glutamatergic receptors upon behavior in the Vogel Conflict Test
Drug Class Species Route (structure) Effect Active dose range Maximum Reference
(strain) change (%)
(S)-4C3HPG mGluRI Ant Rat (W) i.c. (hippocampus) + 6.5 ␮g +225 Chojnacka-Wójcik et al. (1997)
mGluRII agonist
MPEP mGluRI Ant Rat (W) i.p. + 1 and 10 mg/kg +460 Tatarczynska et al. (2001a)
(S)-4CPG mGluRI Ant Rat (W) i.c. (hippocampus) + 20 ␮g +257 Tatarczynska et al. (2001b)
CPCCOEE mGluRI Ant Rat (W) i.c. (hippocampus) + 5 and 15 ␮g +264 Tatarczynska et al. (2001b)
LY354,740 mGluRII agonist Rat (W) i.p. + 0.5 and 1.0 mg/kg +200 Klodzińska et al. (1999)
Rat (W) i.c. (hippocampus) + 1 ␮g +230 Tatarczynska et al. (2001b)
l-CCG-1 mGluRII agonist Rat (W) i.c. (hippocampus) + 10 ␮g +242 Tatarczynska et al. (2001b)
MSOPPE mGluRII Ant Rat (W) i.c. (hippocampus) IA 2.5 and 6.5 ␮g IA Chojnacka-Wójcik et al. (1997)
l-SOP mGluRIII agonist Rat (W) i.c. (hippocampus) + 100 ␮g +164 Tatarczynska et al. (2001b)
MSOP mGluRIII Ant Rat (W) i.c. (hippocampus) + 6.5 ␮g +125 Chojnacka-Wójcik et al. (1997)
Abbreviations—(S)-4C3HPG: (S)-4-carboxy-3-hydroxyphenylglycine; MPEP: 2-methyl-6-(phenylethynyl)pyridine; (S)-4CPG: (S)-4-carboxyphenylglycine;
CPCCOEE: 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester; l-CCG-1: (2S,1 S,2 S)-2-(carboxycyclopropyl)glycine; l-SOP:
l-serine-O-phosphate; MSOP: (RS)-␣-methylserine-O-phosphate; and mGluRI-III: groups I, II and III metabotropic receptor, respectively. For other
abbreviations, see Table 2.

et al., 2001; Schoepp and Marek, 2002; Tizzano et al.,
2002).
3.5.2.2. Group I mGluR antagonists. As concerns
group I mGluR antagonists, parenteral administration of
2-methyl-6-(phenylethynyl)pyridine—a selective (non-com-
petitive) mGluR5 antagonist—or intrahippocampal appli-
cation of other (lipophobic) antagonists, elicited anxiolytic
actions in the VCT as well as other conflict and non-conflict
procedures (Table 8 and Fig. 3) (Chojnacka-Wójcik et al.,
1996b; Klodzińska et al., 1999, 2000; Spooren et al., 2000,
2001; Schulz et al., 2001; Tatarczyńska et al., 2001a,b;
Brodkin et al., 2002; Pilc et al., 2002a,b; Schulz et al.,
2002). For these drugs, anxiolytic actions were seen both
upon acute and upon chronic administration (Pilc et al.,
2002a,b) and were expressed at doses which did not perturb
cognitive function, motor performance or drinking behavior
(op. cit.). These results indicate that blockade of mGluR5
receptors is associated with anxiolytic properties, mimick-
ing the above-discussed anxiolytic properties of NMDA
receptor antagonists in the VCT (Section 3.2.2). Though
postsynaptic mGluR5 sites principally mediate these effects,
blockade of presynaptic populations excitatory to glutamate
release may also be involved (Thomas et al., 2000, 2001).
This parallel between group I mGluR metabotropic and
NMDA receptor antagonists is notable in light of the co-joint
role of postsynaptic NMDA and mGluR5 receptors in medi-
ating neuronal excitation. Moreover, together with NMDA
receptors, mGluR5 receptors are required for the acquisi-
tion of fear-conditioning and long-term potentiation in the
amygdala and, perhaps, the hippocampus, structures impli-
cated in glutamatergic mechanisms for the control of anxiety
(Alagarsamy et al., 1999; Anwyl, 1999; Schulz et al., 2001,
2002; Fendt and Schmid, 2002; Rodrigues et al., 2002).
This common role of metabotropic (mGluR5) and ionotropic
(NMDA) receptors in synaptic plasticity under conditions
of stress suggests, moreover, that their role in the modula-
tion of anxious states is not confined to short-term events:
rather, they may also be involved in more sustained alter-
ations in emotionality and cognition of pertinence to clinical
anxiety disorders (Riedel et al., 1996, 2002; Schoepp et al.,
1999). Though anxiolytic actions of mGluR5 antagonists in
the VCT and other models do not appear to reflect an in-
fluence upon mnesic function, these observations also serve
to emphasize the fundamental notion that specific classes of
modulator (receptor) may be involved in diverse aspects of
the response to stress and fear (Section 18.8).
3.6. Multiple glutamatergic mechanisms for anxiolysis
It appears, then, that several receptorial approaches for
the attenuation of excessive glutamatergic transmission
may—by analogy to multiple strategies for enhancement
of GABAergic transmission—be associated with anxiolytic
properties in the VCT and other conflict procedures. How-
ever, data for glutamatergic agents require consolidation
with highly selective ligands (in particular, for subtypes of
metabotropic receptor), the precise neuronal mechanisms via
which glutamatergic pathways control anxious states await
clarification, and the genuine therapeutic utility of glutama-
tergic drugs remains to be established (Kinsey et al., 2001).
4. Monoamines
4.1. Noradrenaline
4.1.1. Noradrenergic pathways
Ascending noradrenergic projections heavily innervate the
hippocampus, amygdala, PAG, cortex, hypothalamus and
essentially all corticolimbic regions involved in integrat-
ing the response to anxiety Lindvall and Björklund, 1984;
Aston-Jones et al., 1991; Valentino and Aston-Jones, 1995;
Schatzberg and Schildkraut, 1995; Tanaka et al., 2000. A
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
substantial proportion of this input derives from the LC
(Lindvall and Björklund, 1984; Aston-Jones et al., 1991;
Valentino and Aston-Jones, 1995). The marked and sus-
tained activation of noradrenergic pathways arising in this
cell cluster by a confluence of anxiogenic and other stress-
ful stimuli (Bremner et al., 1996a,b; McQuade et al., 1999;
Sands et al., 2000; Feenstra et al., 2001; Ishida et al., 2002;
McIntyre et al., 2002a) is accompanied by emotional, cog-
nitive and autonomic manifestations of fear (Tanaka et al.,
2000; Pardon et al., 2002; Schulz et al., 2002; Shekhar et al.,
2002), and may be of particular significance to the induction
of panic attacks (Uhde et al., 1984b; Gorman et al., 1989,
2000; Coupland et al., 1996; Sullivan et al., 1999; Shekhar
et al., 2002). Accordingly, in response to fear and other stres-
sors, an acceleration of NA release has been quantified in
several corticolimbic regions, including the FCX, amygdala
and hippocampus (op. cit.). As emphasized throughout this
article, then, the LC assimilates a vast number of conver-
gent and neurochemically-distinct inputs transducing the ef-
fects of, and controlling the response to, anxiogenic stimuli
(Aston-Jones et al., 1991; Kawahara et al., 2000; Singewald
and Sharp, 2000; Lapiz et al., 2001).
It is essential to consider the role of multiple classes of
␣1 -, ␣1 - and ␤-AR (Bylund et al., 1994; Hieble et al., 1995;
Hieble, 2000; Piascik and Perez, 2001; Audinot et al., 2002)
in the modulation of anxious states. ␣1A , ␣1B and ␣1D -AR
subtypes are positively coupled via Gq to phospholipase C,
the activation of which leads to an increase in intracellular
levels of Ca2+ : this excitatory influence is amplified by
their engagement of VDCCs. Contrariwise, the inhibitory
influence of ␣2A - (and its rodent homologue, ␣2D -), ␣2B -
and ␣2C -ARs upon neuronal activity reflects their positive
coupling via Gi to adenylyl cylase, their suppression of
the activity of VDCCs and their opening of K+ -channels
(Section 13). CNS-localized ␤1 - and ␤2 -ARs may be distin-
guished from ␣2 -ARs by their activation, via Gs, of adenylyl
cyclase.
4.1.2. α2 -AR agonists
␣2 -AR autoreceptors exert a tonic, inhibitory influence
upon the cerebral (and sympathetic) liberation of NA. Fur-
ther, stimulation of ␣2 -AR heteroceptors brakes the release
of 5-HT in corticolimbic structures: though it remains con-
troversial as to whether this control is exerted tonically or
phasically, the majority of evidence favors the latter pos-
sibility (Hein et al., 1999; Bengtsson et al., 2000; Kable
et al., 2000; Millan et al., 2000b,c,d,e,f). These populations
of ␣2 -AR are considerably more sensitive than their postsy-
naptic counterparts. As a consequence, ␣2 -AR agonists of
even modest efficacy diminish extracellular levels of NA and
5-HT in corticolimbic structures—as well as DA release in
the frontal cortex and, under certain conditions, the nucleus
accumbens (Millan et al., 2000b,d,e; Tuinstra and Cools,
2000; Adell et al., 2002). In addition, ␣2 -ARs have been
shown to suppress the release of glutamate in the cortex,
amygdala, hippocampus and other limbic regions (Kamisaki
115
et al., 1992; Ferry et al., 1997; Boehm, 1999; Forray et al.,
1999; Pralong et al., 2002).
Such neurochemical effects of ␣2 -AR agonists and par-
tial agonists likely participate in the expression of their
anxiolytic actions in procedures employing untrained be-
haviors (Handley and Mithani, 1984; Fontana et al., 1990;
Lopez-Rubalcava and Fernandez-Guasti, 1994; Cole et al.,
1995a,b; Sanchez, 2003), conflict procedures (Söderpalm,
1989; Fontana et al., 1990) and the VCT (Table 9 and Fig. 6)
(Gower and Tricklebank, 1988; MacDonald et al., 1988;
Söderpalm, 1989; La Marca and Dunn, 1994; Söderpalm
et al., 1995a,b; Millan et al., 2000b,e). However, the anxi-
olytic actions of ␣2 -AR agonists are generally exerted over a
confined dose range. There are several possible explanations
for this observation. First, at high doses, ␣2 -AR agonists be-
gin to activate relatively-insensitive populations of ␣2 -ARs
postsynaptic to monoaminergic pathways, the engagement
of which might, in theory, mediate anxiogenic properties.
However, there is currently little evidence to support this
hypothesis. Second, no ␣2 -AR agonist described to date
shows absolute selectivity for ␣2 -ARs versus ␣1 -ARs and it
might be conjectured that the biphasic dose–response rela-
tionships of clonidine and other ␣2 -AR ligands in the VCT
reflect recruitment of anxiogenic, postsynaptic ␣1 -ARs at
high doses (Table 9) (Söderpalm and Engel, 1988; Hieble
et al., 1995; Millan et al., 2000e). Arguing against this
contention, however, is the general inactivity of ␣1 -AR lig-
ands in the VCT (Table 9) (Section 4.1.5). Third, a more
convincing and parsimonious explanation for the generally
bell-shaped dose–response curves of ␣2 -AR agonists in the
VCT and other models invokes a perturbation of motor
function at high doses. Indeed, a narrow therapeutic win-
dow between anxiolytic and motor-disruptive dose ranges
for ␣2 -AR agonists is hardly illogical since both these ac-
tions reflect activation of ␣2 -ARs inhibitory to monoamin-
ergic pathways (Kable et al., 2000; Millan et al., 2000d,e;
Millan, 2002a).
Evidently, the restricted range of active, non-sedative
doses of ␣2 -AR (partial) agonists precludes their broad
exploitation as anxiolytic agents. Nevertheless, there are cir-
cumstances under which the sedative—as well as haemosta-
bilizing and analgesic—actions of ␣2 -AR agonists are
desirable: notably, the peri-operative environment. Corre-
spondingly, clinical evidence has accumulated for mean-
ingful anxiolytic actions of ␣2 -AR agonists upon their ad-
ministration prior to surgery (Ahmed and Takeshita, 1996;
Thomson et al., 1998; Bitsios et al., 1998; Millan, 2002a).
In addition, the anxiolytic properties of ␣2 -AR agonists
contribute to their efficacy in the clinical management of
opioid withdrawal (Buccafusco, 1992; Devoto et al., 2002;
Stine et al., 2002).
4.1.3. Significance of α2 -AR subtypes
4.1.3.1. A key role for α2A -ARs. It is important to address
the question of the role of individual ␣2 -AR subtypes in
116 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Table 9
Influence of drugs interacting with ␣2 - and ␣1 -adrenoceptors upon behavior in the Vogel Conflict Test
Drug Class Species Route Effect Active dose range Maximum Reference
(strain) (structure) change (%)
S18616 ␣2 -AR agonist Rat (W) s.c. + 0.005 mg/kg +212 Millan et al. (2000b)
DMT ␣2 -AR agonist Rat (W) s.c. + 0.005 mg/kg +166 Millan et al. (2000b)
Medetomidine ␣2 -AR agonist Rat (W) s.c. + 0.001–0.005 mg/kg NI MacDonald et al. (1988)
␣2 -AR agonist Rat (SD) i.v. IA 0.002–0.005 mg/kg IA La Marca and Dunn (1994)
Guanabenz ␣2 -AR agonist Rat (SD) i.v. IA 0.03–0.1 mg/kg IA La Marca and Dunn (1994)
Guanfacine ␣2 -AR agonist Rat (SD) i.v. IA 0.1–0.5 mg/kg IA La Marca and Dunn (1994)
Clonidine ␣2 -AR PAGO Rat (SD) i.p. + 0.006 mg/kg +60 Söderpalm and Engel (1988)
Rat (SD) i.p. IA 0.01–0.1 mg/kg IA Gower and Tricklebank (1988)
Rat (WKY) i.p. + 0.025 mg/kg +40 Söderpalm and Engel (1989)
Rat (SHR) i.p. + 0.003 mg/kg +35 Söderpalm and Engel (1989)
Rat (W) s.c. IA 0.003–0.05 mg/kg IA Söderpalm and Engel (1989)
Rat (W) s.c. + 0.02 mg/kg +175 Millan et al. (2000b)
Rat (SD) i.v. + 0.02 mg/kg +210 La Marca and Dunn (1994)
Yohimbine ␣2 -AR Ant Rat (SD) i.p. IA >0.5 mg/kg IA Söderpalm and Engel (1990)
Rat (SD) i.p. + 4.0 mg/kg +90 Söderpalm et al. (1995a)
Rat (LH) i.p. + 2.5 mg/kg +85 Baldwin et al. (1989)
Rat (SD) s.c. + 0.25–2.0 mg/kg +870 Gower and Tricklebank (1988)
Rat (SD) i.v. IA 1.0 and 2.2 mg/kg +870 La Marca and Dunn (1994)
Idazoxan ␣2 -AR Ant Rat (SD) i.p. IA 0.5–2.0 mg/kg IA Söderpalm and Engel (1989)
Rat (SD) s.c. + 0.25–2.0 mg/kg +563 Gower and Tricklebank (1988)
Rat (SD) i.v. + 10.0 mg/kg +460 La Marca and Dunn (1994)
Piperoxan ␣2 -AR Ant Rat (SD) i.v. IA 1.0–5.0 mg/kg IA La Marca and Dunn (1994)
Rauwolscine ␣2 -AR Ant Rat (SD) i.v. + 2.2 mg/kg + 290 La Marca and Dunn (1994)
Atipamezole ␣2 -AR Ant Rat (W) s.c. IA >0.63 mg/kg IA Brocco (unpublished observations)
1-PP ␣2 -AR Ant Rat (SD) s.c. + 1.0–4.0 mg/kg +128 Gower and Tricklebank (1988)
WY26392 ␣2 -AR Ant Rat (SD) s.c. + 1.0 and 2.0 mg/kg +307 Gower and Tricklebank (1988)

ST 587 ␣1 -AR agonist Rat (SD) i.p. IA 0.5 and 2.0 mg/kg IA Söderpalm and Engel (1990)
Prazosin ␣1 -AR Ant Rat (W) i.p. IA 0.5 and 1.0 mg/kg IA Przegaliński et al. (1994b)
Rat (SD) i.p. IA >0.25 mg/kg IA Söderpalm and Engel (1990)
Rat (W) i.c. (hippocampus) IA 0.3–1.0 ␮g IA Przegaliński et al. (1994b)
Abbreviations—DMT: dexmedetomidine; 1-PP: 1-(2-pyrimidyl)piperazine; PAGO: partial agonist; WKY: Wistar Kyoto; SHR: spontaneously hypertensive;
IA: no significant change (inactive) and NI: not indicated. For other abbreviations, see Table 2.

the anxiolytic actions of ␣2 -AR agonists. Anatomical, phar-
macological and genetic approaches all converge upon the
␣2A -AR subtype as of key significance in this respect.
First, pre- and postsynaptic populations of ␣2A -AR are en-
riched in many corticolimbic structures, including the amyg-
dala, PAG, cortex and hippocampus (Nicholas et al., 1996;
Talley et al., 1996; Wang et al., 1996b; Milner et al., 1998).
Though little is known concerning neuronal substrates
transducing the anxiolytic effects of ␣2A -AR agonists, apart
from the LC, microinjection studies indicate that the amyg-
dala represents one major locus of action (Fendt et al., 1994;
Glass et al., 2002). Second, both in rodents and in man,
␣2A -AR autoreceptors exert a suppressive influence upon
the cerebral release of NA, while ␣2A -heteroceptors mediate
the inhibitory control exercised by noradrenergic pathways
upon the corticolimbic release of 5-HT and DA (Palij and
Stamford, 1996; Altman et al., 1999; Hein et al., 1999;
Linner et al., 1999; Feuerstein et al., 2000; Kable et al.,
2000; Millan et al., 2000d,e; Hein, 2001; Hopwood and
Stamford, 2001b; Scheibner et al., 2001; Bücheler et al.,
2002). Of particular note, activation of ␣2A -ARs has
been shown to blunt the cortical release of NA and DA
elicited under conditions of fear (Ihalainen and Tanila,
2002). Third, the inhibitory influence of NA upon hip-
pocampal liberation of glutamate is mediated by ␣2A -ARs
(Boehm, 1999). Fourth, alterations in levels of (probably
presynaptic) ␣2A -ARs in the hippocampus, amygdala and
PAG have been detected upon acute and long-term expo-
sure to stress (Nukina et al., 1987; Tejani-Butt et al., 1994;
Flügge, 1996; Flügge et al., 1997; Fulford and Marsden,
1997; Fuchs and Flügge, 2002). Further, clinical studies
indicate that psychological stress modifies the functional
status of peripheral, platelet-localized ␣2A -ARs which serve
as a surrogate marker for their supraspinal counterparts
(Maes et al., 2002). Fifth, mice with a “null mutation” for
␣2A -ARs reveal an anxious phenotype in behavioral models,
a marked elevation in central turnover of NA and autonomic
signs of anxiety (Schramm et al., 2001; Lähdesmäki et al.,
2002). Finally, pharmacological studies employing the VCT
and other models have shown that selective blockade of
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
750
LICKS/3 MIN
500
250
0
VEH
NO SHOCK
750
LICKS/3 MIN
500
250
0
VEH
NO SHOCK
Fig. 6. Actions of the ␣2 -adrenoceptor agonist, dexmedetomidine, and of the noradrenaline reuptake inhibitor, reboxetine, in the Vogel Conflict Test.
Data are means ± S.E.M.s. Star indicates significance of differences to corresponding vehicle values. ( ) P < 0.05 to vehicle. Data are from Millan
et al. (2000e), and Brocco and Millan (unpublished observations).
␣2A -ARs, but not of ␣2B - or ␣2C -ARs, abrogates the anxi-
olytic properties of ␣2 -AR agonists (Millan et al., 2000e).
A predominant role of ␣2A -ARs in the suppression of
monoaminergic transmission may, then, underlie their me-
diation of the anxiolytic properties of ␣2 -AR agonists.
However, this mechanism similarly accounts for their
motor-sedative actions (Kable et al., 2000; Millan et al.,
2000d,e; Hein, 2001; Franowicz and Arnsten, 2002). More-
over, activation of central and peripheral populations of
␣2A -ARs inhibitory to sympathetic outflow underlies the
hypotensive properties of ␣2A -AR agonists (Hein, 2001; Tan
et al., 2002a). Indeed, ␣2A -ARs are localized on amygdala
output neurones which project to the dorsal vagal complex,
and on catecholaminergic neurones in the nucleus tractus
solitarious, a structure which likewise fulfils a crucial role
in integrating the autonomic response to stress (Kable et al.,
2000; Glass et al., 2001, 2002; Hein, 2001).
In accordance with the above observations, ␣2A -AR sub-
type selective agonists, irrespective of their efficacy and
117
VEH 0.00125 0.0025 0.005 0.01 MG/KG, S.C.
DEXMEDETOMIDINE
SHOCK
VEH 0.63 2.5 10.0 MG/KG, S.C.
REBOXETINE
SHOCK
other characteristics, are unlikely to express anxiolytic ac-
tions in the absence of motor sedation and/or a perturbation
of cardiovascular function (Millan et al., 2000b,e). Though
a procognitive role for postsynaptic ␣2A -ARs in the frontal
cortex has been advanced (Björklund et al., 1999, 2001;
Friedman et al., 1999; Franowicz and Arnsten, 2002), this
is of dubious therapeutic utility since: (1) it is primarily ex-
pressed under conditions where noradrenergic transmission
is reduced (in contrast to anxious states) and (2) ␣2A -ARs
agonists markedly suppress cholinergic and glutamatergic
transmission (Section 4.1.2), actions incompatible with an
improvement of cognitive function (Tellez et al., 1997;
Forray et al., 1999; Linner et al., 1999; Li et al., 2001b;
Shirazi-Southall et al., 2002; Gobert et al., 2003).
4.1.3.2. α2C and α2B -ARs. A role for ␣2B -ARs in the
control of anxious states appears unlikely inasmuch as they
are sparse in the limbic system and do not appear to play
a role in the modulation of monoaminergic or GABAergic
118 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
transmission (Nicholas et al., 1996; Wang et al., 1996b;
Hein, 2001). On the other hand, under certain condi-
tions, ␣2C -ARs may complement the inhibitory control
by ␣2A -ARs of corticolimbic and sympathetic monoamine
release (Sallinen et al., 1997; Lee et al., 1998; Altman
et al., 1999; Hein et al., 1999; Scheibner et al., 2001;
Bücheler et al., 2002; Ihalainen and Tanila, 2002). More-
over, ␣2C -ARs postsynaptic to noradrenergic pathways
are concentrated in the hippocampus, septum, amygdala
and nucleus accumbens (Rosin et al., 1996; Dossin et al.,
2000). Nevertheless, though ␣2C -ARs may be involved in
the control of cognitive function, aggressive behavior and
the emotional and endocrine response to stress, any spe-
cific role in the modulation of anxious states remains to be
directly demonstrated (Sallinen et al., 1997, 1998, 1999;
Björklund et al., 1999; Hein, 2001; Schramm et al., 2001).
4.1.4. α2 -AR antagonists
The ␣2 -AR antagonist, yohimbine, elicits anxiety
in man, most strikingly in (“trait”) anxious subjects,
opioid-dependent patients and individuals susceptible to
panic attacks (Charney et al., 1983; Krystal et al., 1992;
Bremner et al., 1996a,b; Stine et al., 2002). Robust anx-
iogenic actions of yohimbine have also been detected in
several (though not all) experimental models of untrained
behavior (Handley and Mithani, 1984; Johnston and File,
1988; Baldwin et al., 1989; Venault et al., 1993; Redfern
and Williams, 1995; De Boer and Koolhaas, 2003; see
Cole et al., 1995a,b). Such actions involve activation of
the amygdala (Schroeder et al., 2003) and may reflect an
induction of corticolimbic release of NA and DA (Millan
et al., 2000f) together with a suppressive influence upon
the activity of GABAergic neurones (Maurin et al., 1985).
However, the latter action awaits confirmation and several
authors have questioned the significance of ␣2 -AR receptor
blockade to the anxiogenic actions of yohimbine ((Handley
and Mithani, 1984; Johnston and File, 1988; Redfern and
Williams, 1995); see Cole et al., 1995a,b). Complicating
matters further, while certain investigators have documented
anxiogenic properties of yohimbine in conflict models, most
studies, including those of the VCT, have reported anxi-
olytic actions (Table 9) (Gardner and Piper, 1982; Gower
and Tricklebank, 1988; Baldwin et al., 1989; Söderpalm
and Engel, 1989, 1990; La Marca and Dunn, 1994;
Söderpalm et al., 1995a,b; see Cole et al., 1995a,b). A va-
riety of hypotheses have been formulated in an effort to
explain these paradoxical anxiolytic actions of yohimbine.
First, the most compelling advocates a role of 5-HT1A
autoreceptors, inasmuch as their stimulation by yohimbine
has been implicated in its reduction of cerebral 5-HT release
and several other of its functional actions (Söderpalm et al.,
1995a,b; Millan et al., 2000f; Shannon and Lutz, 2000).
A similar combination of ␣2 -AR blockade and 5-HT1A
receptor agonism might account for the variable anxiolytic
and anxiogenic effects of other ␣2 -AR antagonists, such as
idazoxan, in the VCT and other experimental procedures—
though the anxiogenic properties of idazoxan in man are
less pronounced than those of yohimbine (Table 9) (Krystal
et al., 1992; Hieble et al., 1995; Schmidt et al., 1999;
Millan et al., 2000d,f). Second, as mentioned above (Section
4.1.2), any potential role of ␣2 -ARs postsynaptic to nora-
drenergic networks in the control of anxious states remains
to be explored. Thus, it might be contended that anxiolytic
properties of yohimbine and idazoxan reflect blockade of
“anxiogenic”, postsynaptic ␣2 -AR sites. Arguing against
this assumption, however, the highly-selective ␣2 -AR an-
tagonists, fluparoxan, RX821,002 and atipamezole, do
not show anxiolytic (or anxiogenic) actions in the VCT
(Table 9) (Brocco and Millan, unpublished observations).
Third, in view of their modest selectivity at ␣2 -ARs versus
␣1 -AR sites, yohimbine and idazoxan might exert anxiolytic
actions via blockade of postsynaptic ␣1 -ARs. However,
as outlined below (Section 4.1.5), evidence that activation
of postsynaptic ␣1 -ARs enhances anxious states is hardly
overwhelming. Finally, inasmuch as ␣2 -AR antagonists
exert a modest facilitatory influence upon motor function
(Hieble, 2000; Millan et al., 2000e), it is conceivable that
their “disinhibitory” properties contribute to the increase in
responding in the VCT.
Irrespective of the mechanisms underlying the anxiolytic
profile of yohimbine in the VCT, it must be conceded that
this procedure does not reveal its clinically-expressed, anx-
iogenic properties. This discrepancy may—by analogy to
a further class of clinically-active anxiogenic compounds,
adenosine antagonists (Section 7.2)—reflect the fact that
these agents trigger “panic-like” states in man which are
poorly modeled by the VCT (Section 1.4).
4.1.5. Role of α1 -ARs
4.1.5.1. Modulation of anxious states. Despite indications
for a small population of ␣1 -ARs in the LC, they are pre-
dominantly localized postsynaptically to noradrenergic neu-
rones in diverse corticolimbic territories (Section 4.1.5.2)
(Nicholas, et al., 1996). Several reports of anxiolytic ac-
tions of ␣1 -AR antagonists have appeared, though they are
generally ineffective in conflict models and have, with a
singular, unquantified exception (Gardner and Piper, 1982),
proven inactive in the VCT (Table 9) (Söderpalm and Engel,
1990; Przegaliński et al., 1994b; Sanchez, 2003; Brocco
and Millan, unpublished observations). Likewise, selec-
tive ␣1 -AR agonists are essentially inert in this and other
conflict procedures (Table 9) (Handley and Mithani, 1984;
Söderpalm and Engel, 1988, 1990; Salonen et al.,
1992; La Marca and Dunn, 1994; Lopez-Rubalcava and
Fernandez-Guasti, 1994; Söderpalm et al., 1995a,b). Never-
theless, activation of ␣1 -ARs in the amygdala has been im-
plicated in the induction of anxiety by stress (Cecchi et al.,
2002) and anxiogenic actions of centrally-administered
␣1 -AR agonists in rodents have been attributed to recruit-
ment of CRF1 receptors (Berridge and Dunn, 1989; Yang
et al., 1990; Carrasco and Van de Kar, 2003). Further, it
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
has been suggested that the anxiogenic phenotype of mice
genetically lacking angiotensin (AT2 ) sites reflects activa-
tion of ␣1 -ARs in the amygdala (Section 9.1.11) (Okuyama
et al., 1999b). In a similar vein, it has been posited (Section
4.1.2) that stimulation of ␣1 -ARs underlies the paradoxi-
cal, anxiogenic actions of high doses of the ␣2 -AR partial
agonist, clonidine, in the VCT, though this supposition en-
joys little experimental support (Gardner and Piper, 1982;
Söderpalm and Engel, 1988, 1990; Przegaliński et al.,
1994b; Söderpalm et al., 1995a,b). In a opposite fashion,
it has been proposed that engagement of ␣1 -ARs enhances
the anxiolytic actions of BZPs in the VCT (Söderpalm and
Engel, 1988, 1990; Söderpalm et al., 1995a,b). Indepen-
dent support for this rather tenuous assertion of anxiolytic
actions at ␣1 -ARs has likewise not been forthcoming.
Notwithstanding the limited and contradictory nature of
this evidence for a role of ␣1 -ARs in the modulation of anx-
ious behavior, the balance of evidence favors an anxiogenic
action. This issue would merit further evaluation in view of
the marked influence of ␣1 -ARs upon attentional and cog-
nitive processes under conditions of novelty (Hieble et al.,
1995; Arnsten, 1997; Day et al., 1997; Aston-Jones et al.,
1999; Stone and Quartermain, 1999; Nalepa et al., 2002;
Tanoue et al., 2002). Moreover, protracted stress desensitises
cerebral populations of ␣1 -ARs (Stone et al., 1986, 2002;
Izumi et al., 1996). Conversely, long-term administration of
antidepressant agents (which is accompanied by the devel-
opment of anxiolytic properties) has generally, though not
invariably, been found to circumvent this effect of stress and
itself to amplify functional activity at central populations of
␣1 -ARs (Section 4.4) (Vetulani et al., 1984; Vetulani and
Nalepa, 2000; Izumi et al., 1997; Maj et al., 2000).
4.1.5.2. α1 -AR subtypes. Further insights into the signifi-
cance of ␣1 -ARs would likely be gained from a considera-
tion of individual ␣1A -, ␣1B - and ␣1D -AR subtypes which
are differentially distributed in structures involved in the
control of anxious states (Pieribone et al., 1994; Hancock,
1996; Nicholas et al., 1996; Day et al., 1997; Domyancic
and Morilak, 1997).
␣1A -ARs are highly expressed throughout the cor-
tex, hypothalamus and amygdala, and they are also
well-represented in the hippocampus and PAG. While
␣1B -ARs share their predilection for the cortex, they oth-
erwise present a more confined distribution with a striking
density in the lateral nucleus (only) of the amygdala and,
most remarkably, a high concentration in raphe nuclei.
This observation suggests that activation of ␣1B -ARs is
responsible for the tonic, excitatory influence exerted by
NA upon the activity of ascending serotonergic pathways
(Millan et al., 2000d; Hopwood and Stamford, 2001b;
Adell et al., 2002; Brown et al., 2002). ␣1B -ARs are like-
wise facilitatory to VTA-derived dopaminergic pathways
(Auclair et al., 2002). An additional structure presenting
a pronounced density of ␣1B -ARs is the hypothalamus
wherein they are situated on CRF-containing cell bodies:
119
they are, thus, strategically localized for engagement of
the hypothalamo-corticotrophic axis in response to fear
and other stressors (Day et al., 1999a). Reciprocally, the
expression of ␣1B -ARs in these and other cerebral nuclei
is subject to modulation by glucorticoids: most pertinently,
they appear to obviate the reduction in the functional activ-
ity of ␣1B -ARs engendered by chronic stress (Sakaue and
Hoffman, 1991; Day et al., 1999a; Stone et al., 2002). It has
been documented that mice lacking ␣1B -ARs display re-
duced exploratory behavior in a novel environment, though
any attribution of this observation to an increase in anxiety
must be tentative in light of the generalized role of ␣1B -ARs
in the control of spontaneous locomotor drive (Simon et al.,
1994; Stone et al., 1999, 2001; Knauber and Müller, 2000).
Finally, ␣1D -ARs predominate over other ␣1 -AR subtypes
in the hippocampus, they are highly expressed throughout
the cortex, and they are also present in several sub-territories
of the amygdala (Nicholas et al., 1996; Day et al., 1997).
Thus, ␣1B -ARs are currently the most promising candi-
dates for a role in the modulation (enhancement) of anxious
behavior. The recent description of drugs discriminating in-
dividual ␣1 -AR subtypes should accelerate exploration of
their functional roles in the control of anxious states (Hieble,
2000).
4.1.6. Role of β-ARs
Several lines of evidence support a role of ␤-ARs in the
response to and control of anxious states. First, high con-
centrations of ␤1 - and ␤2 -ARs have been visualized in the
cortex, amygdala, hippocampus, PAG and other limbic re-
gions (Rainbow et al., 1984; Ordway et al., 1988, 1991;
Schatzberg and Schildkraut, 1995; Nicholas et al., 1996).
Second, ␤-ARs have been shown to play a critical role in the
modulation of emotion and cognition by effects in the amyg-
dala, hippocampus and FCX, wherein they enhance NMDA
receptor-mediated transmission by both pre- and postsynap-
tic actions (Huang and Kandel, 1996; Huang et al., 1998;
Roozendaal et al., 1999; Zhang et al., 2001b; Crissman and
O’Donnell, 2002; McGaugh et al., 2002; Pralong et al., 2002;
Wang et al., 2002a). Third, ␤1 - and ␤2 -ARs exert a pha-
sic, facilitatory influence upon the release and synthesis of
NA and, probably, 5-HT, in the FCX and subcortical struc-
tures (Bouthillier et al., 1991; Murugaiah and O’Donnell,
1995; Gobert and Millan, 1999a; Tsuiki et al., 2000). Fourth,
␤-AR blockers are therapeutically utilized in the treatment of
situation-specific/performance anxiety (Tyrer, 1988, 1992)
and can prevent the induction of panic attacks in human sub-
jects (Le Mellédo et al., 1998). Fifth, ␤-ARs participate in
the recruitment of the hypothalamus–corticotropic axis by
stress (Carrasco and Van de Kar, 2003). Finally, long-term
administration of several classes of antidepressant agent, in
parallel with the progressive development of their anxiolytic
properties (Section 4.4), down-regulates corticolimbic (in-
cluding amygdala) populations of ␤1 -ARs (Ordway et al.,
1988, 1991; Heal et al., 1989; Schatzberg and Schildkraut,
1995; Newman-Tancredi et al., 1999).
120 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Table 10
Influence of drugs interacting with ␤-adrenoceptors in the Vogel Conflict Test
Drug Class Species Route (structure) Effect Active dose range Maximum Reference
(strain) change (%)
Betaxolol ␤1 -AR Ant Rat (W) i.p. IA 4.0–8.0 mg/kg IA Przegaliński et al. (1994a)
Rat (W) i.c. (hippocampus) IA 3.0 and 10.0 ␮g IA Przegaliński et al. (1995)
Metoprolol ␤1 -AR Ant Rat (SD) i.p. IA 0.5–2.0 mg/kg IA Söderpalm and Engel (1990)
Pindolol ␤1/2 -AR PAGO Rat (W) i.c. (hippocampus) + 0.1–3.0 ␮g +186 Przegaliński et al. (1995)a
Clenbuterol ␤2 -AR agonist Rat (SD) i.p. IA 0.25–1.0 mg/kg IA Söderpalm and Engel (1990)
ICI 118,551 ␤2 -AR Ant Rat (W) i.p. IA 4.0–8.0 mg/kg IA Przegaliński et al. (1994a,b)
Rat (W) i.c. (hippocampus) IA 3.0 and 10.0 ␮g IA Przegaliński et al. (1995)
Propranolol ␤1/2 -AR Ant Rat (SD) i.p. IA 1.0 and 2.0 mg/kg IA Söderpalm and Engel (1990)
Abbreviations—PAGO: partial agonist and IA: no significant change (inactive). For other abbreviations, see Table 2.
a 5-HT
1A receptor-mediated (Section 4.3.2.4).

Notwithstanding the above observations, anxiolytic prop-
erties of ␤-AR antagonists have not, in general, been re-
vealed in experimental models in rodents (Njung’e et al.,
1993; Sanchez et al., 1996; Cao and Rodgers, 1997b; Prut
and Belzung, 2003; Sanchez, 2003), including conflict
paradigms (Durel et al., 1986; Fontana and Commissaris,
1988; Fontana et al., 1989b; Söderpalm and Engel, 1990;
Terry and Salmon, 1991). The VCT is no exception inas-
much as the systemic and intrahippocampal administration
of ␤1 - and ␤2 -ARs antagonists fails to modify behavior
in this procedure (Table 10) (Söderpalm and Engel, 1990;
Przegaliński et al., 1994a, 1995)—though a study of their
direct injection into the amygdala would be of interest.
This irresponsiveness of the VCT and other experimen-
tal paradigms to ␤-AR antagonists possibly reflects the
fact that: (1) they do not themselves modify monoamin-
ergic transmission in rats—which is phasically enhanced
by ␤1 /␤2 -AR agonists and (2) the anxiolytic properties of
␤-AR antagonists in man primarily reflect actions at pe-
ripheral sites controlling autonomic and somatic function
(Durel et al., 1986; Tyrer, 1988, 1992; see Gobert and
Millan, 1999a).
Though anxiolytic properties of the ␤-AR partial ago-
nist, pindolol, have been reported with the VCT and other
models, its actions are probably mediated by stimula-
tion of 5-HT1A autoreceptors (Table 10) (Section 4.3.2.4)
((Przegaliński et al., 1994a, 1995); Cao and Rodgers, 1997b;
Millan et al., 2002). Otherwise, information concerning the
potential influence of agonists at ␤1 - and ␤2 -ARs upon
anxious states does not appear to be available.
4.2. Dopamine
4.2.1. Dopaminergic pathways
4.2.1.1. Clinical disorders, dopamine and anxious states.
Central dopaminergic pathways have been most intensively
studied within the perspective of their role in the pathogene-
sis of depression, drug abuse, schizophrenia and Parkinson’s
disease, disorders involving a marked (though contrasting)
dysregulation of dopaminergic transmission. Indeed, as com-
pared to 5-HT and NA, rather little attention has been de-
voted to the role of DA in the response to, and modula-
tion of, anxious states (Thiel and Schwarting, 2001; Harari
et al., 2002; Stein et al., 2002). This is curious in view
of the well-established role of stress-responsive mesocorti-
cal and mesolimbic dopaminergic pathways—both of which
originate in the VTA—in the control of mood (Swanson,
1982; Le Moal and Simon, 1991; Finlay and Zigmond, 1997;
Millan et al., 2000d; Hasue and Shammah-Lagnado, 2002;
Homberg et al., 2002). Indeed, by analogy to cognitive func-
tion (Nieoullon, 2002), an “optimal” degree of dopaminergic
activity in the FCX may be requisite for an appropriate re-
sponse to stress and fear (Pezze et al., 2003). Anxious symp-
toms are frequently co-morbid with (and may exacerbate)
drug abuse, affective and psychotic disorders, while anxi-
ety is a prominent, precocious and persistent symptom of
Parkinson’s disease (Menza et al., 1993; Merikangas et al.,
1998; Maier and Falkai, 1999; Beekman et al., 2000; Shiba
et al., 2000; Fenton, 2001; Marinus et al., 2002). Further, a
perturbation of dopaminergic input to the amygdala has been
specifically implicated (by functional magnetic resonance
imaging) in the abnormal emotional processing which char-
acterizes parkinsonian patients (Benke et al., 1998; Braak
and Braak, 2000; Tessitore et al., 2002).
4.2.1.2. Modulation of dopaminergic transmission by aver-
sive stimuli. In fact, the relationship of dopaminergic
transmission to clinical anxiety disorders is complex and
poorly understood. There is evidence that social phobia—
which is common in parkinsonian patients—is associated
with a sustained suppression both of dopaminergic trans-
mission and of activity at dopaminergic receptors (Tiihonen
et al., 1997a; Grant et al., 1998; Schneier et al., 2000;
Kennedy et al., 2001; Stein et al., 2002). On the other
hand, non-parkinsonian subjects with unusually high lev-
els of “trait” anxiety and especially susceptible to panic
attacks have revealed an enhancement in the activity of
central dopaminergic pathways (Roy-Byrne et al., 1986;
Pitchot et al., 1992; Finlay and Zigmond, 1997; Mizuki
et al., 1997). In line with the latter findings, experimental
studies have shown that conditioned fear, anxiety and other
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
stressors elicit a (BZP-reversible) activation of VTA-derived
dopaminergic pathways to the amygdala and adjacent bed
nucleus of the stria terminals (Coco et al., 1992; Inglis and
Moghaddam, 1999; Greba et al., 2001; Kozicz, 2002; Suzuki
et al., 2002a,b), to the nucleus accumbens (McCullough
and Salamone, 1992; Kalivas and Duffy, 1995; Pezze et al.,
2001; Levita et al., 2002) and, most strikingly, to the FCX
(Ravard et al., 1989; Finlay and Zigmond, 1997; Wilkinson
et al., 1998; Broersen et al., 2000; Feenstra et al., 2000;
Beaufour et al., 2001a; Dazzi et al., 2001; Del Arco et al.,
2001). Very recently, providing a clinical correlate to these
studies, employing functional magnetic resonance imaging,
it was reported that the psychostimulant and DA releaser,
dextroamphetamine, enhances the response of the amyg-
dala to aversive stimuli in human subjects (Harari et al.,
2002). This observation suggests that dopaminergic input
to the amygdala is specifically involved in mediating the
anxiogenic properties of dextroamphetamine and, possibly,
other dopaminergic agents (Willick and Kokkinidis, 1995;
Paine et al., 2002). A parallel electrophysiological inves-
tigation in the rat suggested that this action of DA in the
amygdala reflects the simultaneous promotion of excitatory
input from the somato-sensory cortex, and suppression of
inhibitory input from the prefrontal cortex (Rosenkranz and
Grace, 2001, 2002).
4.2.1.3. Dopamine, reward and anxious states. Mesolim-
bic dopaminergic projections are critically involved in mech-
anisms of motivation and reward, and a substantial body
of evidence suggests that their engagement contributes to
the preference for (non-aversive) novel stimuli (Hooks and
Kalivas, 1995; Volkow et al., 2002; Wightman and Robinson,
2002). Correspondingly, and in particular in paradigms in-
volving the exploration of unfamiliar environments and other
measures of neophobia, the reinforcing effects of dopamin-
ergic agents may interact with their influence upon anx-
ious states per se (Homberg et al., 2002; Marinelli and
Piazza, 2002). Indeed, it has been proposed that the positive
emotional effects associated with activation of mesolimbic
dopaminergic pathways can outweigh the negative impact of
stress (Marinelli and Piazza, 2002). This may explain why
the imposition of anxiogenic and other modes of stressor
augments the self-administration of dopaminergic drugs of
abuse (Piazza et al., 1990; Homberg et al., 2002)—in line
with the notion of self-medication as a coping behavior, an
issue evoked elsewhere in this review as concerns human
use (and abuse) of ethanol (Section 2.2.5). One further in-
triguing illustration of the interrelationship between anxiety,
reward and dopamine is provided by the phenomenon of
self-grooming in response to stress. This behavior, which in-
volves mesolimbic dopaminergic networks—and may serve
as a “dearousal” process contributing to the restoration of
homeostasis following stress—predicts a high level of mo-
tivation for self-administration of the DA releaser, cocaine
(Spruijt et al., 1992; Bandler et al., 2000; Homberg et al.,
2002).
121
In interpreting actions of dopaminergic ligands in mod-
els of potential anxiolytic properties, it should also be re-
called that dopaminergic pathways fulfil an important role
in the formation, retention and extinction of fear-related as-
sociations and memory (Morrow et al., 1999; Arnsten et al.,
2000; Greba et al., 2001; Pezze et al., 2001; Nieoullon,
2002).
4.2.2. Multiple classes of dopamine receptor
One difficulty confronted in the study of DA and anx-
ious states is the particularly marked influence of genetic
background upon the actions of dopaminergic agonists in
models of anxious (and other) behavior(s) (Gendreau et al.,
1998; Kelly et al., 1998; Rodgers et al., 2002a,b). Fur-
thermore, dopaminergic receptors are localized both pre-
and postsynaptically to dopaminergic projections (Section
4.2.3.1) (Levant, 1997; Vallone et al., 2000), while DA ex-
erts its actions via multiple classes of dopamine receptor
poorly-differentiated by many widely-used agents (Shafer
and Levant, 1998; Helmeste and Tang, 2000; Oak et al.,
2000; Vallone et al., 2000; Millan et al., 2002).
Closely-related D2 , D3 and D4 receptors share negative
coupling via Gi to adenylyl cyclase: D2 and D3 sites also
couple negatively to GIRKs (Section 13.3), though such ac-
tions are less well established for D4 sites. On the other hand,
closely-related D1 and D5 receptors both stimulate adenylyl
cyclase via Gs (Sibley, 1999; Vallone et al., 2002).
4.2.3. Dopamine “D2 -like” receptors
4.2.3.1. Cerebral distribution of D2 , D3 and D4 receptors:
influence upon GABAergic transmission. Dopamine D2
receptors are widely-distributed throughout the brain, dis-
playing a high density in the FCX, nucleus accumbens,
amygdala and septum. They are present in far higher con-
centrations than cerebral populations of D3 sites in rodents,
though in primate (and human) brain, D3 receptors are bet-
ter represented (Levant, 1997; Sibley, 1999; Vallone et al.,
2000; Joyce, 2001). Further, across all species, D3 receptors
are principally localized in limbic regions, including the
nucleus accumbens, hippocampus, olfactory tubercles, cere-
bral cortex and thalamus (Jackson and Westlind-Danielsson,
1994; Levant, 1997; Joyce, 2001). Dopamine D2 receptors
predominate as autoreceptors on dopaminergic cell bodies
and terminals, though D3 receptors fulfil a complementary
role in the inhibitory control of cortical and subcortical DA
release, both as autoreceptors and, conceivably, via a post-
synaptic feedback loop (Millan et al., 2000d; Zapata et al.,
2001; Centonze et al., 2002; Joseph et al., 2002). Though
likewise less prominent than their D2 receptor counterparts,
the enrichment of D4 sites in the lateral septum, amygdala,
hypothalamus, hippocampus and, most strikingly, the FCX,
is of particular pertinence in the present context, together
with their localization on cortical GABAergic interneurones
in rodents and primates (Rossetti et al., 1989; Mrzlkak
et al., 1996; Oak et al., 2000; Wedzony et al., 2000).
122 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Indeed, DA exerts a complex and receptor-dependent in-
fluence upon GABAergic transmission reflecting both: (1)
presynaptic changes in the excitability of GABAergic neu-
rones and of GABA release and (2) postsynaptic interactions
with GABAergic receptors. Dopamine D1 and D2 (D4 ) re-
ceptors exert facilitatory and inhibitory effects, respectively,
upon GABAergic inhibition of cortical pyramidal neurones.
Moreover, activation of dopamine D4 receptors interferes
with the operation of topographically-adjacent postsynaptic
GABAA receptors by a complex mechanism involving re-
cruitment of protein kinase A (Grobin and Deutch, 1998;
Seamans et al., 2001; Wang et al., 2002b). However, the
interrelationship between GABAergic neurones and multi-
ple classes of dopaminergic receptor remains poorly-defined
and this issue would be of interest to further explore in sub-
cortical, limbic structures.
4.2.3.2. Dopamine D2 receptors. Varicose dopaminergic
fibers originating in cell bodies of the VTA and hypothala-
mus have been visualized in the DRN and LC (Kitahama
et al., 2000), and certain studies have indicated a minor,
modulatory influence of D2 receptors upon the activity of
corticolimbic serotonergic (facilitatory) and noradrenergic
(inhibitory) pathways. However, the physiological signifi-
cance of these roles remains unclear and neither agonists
nor antagonists at dopamine D2 receptors elicit marked al-
terations in the release of NA and 5-HT in corticolimbic
structures (Rossetti et al., 1989; Ferré et al., 1994; Mendlin
et al., 1999; Vanderschuren et al., 1999; Millan et al., 2000d;
Adell et al., 2002; Szumlinski and Szechtman, 2002).
Comparatively, few behavioral data have been forthcom-
ing in support of potential anxiolytic effects of D2 receptor
agonists (Bartoszyk, 1998; Rodgers et al., 2000; Sanchez,
2003). Nevertheless, the prototypical agonists, apomorphine
and quinpirole, both elicited significant increases in pun-
ished responses in the VCT (Table 11) (Hjorth et al., 1986,
1987a; Siemiatkowski et al., 2000b). Neither of these drugs
distinguishes D2 from D3 and D4 receptors (Levant, 1997;
Oak et al., 2000; Vallone et al., 2000; Millan et al., 2002)
but the novel agent, S32504, which is devoid of activity at
D4 receptors, reproduces their anxiolytic effects in the VCT
(Table 11) (Dekeyne et al., 2001). Further, anxiolytic ac-
tions of S32504 are blocked by selective antagonists at D2
receptors, whereas D3 or D4 receptor antagonists are inef-
fective (Dekeyne et al., 2001; Brocco and Millan, unpub-
lished observations). These data indicate that activation of
D2 receptors underlies the anxiolytic actions of “D2 -like”
agonists. Support for this contention has not, as yet, been
derived from D2 receptor knock-out mice, possibly since al-
terations in motor function compound interpretation of their
phenotype Sibley, 1999; Waddington et al., 2001. Notwith-
standing several (preliminary) reports of anxiolytic actions
of non-selective dopaminergic (D2 -like) agonists in man
(Ferrier et al., 1985; Mizuki et al., 1997), such findings re-
main to be corroborated by more extensive and rigorous in-
vestigations.
Dopamine D2 autoreceptors are substantially more re-
sponsive than postsynaptic populations of D2 receptors,
manifesting greater sensitivity to low doses of agonists and
responding even to ligands of modest efficacy (Levant, 1997;
Millan et al., 2000d; Joyce, 2001). A role of highly-sensitive
D2 autoreceptors in the anxiolytic properties of dopaminer-
gic agonists would be consonant with the observation that
low doses are sufficient for expression of their actions in the
VCT and other models (Hjorth et al., 1986; Borowski and
Kokkinidis, 1996; Munro and Kokkinidis, 1997; Bartoszyk,
1998; Rodgers et al., 2000). This interpretation is further
underpinned by anxiolytic actions in the VCT of (−)PPP, a
weak (partial) agonist known to preferentially stimulate pre-
as compared to postsynaptic populations of dopamine D2
receptor (Table 11) (Hjorth et al., 1987a). Further, local in-
jection of dopamine (D2 ) receptor agonists into the VTA is
associated with anxiolytic properties (Gifkins et al., 2002).
A D2 autoreceptor-mediated reduction of stress-induced
DA release to the FCX (Section 4.2.1) may be of especial
importance to the actions of dopamine receptor agonists in

Table 11
Influence of dopaminergic agents upon behavior in the Vogel Conflict Test
Drug Class Species Route Effect Active dose Maximum Reference
(strain) (structure) range (mg/kg) change (%)
Apomorphine D1 /D2 agonist Rat (SD) s.c. + 0.006–0.025 +110 Hjorth et al. (1986)
(+)3-PPP D2 /D3 /D4 agonist Rat (SD) s.c. + 0.006–0.5 +45 Hjorth et al. (1987a,a)
(−)3-PPP D2 /D3 /D4 agonist Rat (SD) s.c. + 0.016–0.25 +50 Hjorth et al. (1987a,b)
Quinpirole D2 /D3 /D4 agonist Rat (W) i.p. + 1.0 +220 Siemiatkowski et al. (2000b)
S32504 D2 /D3 agonist Rat (W) s.c. + 5.0 +89 Brocco (unpublished observations)
Haloperidol D2 /D3 /D4 Ant Rat (W) s.c. IA 0.01–0.16 IA Millan et al. (1999a)
Rat (W) i.p. IA >0.2 IA Siemiatkowski et al. (2000b)
Sulpiride D2 /D3 Ant Rat (W) s.c. + 25.0 +160 Siemiatkowski et al. (2000b)
Nafadotride D3 > D2 Ant Rat (?) s.c. + 0.2–1.0 NI (Rogoz et al., 2000)
L745,870 D4 Ant Rat (W) s.c. IA 0.16–2.5 IA Brocco (unpublished observations)
S18126 D4 Ant Rat (W) s.c. IA 0.16–2.5 IA Brocco (unpublished observations)
SCH 23390 D1 Ant Rat (W) s.c. IA >0.01 IA Brocco (unpublished observations)
Abbreviations—(+)3-PPP: R(+)-3(3-hydroxyphenyl)-N-propylpiperidine; (−)3-PPP: preclamol; IA: no significant change (inactive) and NI: not indicated.
For other abbreviations, see Table 2.
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
the VCT and other procedures (Ravard et al., 1990; Espejo,
1997). However, the precise sites and mechanisms of action
underlying anxiolytic properties of D2 receptor agonists
have, to date, eluded identification.
4.2.3.3. Dopamine D3 receptors. Though isolated reports
of anxiogenic effects of “D2 receptor antagonists” in ex-
perimental studies (Bartoszyk, 1998; Timothy et al., 1999;
Siemiatkowski et al., 2000b) would be consistent with
above-discussed findings indicative of an anxiolytic role
for D2 receptors, they are inactive in the VCT (Dekeyne
et al., 2001; Siemiatkowski et al., 2000b; Brocco and Mil-
lan, unpublished observations). Further, there have also
been reports (albeit conflicting) of anxiolytic actions of
“D2 receptor antagonists” in conflict and other procedures
(Pich and Samanin, 1986; Cools et al., 1993; Rodgers et al.,
1994; Costall and Naylor, 1997; Bartoszyk, 1998; Cavazzuti
et al., 1999; De Boer and Koolhaas, 2003). Inasmuch as
drugs employed in these studies fail to discriminate D2 and
D3 receptors—“D2 receptor antagonists” is something of a
misnomer—their respective participation in such actions is
unclear. However, in the light of data discussed in the pre-
ceding paragraphs, a specific role of D2 receptor blockade
in the expression of anxiolytic properties seems unlikely.
It might, thus, be postulated that D3 receptor blockade
underlies potential anxiolytic actions of mixed D2 /D3 re-
ceptor antagonists. This contention is favoured by reports
that knock-out mice deficient in D3 receptors generally dis-
play an anxiolytic phenotype (Accili et al., 1996; Xu et al.,
1997; Steiner et al., 1998; Karasinska et al., 2000;
Blednov et al., 2001; Vallone et al., 2002). Further, anx-
iolytic actions of preferential D3 antagonists have been
reported in the VCT and certain other—though not all—
procedures of anxiolytic activity (Gendreau et al., 1997;
Bartoszyk, 1998; Rodriguez-Arias et al., 1999; Rogoz et al.,
2000; Dekeyne et al., 2001; Brocco and Millan, unpub-
lished observations). Such findings must be substantiated
by studies with highly-selective agents unambiguously dif-
ferentiating D3 from D2 receptors. Nevertheless, supporting
a role of D3 receptors in the facilitation of anxious states,
stimulation of D3 receptors is associated with anxiogenic
actions in several experimental models (Kahaya et al., 1996;
Gendreau et al., 2000).
The—to date, tentative—possibility that D3 receptors
facilitate anxious behavior (Table 11) deserves additional
study inasmuch as it would provide an interesting parallel to
the opposite roles of (postsynaptic) D2 versus D3 receptors
in the enhancement and suppression of locomotor behavior,
respectively (Levant, 1997; Joyce, 2001).
4.2.3.4. Dopamine D4 receptors. Dopamine D4 receptor
knock-out mice display alterations in their cognitive perfor-
mance and in their motor response to novelty, complicating
interpretation of their behavior in response to anxiogenic
stimuli. Nevertheless, a specific, BZP-preventable increase
in unconditioned fear was recently detected in D4 receptor
123
knock-out mice. This was tentatively attributed to a loss of
D4 receptor function in the FCX, despite the fact that D4
receptors are inhibitory to GABAergic neurones in this re-
gion (Section 4.2.1.2) (Rubinstein et al., 1997; Dulawa et al.,
1999; Sibley, 1999; Arnsten et al., 2000; Okuyama et al.,
2000; Falzone et al., 2002). While selective D4 receptor an-
tagonists do not display anxiolytic properties in the VCT
and other procedures (Table 11) (Cao and Rodgers, 1997a;
Bartoszyk, 1998; Brocco and Millan, unpublished observa-
tions), evaluation of the actions of selective D4 agonists
would be of interest in such paradigms.
4.2.4. Dopamine “D1 -like” receptors
Dopamine D1 receptors are enriched in the FCX, nucleus
accumbens, amygdala and hippocampus, wherein they dis-
play a complex pattern of interaction with GABAergic and
glutamatergic neurones (Jackson and Westlind-Danielsson,
1994; Ng et al., 2001). In line with this pattern of distribu-
tion, D1 receptors play an important role in the cognitive
component (primarily extinction, rather than acquisition or
consolidation) of fear-conditioning (Greba and Kokkinidis,
2000; El-Ghundi et al., 2001). Chronic stress is accompa-
nied by a BZP-reversible decrease in D1 receptor density
in the nucleus accumbens (Giardino et al., 1998) and cer-
tain authors have speculated that the activation of D1 recep-
tors enhances, or elicits, anxious states (Simon et al., 1993;
Siemiatkowski et al., 2000a; Cancela et al., 2001). However,
other studies contradict this assertion and there is little ev-
idence for anxiolytic profiles of either dopamine D1 recep-
tor antagonists or D1 receptor-knock-out mice in either the
VCT or other procedures (Table 11) (Rodgers et al., 1994;
Bartoszyk, 1998; El-Ghundi et al., 1999, 2001; Sibley, 1999;
Karasinska et al., 2000; Waddington et al., 2001; Blednov
et al., 2002). Nevertheless, studies of D1 /D3 double mutant
mice suggest that D1 receptors may interact with (possibly
colocalized) D3 receptors in modulating the behavioral re-
sponse to a novel, fear-inducing environment (Sibley, 1999;
Karasinka et al., 2000; Joyce, 2001).
Dopamine D5 receptors are found predominantly in the
hippocampus, but they are also localized in the FCX, hy-
pothalamus, LC and DRN (Ariano et al., 1997; Ciliax et al.,
2000; Pralong et al., 2002). No drug is currently known to
differentiate D5 from D1 sites, but mice lacking D5 recep-
tors have been described. Their phenotype reveals no signs
of alterations in emotionality or in the response to stress
suggesting that they do not play a major role in the con-
trol of anxious states (Sibley, 1999; Holmes et al., 2001;
Waddington et al., 2001; Hollon et al., 2002).
Interestingly, D5 receptors can form functional het-
erodimers with GABAA receptors. Assuming their occur-
rence in the CNS, the potential significance of these con-
structs to anxious states would be of interest to explore (Liu
et al., 2001). Similarly, if—by analogy to D3 /D2 receptor
heterodimers—D1 /D2 and D1 /D3 heterodimers were found
to exist, this would add a novel dimension to the roles
of multiple classes of dopamine receptor in the control of
124 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
emotion and other functions (Section 18.2) (Scarscelli et al.,
2001; George et al., 2002).
4.3. Serotonin
4.3.1. Serotonergic pathways
Though it is well known that the rate-limiting enzyme,
tryptophan hydroxylase, catalyses the synthesis of 5-HT, it
has long remained a mystery as to why its levels are so low
in raphe nuclei as compared to the pineal gland—wherein
it undertakes the initial step in the generation of melatonin
(Section 10). Even more surprisingly, mice deficient in this
enzyme maintain essentially normal levels of 5-HT in the
CNS despite a pronounced depletion of 5-HT in peripheral
tissues (Walther et al., 2003). This paradox was recently
resolved with the discovery of a second and brain-specific
form of tryptophan hydroxylase responsible for generation
of 5-HT in cerebral tissue (Walther et al., 2003).
Serotonergic neurones originating in raphe nuclei provide
a massive input to corticolimbic structures involved in the
control of anxious states. The DRN primarily innervates the
FCX, dorsal hippocampus and amygdala, while the median
raphe nucleus (MRN) principally projects to the (dorsal and
ventral) hippocampus, septum, nucleus accumbens and hy-
pothalamus (Azmitia and Segal, 1978; Gray, 1987; Deakin
and Graeff, 1991; Wilson et al., 1993; Eison and Eison,
1994; Handley, 1995; Baumgarten and Grozdanovic, 1997;
McQuade and Sharp, 1997; Vertes et al., 1999; Kirby et al.,
2003). These DRN and MRN-derived networks show con-
trasting patterns of organization and modulation (Table 12)
(Azmitia and Segal, 1978; Kosofsky and Mollinver, 1987;
Deakin and Graeff, 1991; Wilson et al., 1993; Netto et al.,
2002; Kirby et al., 2003) and may fulfil differential roles
in the control of anxious states. For example, serotonergic
pathways emanating from the DRN have been specifically
implicated in the control of behavior in the VCT (Thiébot
et al., 1983; Pratt, 1992). A complex and non-uniform role
for 5-HT in the control of anxiety disorders has also been
forwarded as a function of: (1) whether the anxious state is
provoked by conditioned or unconditioned fear and (2) con-
trasting actions of 5-HT in specific cerebral regions, notably
the amygdala as compared to the PAG (Deakin, 1988, 1991;
Deakin and Graeff, 1991; Graeff et al., 1993, 1996a; Eison
and Eison, 1994; Handley, 1995; Green and McGregor,
2002). Moreover, in assessing the role of 5-HT in the mod-
ulation of anxious states, it is advisable to consider the
potentially confounding influence of serotonergic pathways
upon other behaviours, such as motor function, impulsiv-
ity and cognition (Evenden, 1999; Meneses, 1999; Dalley
et al., 2002; Green and McGregor, 2002; Harro, 2002).
Serotonergic pathways innervating structures such as the
FCX, amygdala, hypothalamus and hippocampus are acti-
vated by anxiogenic stimuli, including psychosocial stress,
conditioned fear and conflict procedures (Pratt, 1992; Wright
et al., 1992; Adell et al., 1997; Rueter et al., 1997; Amat
et al., 1998; Berton et al., 1998; Martinez et al., 1998;
Beaufour et al., 2001b; Ishida et al., 2002; Miura et al.,
2002). Moreover, it has been demonstrated that responding
in the VCT is accompanied by a concurrent increase in 5-HT
release in the hippocampus (Matsuo et al., 1996 though see
also Beaufour et al., 2001b). These observations underline
the significance of serotonergic mechanisms to the control of
performance in this procedure, though their precise role(s),
and their involvement in the actions of BZPs, have been ex-
tensively debated (Section 2.2.2.3) (Pratt, 1992).
As discussed below (Sections 4.3.2, 4.4 and 4.5), sero-
tonergic mechanisms participate in the influence of a broad
range of therapeutically-employed drugs upon emotionality
in general, and upon anxious states in particular. Moreover,
the 5-HT releaser, methylenedioxymethylamphetamine (ec-
stasy), has been shown to modify anxiety states in a dose
and test-dependent manner both in experimental studies and
in human subjects (Parrott, 2000; Liechti and Vollenweider,
2001; Fone et al., 2002; Green and McGregor, 2002; Navarro
and Maldonado, 2002). It’s escalating and illicit recreational
abuse in many countries underscores the urgency of enhanc-
ing our understanding of the role of serotonergic mecha-
nisms in the control of anxious behaviour.
4.3.2. 5-HT1A receptors
4.3.2.1. Coupling and organization. The role of 5-HT1A
receptors in the modulation of anxious states has been par-
ticularly well studied (Chopin and Briley, 1987; Handley,
1995; Barnes and Sharp, 1999; Olivier et al., 1999, 2001;
Gross et al., 2002).
Activation of Gi -coupled 5-HT1A receptors enhances
K+ -currents (GIRKs) and inhibits the activity of adenylyl
cyclase: their engagement may also suppress the operation
of VDCCs (Gerhardt and Heerikhuizen, 1997; Barnes and
Sharp, 1999; Raymond et al., 1999). 5-HT1A receptors,
which are localized as inhibitory autoreceptors on the den-
drites of serotonergic cell bodies in raphe nuclei, are also
localized postsynaptically to serotonergic neurones in the
hippocampus, septum, amygdala, PAG, entorhinal cortex
and FCX: in the latter structure, they exert a “long-loop”,
inhibitory feedback influence upon the electrical activity of
serotonergic perikarya in the DRN (Celada et al., 2001).
Interestingly, prolonged stress modifies cerebral levels of
5-HT1A sites and may preferentially densensitize pre- as
compared to postsynaptic populations of 5-HT1A receptors
(McKittrick et al., 1995; Barton et al., 1999; Laaris et al.,
1999), a process contributing to the overall potentiation of
serotonergic transmission under these conditions.
5-HT1A receptor agonists elicit a pronounced increase in
the activity of the hypothalamo-corticotropic axis, acting
via multiple loci in the hypothalamus itself as well as in
limbic structures. Further, activation of 5-HT1A receptors is
involved in the induction of ACTH and corticosteroid secre-
tion in response to stress (Chaouloff, 1995; Fletcher et al.,
1996; Jorgensen et al., 1998, 2001; Carrasco and Van de Kar,
2003). This action is of considerable pertinence inasmuch
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 125

Table 12
A comparison of the principle characteristics of the dorsal raphe nucleus (DRN) as compared to the median raphe nucleus (MRN)
MRN DRN

Major projection targets Olfactory bulb, ventral and dorsal hypothalamus, Frontal CX and pre-frontal CX, dorsal hippocampus,
parietal cortex, septum, nucleus accumbens amygdala, hypothalamus, nucleus accumbens
GABA inhibition (cell bodies) Mild Strong
␣1 -AR excitation (cell bodies) Strong Mild
5-HT1A inhibition (cell bodies) Mild Strong
5-HT1B inhibition (terminals) Strong Mild
Glutamatergic stimulation Mild Strong
(cell bodies)
Non-5-HT cells Many Few
Fibre type (projections) Varicose Fine
Focalized Diffuse, widespread
PCA, MDMA vulnerability Low High
SERT density Low High
Abbreviations—CX: cortex; GABA: ␥-amino-butyric acid; AR: adrenoceptor; 5-HT: serotonin; PCA: parachloroamphetamine; MDMA: methylenediethyl-
metamphetamine and SERT: 5-HT transporters. PCA and MDMA (ecstasy) are neurotoxins which acutely release, and chronically deplete, 5-HT.

as corticosteroids exert a reciprocal modulatory influence
upon the activity of pre- and postsynaptic populations of
5-HT1A receptors and have been likewise implicated in the
control of mood (Section 11.2). 5-HT1A receptor agonists,
principally via central actions, also facilitate the release of
NA from sympathetic neurones, an action which may secon-
darily enhance the activity of the hypothalamo-corticotropic
axis. Whether 5-HT1A receptors are involved in triggering
the rapid increase in sympathetic outflow in response to
stress and fear remains, however, to be ascertained (McCall
and Clement, 1994; Chaouloff, 1995; Saphier and Welch,
1994; Korte et al., 1996).
4.3.2.2. Interactions with GABAergic, glutamatergic and
catecholaminergic neurones: the 5-HT1A receptor knock-out
phenotype. Human volunteers possessing a low density
of central 5-HT1A receptors were found to be more anx-
ious than control groups displaying higher levels (Tauscher
et al., 2001; Condren et al., 2002). This observation is
reminiscent of findings in mice genetically lacking 5-HT1A
receptors which generally show an anxiogenic phenotype
and an enhanced sensitivity to stress as regards both be-
havioural and autonomic variables (Heisler et al., 1998b;
Sibille and Hen, 2001; Pattij et al., 2002a,b; Groenink et al.,
2003; Toth, 2003). Though the precise mechanistic bases
for this enhanced anxiety remain uncertain, it has been pos-
tulated to reflect a loss of activity at postsynaptic rather than
presynaptic 5-HT1A sites inasmuch as extracellular levels
of 5-HT are little modified in animals lacking 5-HT1A re-
ceptor. This lack of alteration in 5-HT release may appear
surprising. However, it presumably reflects changes in the
control of serotonergic transmission compensatory to the
loss of 5-HT1A autoreceptors which exert, in any case, only
a limited, tonic influence upon corticolimbic 5-HT release
(see Millan et al. (2000d)). Direct support for the contention
that a loss of postsynaptic 5-HT1A receptors underlies en-
hanced anxiety may be derived from recent studies of a
tissue-specific, “conditional” 5-HT1A receptor knock-out
model. Thus, in mice in which functional 5-HT1A recep-
tors were preserved in the amygdala, hippocampus and
FCX, whereas raphe-localized 5-HT1A autoreceptors were
disabled, the anxious phenotype was absent Gross et al.
(2002)—though see Section 4.3.2.5.
5-HT1A receptors exert an inhibitory influence upon
limbic (e.g. amygdala) and cortical release of glutamate
Cheng et al., 1998; Lin et al., 2001; Wang et al., 2002a.
Correspondingly, a disinhibition of glutamatergic activity
(Section 3) may contribute to anxious behavior in mice
deficient in 5-HT1A receptors. Moreover, an ingenious hy-
pothesis for the anxiogenic phenotype of 5-HT1A receptor
knock-out mice invokes an interaction between postsynaptic
5-HT1A receptors and glutamatergic transmission at pyra-
midal cells in the frontal cortex and, possibly, subcortical
structures (Cai et al., 2002b). AMPA receptors excitatory
to these neurones are under the facilitatory control of
Ca2+ -calmodulin-dependent kinase II which: (1) enhances
their conductance by phosphorylation of GluR1 subunits
and (2) coordinates their anchoring at neuronal membranes
(Lee et al., 2000; Hayashi et al., 2000a,b). Serotonin1A
receptors are inhibitory to Ca2+ -calmodulin-dependent
kinase II. Their genetic ablation is speculated, then, to
potentiate the activity of presumptively anxiogenic (and
colocalized) AMPA receptors (Section 3.3) (Cai et al.,
2002a,b). This mechanism would be consistent with the
anxiolytic phenotype of mice deficient in the ␣-isoform of
Ca2+ -calmodulin-dependent kinase II itself (Chen et al.,
1994).
Alternatively, it has been contended that the anxious
phenotype of 5-HT1A receptor knock-out mice may involve
an indirect disturbance of the function of amygdala and
hippocampus-localized BZP/GABAA receptors (involving
a down-regulation of ␣2 -subunits), which are presumably
expressed by neurones bearing both 5-HT1A and GABAA
receptors. However, it is unclear as to how this change
126 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
is brought about and equivalent observations have not
been obtained in all 5-HT1A receptor knock-out mice lines
with divergent genetic backgrounds (Sibille et al., 2000;
Belzung and Griebel, 2001; Olivier et al., 2001; Sibille
and Hen, 2001; Gross et al., 2002; Pattij et al., 2002a,b;
Toth, 2003). Irrespective of this uncertainty, other studies
have provided evidence for a complex pattern of functional
interactions amongst 5-HT1A receptors and GABAergic
mechanisms (Peričić and Tvrdeić, 1993; Fernández-Guasti
and López-Rubalcava, 1998; Sakaue et al., 2001; Pralong
et al., 2002). Indeed, while colocalized GABAA/B and
5-HT1A receptors exert mutually inhibitory effects upon the
activity of neurones (including raphe-localized serotonergic
cell bodies), it has been shown that 5-HT1A receptors can
suppress the limbic release of GABA (Halasy et al., 1992;
Schmitz et al., 1995; Matsuyama et al., 1997; Koyama et al.,
1999, 2002; Kishimoto et al., 2000a, 2001; Koyama et al.,
2002). As pointed out below, (Section 4.3.2.5), the latter
action may participate in anxiogenic actions of 5-HT1A
agonists at postsynaptic 5-HT1A receptors.
Presynaptic (and, possibly, postsynaptic) populations of
5-HT1A receptor exert an indirect and tonic facilitatory in-
fluence upon mesolimbic and mesocortical dopaminergic
pathways, and upon corticolimbic noradrenergic projec-
tions (Millan et al., 2000d; Szabo and Blier, 2001). This
acceleration of the release of DA and NA by 5-HT1A re-
ceptor agonists may counteract the beneficial effects of
their autoreceptor-mediated reduction in 5-HT release and
account for the variable and/or biphasic actions of 5-HT1A
receptor agonists in certain models of anxiolytic activity
(Section 4.3.2.3). Furthermore, unrestrained corticolimbic
release of NA may underlie the relative inefficacy of 5-HT1A
receptor agonists in the control of panic attacks (Section 4.1).
On the other hand, it has been suggested that, under con-
ditions of stress, activation of 5-HT1A receptors attenu-
ates the engagement of frontocortical dopaminergic path-
ways (Rasmusson et al., 1994). Moreover, the inhibitory
influence of 5-HT1A receptors upon stress-induced CCK
release may be considered as favouring the expression of
anxiolytic properties (Becker et al., 1999).
Clearly, then, the role(s) of 5-HT1A receptors in the mod-
ulation of anxious states is complex, reflecting contrasting
roles of pre versus postsynaptic sites and of individual pop-
ulations of 5-HT1A receptors in discrete supraspinal regions.
As outlined below, this assertion is borne out by pharmaco-
logic studies with the VCT and other experimental models.
4.3.2.3. Anxiolytic properties of selective 5-HT1A recep-
tor agonists. Studies of 5-HT1A receptor knock-out mice
(Section 4.3.2.2) notwithstanding, selective 5-HT1A recep-
tor antagonists do not display anxiogenic properties. More-
over, their (rare) anxiolytic actions may involve blockade
of postsynaptic 5-HT1A receptors (probably on GABAergic
neurons in the ventral hippocampus) since they exert little
influence upon forebrain 5-HT release (Millan et al., 1997,
2000d; Nunes-de-Souza et al., 2002). A report that injec-
tion of 5-HT1A receptor antagonists into the MRN acts anx-
iolytically in the plus-maze was attributed to a (conjectural)
disinhibition of 5-HT release in the PAG (Canto-de-Souza
et al., 2002). However, this remains to be formally demon-
strated and neuronal substrates involved in the occasional
anxiolytic properties of 5-HT1A antagonists are still poorly
defined (Cao and Rodgers, 1997b; Griebel et al., 1999b,
2000; Canto-de-Souza et al., 2002; Nunes-de-Souza et al.,
2002; Blanchard et al., 2003; Bourin and Hascoët, 2003;
Prut and Belzung, 2003).
In contrast to antagonists at 5-HT1A receptors, systemic
administration of partial agonists and agonists is character-
ized by reproducible anxiolytic actions in a broad range of
procedures—though the plus-maze paradigm has yielded a
variable and equivocal pattern of data (Schreiber and De
Vry, 1993a,b; Charrier et al., 1994; De Vry, 1995; Molewijk
et al., 1995a; Millan et al., 1997; Graeff et al., 1998; Dekeyne
et al., 2000b; Blanchard et al., 2003; Bourin and Hascoët,
2003; File and Seth, 2003; Prut and Belzung, 2003; Sanchez,
2003). Conflict models have generally revealed positive
effects (Barrett, 1992; Hascoët et al., 1994; Stanhope
and Dourish, 1996; King et al., 1997). With one exception,
5-HT1A receptor antagonists have proven inactive in the
VCT. Conversely, a broad ensemble of chemically-diverse
agonists has displayed significant activity—though not
necessarily with monophasic dose–response relationships
(Table 13 and Fig. 7) (Shimizu et al., 1987; Wada and
Fukuda, 1991; Barrett, 1992; Stefański et al., 1992; Amano
et al., 1993; Meneses and Hong, 1993; Kennett et al., 1998;
Griebel et al., 1999b, 2000; Vanover et al., 1999; Dekeyne
et al., 2000b; Paluchowska et al., 2000; Vaidya et al., 2002).
Anxiolytic actions of 5-HT1A receptor ligands in the mouse
VCT have not, as yet, been documented (Umezu, 1999).
It is of note that the anxiolytic (anticonflict) actions of
5-HT1A agonists such as buspirone and gepirone in the rat
VCT are more pronounced following their prolonged ad-
ministration, an observation which parallels their compara-
tively slow onset of efficacy in patients (Schefke et al., 1989;
Yamashita et al., 1995; Silva and Brandao, 2000; Sramek
et al., 2002). This delay may involve adaptive changes post-
synaptic to serotonergic neurones, such as the down-regulation
of anxiogenic 5-HT2C and 5-HT2A receptors (Section 4.3.4)
(Millan et al., 1997). However, in man, the retarded re-
sponse to buspirone may reflect prior treatment with BZPs
to which extended exposure compromises expression of the
anxiolytic actions of 5-HT1A agonists (Section 18.3) (De
Martinis et al., 2000).
4.3.2.4. Role of 5-HT1A receptors in the anxiolytic ac-
tions of diverse drug classes. The ␤-AR partial agonist,
pindolol (Section 4.1.6), is under intensive clinical inves-
tigation for its ability to accelerate the therapeutic actions
of antidepressant agents in the treatment both of major de-
pression and of anxiety disorders (Section 4.4) (McAskill
et al., 1998; Hirschmann et al., 2000; Ziegenbein et al.,
2000; Artigas et al., 2001; Stein et al., 2001a,b). It has been
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 127

Table 13
Influence of 5-hydroxytryptophan (5-HTP) and of 5-HT1 receptor ligands upon behaviour in the Vogel Conflict Test
Drug Class Species Route (structure) Effect Active dose range Maximum Reference
(strain) change (%)
5-HTP 5-HT precursor Rat (SD) i.p. + 50 mg/kg +90 Hjorth et al. (1987)
Dihydroergosine 5-HT agonist Rat (W) i.p. + 10–50 mg/kg +380 Peričić and Tvrdeić (1993)
8-OH-DPAT 5-HT1A agonist Rat (SD) i.p. + 0.125–0.25 mg/kg +34 Engel et al. (1984)
Rat (W) i.p. + 0.025–0.05 mg/kg +67 Stefanski et al. (1992)
Rat (W) s.c. + 0.04 mg/kg +300 Dekeyne et al. (2000a)
Rat (LH) i.c. (DRN) + 20–500 ng +448 Higgins et al. (1988)
Rat (W) i.c. (hippocampus) IA >1 ␮g IA Belcheva et al. (1994)
Rat (W) i.c. (hippocampus) + 1–3 ␮g +275 Przegaliński et al. (1994b)
Rat (W) i.c. (hippocampus) + 0.5–1.0 ␮g +72 Stefanski et al. (1993a)
Rat (W) i.c. (N. accumbens) + 1 and 2.5 ␮g +67 Stefanski et al. (1993a)
Buspirone 5-HT1A PAGO Rat (W) i.p. + 5–10 mg/kg +105 Yamashita et al. (1995)
Rat (W) s.c. + 0.63 mg/kg +200 Dekeyne et al. (2000a)
Rat (SD) s.c. + 0.3–1.0 mg/kg +240 Gower and Tricklebank (1988)
Rat (W) p.o. + 10–20 mg/kg +192 Wada and Fukuda (1991)
Rat (LH) i.c. (DRN) + 0.2 ␮g +272 Higgins et al. (1988)
Rat (W) i.c. (hippocampus) + 1–3 ␮g +175 Przegaliński et al. (1994b)
Rat (W) i.c. (hippocampus) − 5 ␮g −65 Stefanski et al. (1993a)
Rat (W) i.c. (N. accumbens) − 5 ␮g −60 Stefanski et al. (1993a)
Ipsapirone 5-HT1A PAGO Rat (W) i.p. + 2.5–10 mg/kg +274 Przegaliński et al. (1992)
Rat (LH) i.c. (DRN) + 0.2 ␮g +198 Higgins et al. (1988)
Rat (W) i.c. (hippocampus) + 1 and 3 ␮g +175 Przegaliński et al. (1994a,b)
Gepirone 5-HT1A PAGO Rat (W) i.p. + 0.3 and 0.6 mg/kg +33 Stefanski et al. (1992)
Rat (W) i.p. + 2–10 mg/kg +220 Yamashita et al. (1995)
Rat (LH) i.c. (DRN) + 1 ␮g +300 Higgins et al. (1992)
Rat (W) i.c. (hippocampus) + 10 and 30 ␮g/side +175 Przegaliński et al. (1994b)
Tandospirone 5-HT1A PAGO Rat (SD) i.p. + 5.0 mg/kg +1000 Shimizu et al. (1987)
Rat (SD) s.c. + 1.0 mg/kg +420 Shimizu et al. (1992)
Rat (SD) i.c. (hippocampus) + 30 and 60 ␮g/side +442 Kataoka et al. (1991)
Indorenate 5-HT1A PAGO Rat (W) i.p. + 3–10 mg/kg +410 Meneses and Hong (1993)

S15535 5-HT1A PAGO Rat (W) s.c. + 2.5–40 mg/kg +300 Dekeyne et al. (2000a)
WAY100,635 5-HT1A Ant Rat (W) s.c. IA >0.63 mg/kg IA Dekeyne et al. (2000a)
Rat (W) s.c. IA 5–10 mg/kg IA Przegaliński et al. (1995)
Rat (W) s.c. + 0.3 and 1.0 mg/kg +325 Griebel et al. (2000)
Rat (SD) s.c. IA >0.3 mg/kg IA Kennett et al. (1998)
Rat (W) i.c. (hippocampus) IA 0.03–0.3 ␮g IA Przegaliński et al. (1995)
NAN190 5-HT1A Ant Rat (W) i.p. IA 0.5–1.0 mg/kg IA Przegaliński et al. (1994b)
Rat (W) i.c. (hippocampus) IA 0.1–1.0 ␮g IA Przegaliński et al. (1994b)
CGS12066B 5-HT1B agonist Rat (LH) i.c. (DRN) IA >2.5 ␮g IA Higgins et al. (1992)
SB224,289 5-HT1B Ant Rat (W) s.c. IA >10 mg/kg IA Brocco (unpublished observations)
Abbreviations—8-OH-DPAT: 8-hydroxydipropylaminotetralin; PAGO: partial agonist; N. accumbens: nucleus accumbens and IA: no significant change
(inactive). For other abbreviations, see Table 2.

proposed that its distinctive partial agonist properties at
␤1 - and ␤2 -ARs facilitatory to corticolimbic dopaminergic
and noradrenergic pathways contribute to its favourable
influence upon depressive—though not anxious—states
(Gobert and Millan, 1999a). Nevertheless, “antagonist” ac-
tions of pindolol at 5-HT1A autoreceptors have generally
been advanced as the mechanism underlying its reinforce-
ment of the actions of antidepressant agents (Corradetti
et al., 1998; Artigas et al., 2001; Newman-Tancredi et al.,
2001). Pindolol is, thus, posited to rapidly mimic the grad-
ual (long-term) antidepressant-induced desensitisation of
5-HT1A autoreceptors by their direct blockade (Haddjeri
et al., 1998; Artigas et al., 2001; Castro et al., 2003). One
difficulty with this hypothesis is that doses of pindolol em-
ployed clinically are too low to attain marked occupation
of 5-HT1A autoreceptors (Cremers et al., 2001; Martinez
et al., 2001; Rabiner et al., 2001). Further, several stud-
ies have shown that pindolol can behave as an agonist
at 5-HT1A autoreceptors in rodents (Gobert and Millan,
1999a; Lejeune and Millan, 2000; Sprouse et al., 2000;
Artigas et al., 2001; Millan et al., 2001f). Though incon-
sistent with long-term, adjunctive antidepressant properties,
128 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

750
LICKS/3 MIN
LICKS/3 MIN

500 500

250 250

0 0
VEH VEH 0.16 0.63 2.5 10.0 MG/KG, S.C. VEH VEH 0.04 0.16 0.63 2.5 MG/KG, S.C.
FLESINOXAN MDL 100,907
NO SHOCKS SHOCK NO SHOCK SHOCK

750
750
LICKS/3 MIN

LICKS/3 MIN

500
500

250
250

0 0
VEH VEH 0.63 2.5 10.0 40.0 MG/KG, I.P. VEH VEH 0.63 10.0 40.0 MG/KG, S.C.
SB 242,084 CITALOPRAM

NO SHOCK SHOCK NO SHOCK SHOCK

Fig. 7. Actions of the 5-HT1A receptor agonist, flesinoxan, the 5-HT2A antagonist, MDL100,907, the 5-HT2C antagonist, SB242,084, and the selective
5-HT reuptake inhibitor, citalopram, in the Vogel Conflict Test. Data are means ± S.E.M.s. Star indicates significance of differences to corresponding
vehicle values. ( ) P < 0.05. Data are from Gobert et al. (2000), Dekeyne et al. (2000a,b), and Brocco and Millan (unpublished observations).

the activation of presynaptic 5-HT1A receptors by pindolol
likely underlies its acute anxiolytic actions in the VCT and
other procedures (Table 10) (Przegaliński et al., 1994a). In
this light, it is conceivable that the intrinsic partial agonist
properties of several novel antidepressant agents at 5-HT1A
receptors, such as vilazadone (Bartoszyk et al., 1997; Treit
et al., 2001; Page et al., 2002; Tordera et al., 2002), may
permit rapid and sustained anxiolytic actions via a com-
parable mechanism. Their effects in the VCT would merit
evaluation.
As argued elsewhere (Millan, 2000; Bantock et al., 2001),
stimulation of presynaptic 5-HT1A receptors imparts benefi-
cial properties to antipsychotic agents in terms of: (1) an aug-
mented therapeutic window of desirable versus secondary
actions: (2) improved control of cognitive-deficit symptoms
and (3) auxiliary antidepressive and anxiolytic properties
which improve patient compliance and, more generally, en-
courage patient recovery. As outlined in Section 4.5, sev-
eral antipsychotic agents have been shown to interact with
5-HT1A receptors—in addition to dopamine D2 receptors
and other monoaminergic sites. Of these, the benzopyrro-
lidine derivative, S16924, is of special note inasmuch as it
displays potent agonist properties at 5-HT1A receptors and
has been shown to express robust anxiolytic effects in the
VCT via activation of 5-HT1A autoreceptors (Millan et al.,
1999a; Cussac et al., 2002a).
It has recently been recognized that many antiparkinson
agents, such as apomorphine, possess significant affinity for
5-HT1A receptors (Seyfried et al., 1989; Newman-Tancredi
et al., 1999, 2002a,b; Millan et al., 2002). They almost in-
variably behave as partial agonists exhibiting intrinsic ac-
tivity sufficient to stimulate presynaptic, but not postsynap-
tic, populations (Seyfried et al., 1989; Newman-Tancredi
et al., 1999, 2002b; Millan et al., 2002). Interestingly, several
antiparkinsonian agents manifest anxiolytic properties in
experimental models, including the VCT. While not chal-
lenging the significance of D2 autoreceptor activation in the
actions of those agents which preferentially act at D2 versus
5-HT1A sites (Section 4.2.3.2), recruitment of 5-HT1A re-
ceptors may contribute to the anxiolytic profiles of other an-
tiparkinsonian drugs—such as roxindole—which show more
pronounced agonist properties at 5-HT1A than at D2 recep-
tors (Seyfried et al., 1989; Newman-Tancredi et al., 1999).
Anxious symptoms are a common and troubling feature of
Parkinsons disease which may even anticipate motor dys-
function (Section 4.2.1), so it would be judicious to further
characterize the role of 5-HT1A receptor activation in the
influence of antiparkinson drugs upon mood.
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Fig. 8. Schematic illustration of the sites of action of agents interacting with serotonergic receptors in the Vogel Conflict Test. The loci of action indicated
are based upon results published for the Vogel Conflict Test (see tables). Additional sites of action revealed by other procedures should be borne in
mind. Abbreviations—5-HT: serotonin; D/MRN: dorsal/median raphe nucleus and PAG: periaqueductal gray.
4.3.2.5. Pre- and postsynaptic sites of action of 5-HT1A
receptor agonists. Notwithstanding extensive efforts, it is
currently impossible to specify the precise contribution of
pre- as compared with postsynaptic receptors to the anxi-
olytic properties of 5-HT1A receptor agonists (Fig. 8). In-
deed, it is arguably illusory to insist upon a unitary response
to this question in light of the plethora of factors which bear
on the results of studies addressing this issue. For exam-
ple: the choice of drug, its dose, duration and site of ap-
plication; the species, strain and gender under investigation;
the experimental model, its end-point and the magnitude of
stress provoked, and the degree of activation of serotoner-
gic neurones (Blanchard et al., 1992; Crespi et al., 1992;
Schreiber and De Vry, 1993a,b; De Vry, 1995; Handley,
1995; Menard and Treit, 1999; Olivier et al., 2001; Vaidya
et al., 2002). Moreover, as exemplified by (Jolas et al., 1995),
even microinjection studies may not provide definitive ev-
idence in this regard owing to the rapid and extensive dif-
fusion through neuronal tissue of lipophylic ligands such as
the 5-HT1A agonist, 8-OH-DPAT, which quickly attains the
DRN even upon introduction into the dorsal hippocampus.
Supporting a role for 5-HT1A autoreceptors in the VCT: (1)
anxiolytic effects were reported upon direct introduction of
5-HT1A receptor agonists into raphe nuclei (Eison et al.,
1986; Carli and Samanin, 1988); (2) agonists of modest ef-
ficacy which stimulate pre but not postsynaptic populations
of 5-HT1A receptor exert robust anxiolytic effects (Millan
et al., 1997; Cervo et al., 2000; Dekeyne et al., 2000b;
Bojarski et al., 2002) and (3) in certain studies, elimination
of serotonergic neurones exerted anxiolytic effects and inter-
fered with the anxiolytic actions of 5-HT1A agonists (Engel
et al., 1984; Eison et al., 1986; Carli et al., 1989; Söderpalm
et al., 1992, 1997; Schreiber and De Vry, 1993a; Cervo and
Samanin, 1995; Nazar et al., 1999a,b; Andrade and Graeff,
2001; Green and McGregor, 2002; Netto et al., 2002). Data
from other conflict models may also be advanced to bolster
129
the assertion that 5-HT1A autoreceptors play a major role
in mediating the anxiolytic actions of 5-HT1A receptor ag-
onists.
First, anxiogenic actions have been documented upon
administration of 5-HT1A receptor agonists into the septum,
hippocampus and amygdala (Hodges et al., 1987; Andrews
et al., 1994; Belcheva et al., 1994, 1997; Gonzalez et al.,
1996a; Micheau and Van Marrewijk, 1999; Nunes-de-Souza
et al., 2000, 2002), while recruitment of postsynaptic
5-HT1A receptors has been implicated in the anxiogenic
effects of CCK (Section 9.1.1) (Bickerdike et al., 1995).
These anxiogenic effects may be provoked by activation
of postsynaptic 5-HT1A receptors inhibitory to GABAergic
neurones (Section 4.3.2.2) (Halasy et al., 1992; Matsuyama
et al., 1997; Koyama et al., 1999; Kishimoto et al., 2000a,
2001). Second, introduction of 5-HT1A receptor agonists
into the DRN and (less prominently) the MRN is accompa-
nied by anxiolytic effects (Carli et al., 1989; Higgins et al.,
1992; Schreiber and De Vry, 1993a; Andrews et al., 1994;
Maurel-Remy et al., 1996; Cervo et al., 2000). Third, par-
enteral administration of selective 5-HT1A partial agonists
possessing efficacy adequate for stimulation of pre but not
postsynaptic populations may evoke anxiolytic actions more
pronounced than those elicited by full agonists which like-
wise activate postsynaptic receptors (De Vry, 1995; Millan
et al., 1997; Przegaliński et al., 1995; Dekeyne et al., 2000b).
Fourth, anxiolytic effects of 5-HT1A partial agonists and
5,7-dihydroxytryptamine lesions of serotonergic pathways
in the VCT and other models are blunted by antagonists at
GABAA receptors (Söderpalm and Engel, 1991; Söderpalm
et al., 1992, 1997; Fernández-Guasti and López-Rubalcava,
1998; Nazar et al., 1999a,b). These findings reflect either:
(1) indirect suppression of an inhibitory influence of postsy-
naptic 5-HT1A receptors upon GABA release (see above);
(2) release of a positive allosteric modulatory of GABAA
sites, such as neurosteroids (Söderpalm et al., 1997) and/or
130 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
(3) removal of the inhibitory influence of 5-HT2C receptors
upon hippocampal populations of colocalized GABAA re-
ceptors (Section 4.3.4.4) (Huidobro-Toro et al., 1996). Fifth,
as considered in Section 4.4.2, the prolonged administration
of SSRIs and other classes of antidepressant agent is ac-
companied by the progressive transformation of their acute,
anxiogenic properties into long-term anxiolytic actions. In
parallel, postsynaptic 5-HT1A receptors develop an increase
in sensitivity, a finding incompatible with a qualitatively
different influence of chronic versus acute treatment by an-
tidepressants upon anxious states (Blier and De Montigny,
1994; Newman et al., 1998; Haddjeri et al., 1998; Hjorth
et al., 2000; Artigas et al., 2001; Hensler et al., 2002; Castro
et al., 2003).
Contrariwise, in support of a role of postsynaptic sites,
the anxiolytic properties of 5-HT1A receptor agonists in the
VCT were (in certain studies) unaffected by 5-HT depletion,
and they are generally seen upon direct application into the
hippocampus—and nucleus accumbens (Commissaris et al.,
1981; Chojnacka-Wójcik and Przegaliński, 1991; Kataoka
et al., 1991; Przegaliński et al., 1992, 1994b; Shimizu et al.,
1992; Stefański et al., 1993a; Belcheva et al., 1994, 1997). A
predominant role of postsynaptic sites in the VCT is under-
scored by studies of other conflict procedures showing that
microinjection of 5-HT1A receptor agonists into the septum,
hippocampus and/or amygdala is accompanied by anxiolytic
actions, while lesions of serotonergic neurones little modi-
fies the effects of their systemic administration (Kostowski
et al., 1989; Schreiber and De Vry, 1993a,b; Menard and
Treit, 1998; Zangrossi et al., 1999; Groenink et al., 2000).
Moreover, while bearing in mind the contrasting nature of
the model (Section 1.3) (Graeff et al., 1993), direct introduc-
tion of 5-HT1A agonists into the PAG eliminates the aver-
sive effects of its electrical stimulation: though they are in-
active upon systemic administration, this may reflect their
acceleration of corticolimbic NA release (Section 4.3.2.2)
(Noguiera and Graeff, 1995; Beckett and Marsden, 1997;
Jenck et al., 1999; Millan et al., 2000d; Canto-de-Souza
et al., 2002; Graeff, 2002; Jacob et al., 2002).
4.3.2.6. Multiple sites of action of 5-HT1A receptor lig-
ands: clinical studies. From the above discussion of
innumerable—ostensibly contradictory—findings, the ques-
tion of the respective roles of pre versus postsynaptic
5-HT1A receptors may appear virtually insoluble. Indeed,
it would seem unrealistic to categorically advocate an ex-
clusive role for either in mediating the anxiolytic actions of
5-HT1A receptor agonists (Fig. 7). The following comments
are of pertinence in this regard.
First, as a function of serotonergic tone, an intermedi-
ate degree of drug efficacy at 5-HT1A receptors sufficient
for the maximal and submaximal activation of pre- and
postsynaptic sites, respectively, may result in optimal anxi-
olytic activity. Second, it is entirely plausible that both pre-
and postsynaptic populations of 5-HT1A receptors medi-
ate anxiolytic properties. For example, in relation to the
well-documented anxiogenic role of postsynaptic 5-HT2C
receptors (Section 4.3.4.4), activation of 5-HT1A autore-
ceptors, in moderating serotonergic transmission, will indi-
rectly relieve their engagement by reducing 5-HT release.
On the other hand, inasmuch as postsynaptic 5-HT1A recep-
tors are inhibitory to neuronal activity, their activation will
interfere with the excitatory effects of co-expressed 5-HT2C
receptors (Millan et al., 1992). Third, postsynaptic 5-HT1A
receptors exert opposing functional influences upon
GABAergic transmission. Thus, while 5-HT1A receptors
can directly inhibit the activity of GABAergic interneurones
(Section 4.3.2.2), where colocalized with GABAA receptors
on individual neurones in the hippocampus and other struc-
tures, 5-HT1A sites will synergistically act to suppress neu-
ronal excitability. This configuration is consistent with the
concurrent expression of anxiolytic and anxiogenic actions
by postsynaptic 5-HT1A receptors—perhaps subject to fine
tuning at the level of serotonergic terminals presynaptic to,
or in series with, GABAergic neurones. Fourth, no 5-HT1A
receptor agonist is absolutely selective, so it should not be
forgotten that actions at sites other than 5-HT1A receptors
will modify (in a drug-specific fashion) actions in the VCT
and other procedures.
Regardless of the role(s) of specific populations of
5-HT1A receptor, from a clinical perspective, the overall in-
fluence of drugs upon parenteral administration is a crucial
consideration. In this regard, in analogy to observations in
the VCT, partial agonists at 5-HT1A receptors have repro-
ducibly shown anxiolytic activity in GAD patients—though,
as discussed elsewhere, any efficacy in the management of
other anxiety disorders remains to be proven (Pecknold,
1997; Rickels et al., 1997; Laakman et al., 1998; Apter
and Allen, 1999; Broocks et al., 2000; Landen et al., 2001;
Oshima et al., 2001). In healthy volunteers, furthermore,
buspirone exerted anxiolytic actions against both condi-
tioned and, at higher doses, unconditioned aversive stimuli
(Hellewell et al., 1999; Bond et al., 2003).
Thus, though the influence of 5-HT1A receptors upon anx-
ious states is highly complex, their activation is generally as-
sociated with anxiolytic actions amenable to analysis by use
of the VCT. This procedure will prove of continued utility in
the further elucidation of their roles. Moreover, in analogy
to BZPs (Section 2.2.2), the anxiolytic properties of 5-HT1A
partial agonists in the VCT provide an important parallel to
clinical studies demonstrating their therapeutic efficacy in
the management of GAD.
4.3.3. 5-HT1B receptors
4.3.3.1. Coupling, localization and interactions. 5-HT1B
receptors share the negative coupling of 5-HT1A receptors
to adenylyl cyclase via engagement of Gi . Postsynaptic
populations are found in the FCX, hippocampus, amygdala
and several other corticolimbic structures of rodents and,
at particularly high levels, of man (Bruinvels et al., 1994;
Bonaventure et al., 1998). As concerns their role in the
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
modulation of mood, most attention has, however, been fo-
cussed on inhibitory 5-HT1B autoreceptors localized on the
terminals of serotonergic neurones (Bruinvels et al., 1994;
Millan et al., 2000d; Hopwood and Stamford, 2001a; De
Groote et al., 2002). Complementary to dendritic 5-HT1A
autoreceptors, these terminal-localized 5-HT1B autorecep-
tors play a key role in the phasic, inhibitory control of
5-HT release (Barnes and Sharp, 1999; Millan et al., 1999b,
2000d). Furthermore, these presynaptic populations have
been specifically implicated in the control of anxiety under
conditions of stress (Clark et al., 2002).
It should also be pointed out that postsynaptic popula-
tions of 5-HT1B receptor are inhibitory to glutamatergic and
GABAergic neurones in the cortex and LC (Bobker and
Williams, 1989; Tanaka and North, 1993).
4.3.3.2. Control of anxious states. In view of the mutual
inhibitory control exercised by 5-HT1B and 5-HT1A autore-
ceptors upon 5-HT release—and arguing by analogy—it
might be predicted that: (1) mice overexpressing 5-HT1B
receptors would present an anxiolytic phenotype; (2) mice
deficient in 5-HT1B receptors would mimic the anxiogenic
profile of their 5-HT1A receptor knock-out counterparts
and (3) 5-HT1B agonists would elicit anxiolytic actions
in parallel with a suppression of corticolimbic 5-HT re-
lease. However, overexpression of 5-HT1B autoreceptors
potentiated the anxious behaviour elicited by stress (Clark
et al., 2002). Further, the rather unspectacular phenotype
of mice lacking 5-HT1B receptors suggests a decrease
in anxiety (Ramboz et al., 1996; Malleret et al., 1999;
Zhuang et al., 1999; Belzung, 2001; Dirks et al., 2001;
Lesch, 2001). Alterations in coupling efficiency at pre- and
postsynaptic (amygdala-localized) populations of 5-HT1A
receptors in animals lacking 5-HT1B sites complicates in-
terpretation of their phenotype (Knobelman et al., 2001;
Ase et al., 2002), and a compensatory reduction in activ-
ity at cerebral 5-HT2C receptors may contribute to their
low level of anxiety (Clifton et al., 2003). In any case,
the lack of alteration in 5-HT release suggests (by anal-
ogy to 5-HT1A receptor knock-out mice) (Section 4.3.2.2)
that the reduced anxiety cannot automatically be assigned
to a loss of inhibitory, presynaptic populations of 5-HT1B
receptor.
Indeed, a putative anxiogenic role of postsynaptic 5-HT1B
receptors might explain the paradoxical finding that, at
doses which elicit reductions in 5-HT release comparable
to those induced by 5-HT1A agonists, 5-HT1B receptor ag-
onists do not, in general, elicit anxiolytic effects. Indeed,
several reports of anxiogenic actions of 5-HT1B agonists
in paradigms of exploratory behaviour were recently un-
derpinned by a rigorous pharmacological demonstration
that activation of 5-HT1B receptors enhances anxiety in
the plus-maze procedure (Moret and Briley, 2000; Lin and
Parsons, 2002). Data from conflict procedures are limited
but, in line with these findings, it has been reported that the
5-HT1B agonist, RU24969, enhanced punished responding
131
in a VCT (Gardner, 1985). Other 5-HT1B receptor agonists
have likewise failed to display anxiolytic effects either upon
systemic administration or upon direct introduction into the
DRN—wherein a minor population of 5-HT1B autorecep-
tors also occurs (Table 13) (Higgins et al., 1992; Millan
et al., 2000d; Brocco and Millan, unpublished observa-
tions). Though anxiolytic actions of the poorly-selective
serotonergic agonist, meta-chlorophenylpiperazine (mCPP)
(Section 4.3.4.1), in the VCT were ascribed to activation
of 5-HT1B receptors, selective antagonists were not at that
time available for study. Retrospectively, it is more likely
that other mechanisms were involved, probably engagement
of 5-HT1A receptors or blockade of 5-HT3 sites (Sections
4.3.2 and 4.3.5) (Chojnacka-Wójcik and Klodzińska,
1992).
The above comments indicate that the engagement of
postsynaptic 5-HT1B receptors may enhance anxious states.
In line with this interpretation, it has been reported that
(presumably postsynaptic) 5-HT1B receptor blockade is as-
sociated with anxiolytic properties (Chopin et al., 1994).
However, such observations require confirmation with gen-
uinely selective antagonists such as the highly-selective
agent, SB224,289, which was ineffective in the VCT
(Table 13). Further, in certain paradigms, evidence has
been acquired for anxiolytic properties of 5-HT1B ago-
nists (Bourin and Hascoët, 2003; Sanchez, 2003). Thus,
it would be premature to form any definitive conclusions
as regards the role of pre- and postsynaptic populations of
5-HT1B receptors in view of: (1) the relative poverty of
data concerning actions of selective agonists and antago-
nists; (2) difficulties in pharmacologically distinguishing
the roles of pre versus postsynaptic populations of 5-HT1B
receptors, an issue requiring direct exploration in mice
sustaining regionally-circumscribed (pre or post synaptic)
genetic elimination of 5-HT1B receptors; (3) lack of infor-
mation concerning the neuronal substrates underlying the
putative anxiogenic role of postsynaptic 5-HT1B sites and
(4), the need for studies of the influence of 5-HT1B autore-
ceptors upon stress and fear-induced activation of seroton-
ergic pathways. Additional analysis of the significance of
5-HT1B receptors would be of interest in the light of evi-
dence that adaptive changes (desensitization) in presynaptic
populations of 5-HT1B receptors upon long-administration
of antidepressant agents develop with a time-course par-
alleling that required for onset of their anxiolytic actions
(Section 4.4.2) ((Blier and De Montigny, 1994; Anthony
et al., 2000; Davidson and Stamford, 2000); Hjorth et al.,
2002).
Regardless of the precise role of 5-HT1B receptors in the
modulation of anxious states, the above comments underline
arguments forwarded elsewhere (Sections 2.2.2.1, 4.3.2.4
and 18.1) that: (1) a reduction in 5-HT release is not invari-
ably accompanied by an anxiolytic profile; and (2) it would
be naı̈ve to automatically attribute changes in anxious states
to actions at presynaptic as compared to postsynaptic popu-
lations of 5-HT1B and 5-HT1A receptor.
132 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
4.3.4. Serotonin 5-HT2 receptor subtypes
4.3.4.1. The 5-HT2 receptor family: cellular coupling.
The three closely-related members of the 5-HT2 recep-
tor family, 5-HT2A , 5-HT2B and 5-HT2C receptors, are
poorly differentiated by first-generation pharmacologi-
cal agents such as the “5-HT2 ” receptor agonist, mCPP
(which also interacts with 5-HT1A , 5-HT1B and 5-HT3 re-
ceptors), and the “5-HT2 ” receptor antagonist, ritanserin
(Barnes and Sharp, 1999). Only more recently, with
the discovery of highly-selective ligands distinguishing
5-HT2A , 5-HT2B and 5-HT2C sites, and the generation of
5-HT2C receptor knock-out mice, has it become feasible
to address the issue of their individual roles (Barnes and
Sharp, 1999). Paralleling their similar patterns of ligand
recognition, 5-HT2A , 5-HT2B and 5-HT2C receptors all
stimulate the activity of phospholipase C (resulting in an
increase in intracellular levels of Ca2+ ) via the recruitment
of Gq (Gerhardt and Heerikhuizen, 1997; Barnes and Sharp,
1999; Cussac et al., 2002a,b).
4.3.4.2. 5-HT2A receptors. Though a possible role of
5-HT2A receptors in the modulation of anxious states has
attracted comparatively little attention, they are found at
a high concentration in the entorhinal cortex, amygdala,
nucleus accumbens and hippocampus (Lopez-Giménez
et al., 1997, 1998; Cornea-Hébert et al., 1999; Xu and
Pandey, 2000; Vaidya et al., 2001; Millan, 2002a). Further,
alterations in the functional status of 5-HT2A receptors
have been seen upon acute imposition of stress, while a
pronounced elevation in the cortical density of 5-HT2A re-
ceptors was evoked by protracted exposure to anxiogenic
stimuli (Chaouloff et al., 1994; Vaidya et al., 1999; Izumi
et al., 2002). Under resting and stressful conditions, 5-HT2A
receptor agonists exert a marked facilitatory influence upon
the activity of the hypothalamo-corticotropic axis and upon
sympathetic outflow (McCall and Clement, 1994; Welch
and Saphier, 1994; Chaouloff, 1995; McKittrick et al.,
1995; Nankai et al., 1995; Jorgenson et al., 1998; Rivet
et al., 2001; Hemrick-Lubecke and Evans, 2002; Carrasco
and Van de Kar, 2003).
Several complementary lines of evidence suggest that the
engagement of 5-HT2A receptors may contribute to anxious
states: (1) activation of 5-HT2A receptors enhances the cor-
ticolimbic efflux of glutamate, derived form both glial as
well as neuronal sources Rocher et al., 1999; Meller et al.,
2002; (2) 5-HT2A receptors are localized on cell bodies of
the LC and the ventrotegmental area wherein they exert
an excitatory influence upon corticolimbic noradrenergic
and dopaminergic pathways, respectively. 5-HT2A recep-
tors also, via actions in the FCX and, possibly, the DRN
itself, potentiate 5-HT output in cortical regions, though
not necessarily in other cerebral structures Gobert and
Millan, 1999b; Doherty and Pickel, 2000; Liu et al., 2000;
Millan et al., 2000d; Martin-Ruiz et al., 2001; Pehek et al.,
2001; Nocjar et al., 2002. (3) Several studies have docu-
mented anxiolytic properties of 5-HT2A receptor antago-
nists (Stutzmann et al., 1991; Motta et al., 1992; Costall
and Naylor, 1995; Mora et al., 1997; Graeff et al., 1998).
Anxiolytic actions of selective 5-HT2A antagonists have
also been seen—albeit at relatively high doses—in the
VCT (Table 14 and Fig. 7) ((Griebel et al., 1997a); Brocco
and Millan, unpublished observations); (4) at the postsy-
naptic level, stimulation of 5-HT2A receptors suppresses
GABAergic transmission in the FCX (Feng et al., 2001)
via the protein kinase C-mediated phosphorylation of the
␥2 subunit of colocalized GABAA receptors (Yan, 2002).
Whether similar interactions occur in other limbic struc-
tures awaits elucidation. (5) By analogy to the effects of
long-term agonist administration, down-regulation (desen-
sitisation and internalisation) of cortical and sub-cortical
populations of 5-HT2A receptors is provoked by chronic
treatment with antidepressant agents: this may contribute
to their delayed onset of anxiolytic (and other therapeutic)
properties (Section 4.4) (Deakin, 1988, 1991; Graeff et al.,
1996a,b; Burnet et al., 1994, 1996; Bhatnagar et al., 2001;
Millan et al., 2001c,d; Bhattacharyya et al., 2002; Van
Oekelen et al., 2003).
Notwithstanding the above findings, 5-HT2A receptor an-
tagonists have proven essentially inactive in several models
of potential anxiolytic activity (Gleeson et al., 1989; Griebel
et al., 1997a; Setem et al., 1999; Blanchard et al., 2003;
Bourin and Hascoët, 2003). Moreover, there are also reports
of anxiogenic actions of 5-HT2A receptor antagonists, prin-
cipally in models of untrained behaviours, but also including
a conflict procedure in mice. One locus of action appears
to be the amygdala (Olivier et al., 1998; Setem et al., 1999;
Maisonette et al., 2000). An explanation for the anxiogenic
effects of 5-HT2A receptor antagonists may be their relief
of a presynaptic, tonic, excitatory influence of 5-HT2A re-
ceptors upon GABAergic neurones in the amygdala and the
hippocampus (Cozzi and Nichols, 1996; Shen and Andrade,
1998; Abi-Saab et al., 1999; Rainnie, 1999; Stutzmann
and LeDoux, 1999; Zhou and Hablitz, 1999; Jakab and
Goldman-Rakic, 2000; Xu and Pandey, 2000; Martin-Ruiz
et al., 2001). Thus, a loss of a spontaneous activity at 5-HT2A
receptors, via a reduction of GABA release, may lead to an
enhancement of anxious states. Further, in contrast to the
direct, excitatory influence of 5-HT2A receptors upon nora-
drenergic perikarya in the LC (vide supra), they may exert an
indirect, inhibitory influence via the activation of GABAer-
gic interneurones (Szabo and Blier, 2001). Despite the in-
activity of 5-HT2A receptor agonists in the VCT (Table 14),
a similar, positive influence of 5-HT2A receptors upon
GABAergic neurones in the PAG and the inferior colliculus
may account for the generally BZP-like anxiolytic actions
of 5-HT2A agonists in models of anti-aversive (defensive)
activity generated from these structures (Jenck et al., 1990,
1998; Melo and Brandao, 1995; Nogueira and Graeff, 1995;
Brandao et al., 2002; Castilho et al., 2002; Graeff, 2002;
Griffiths and Lovick, 2002; Jacob et al., 2002), as well as
their anxiolytic effects in several other procedures (Onaivi
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 133

Table 14
Influence of drugs interacting with 5-HT2 receptor subtypes upon behaviour in the Vogel Conflict Test
Drug Class Species Route (structure) Effect Active dose range Maximum Reference
(strain) change (%)
DOI 5-HT2A agonist Rat (W) s.c. IA >0.63 mg/kg IA Brocco (unpublished observations)
MDL100,907 5-HT2A Ant Rat (SD) i.p. + 1.0 mg/kg +181 Griebel et al. (1997a)
Rat (W) s.c. + 0.16–2.5 mg/kg +265 Brocco (unpublished observations)
Ketanserin 5-HT2A Ant Rat (W) s.c. IA >2.5 mg/kg IA Brocco (unpublished observations)
BW723C86 5-HT2B agonist Rat (SD) i.p. + 10 and 30 mg/kg +193 Kennett et al. (1998)
Rat (SD) i.c. (amygdala) IA 0.03–0.3 ␮g IA Duxon et al. (1997a)
SB204,741 5-HT2B Ant Rat (W) i.p. IA >40 mg/kg IA Brocco et al. (1998)
SB215,505 5-HT2B Ant Rat (SD) p.o. IA >3.0 mg/kg IA Kennett et al. (1998)
mCPP 5-HT2C agonist Rat (SD) i.p. IA 0.6–3.0 mg/kg IA Kennett et al. (1998)
Rat (W) i.p. + 0.12–0.5 mg/kg +367 Chojnacka-Wójcik and Klodzińska
(1992)
Rat (LH) i.c. (DRN) IA >12.5 ␮g IA Higgins et al. (1992)
Ro60-0175 5-HT2C agonist Rat (SD) s.c. IA 0.1–3.0 mg/kg IA Kennett et al. (2000)
Rat (W) s.c. IA >2.5 mg/kg IA Brocco (unpublished observations)
SB206,553 5-HT2C Ant Rat (SD) i.p. + 3–30 mg/kg +319 Griebel et al. (1997a)
Rat (W) i.p. + 10–40 mg/kg +610 Dekeyne et al. (2000a)
SB242,084 5-HT2C Ant Rat (W) i.p. + 0.16–2.5 mg/kg +50 Millan et al. (2001a,b,c,d,e,f)
Ritanserin 5-HT2C Ant Rat (W) i.p. + 2.5–5.0 mg/kg +57 Stefanski et al. (1992)
Rat (W) s.c. IA 0.63–40 mg/kg IA Brocco et al. (1990)
Abbreviations—DOI: 2,5-dimethoxy-4-iodoamphetamine; mCPP: 1-(3-chlorophenyl)piperazine and IA: no significant change (inactive). For other abbre-
viations, see Table 2.

et al., 1995; Hawkins et al., 2002; Sanchez, 2003).
These observations concur, further, with the ability of 5-
HT2A receptor antagonists to attenuate the suppression of
fear-associated ultrasonic vocalizations in rats by SSRIs
(Section 4.4.2) (Schrieber et al., 1998; Sanchez and Mork,
1999).
Thus, the opposing presynaptic (facilitatory) and post-
synaptic (inhibitory) influence of 5-HT2A receptors upon
GABAergic transmission may contribute to their multiple,
contrasting roles in the modulation of anxious states. The in-
fluence of 5-HT2A receptor ligands clearly depends upon the
type of anxious state under experimental or clinical study.
Currently, the balance of evidence favors predominantly anx-
iolytic properties of 5-HT2A receptor antagonists, at least in
models of conditioned fear, and there is a preliminary re-
port of anxiolytic actions of a preferential 5-HT2A receptor
antagonist in man (Deakin, 1988; Deakin and Graeff, 1991;
Connell et al., 1995). Furthermore, as pointed out above,
sustained activation of 5-HT2A receptors ultimately leads to
their functional disengagement by down-regulation.
In view of the extensive use of agents possessing 5-HT2A
antagonist properties in the management of anxiety dis-
orders (for example, the antidepressants, mirtazapine and
trazodone), schizophrenia (for example, the antipsychotics,
clozapine and risperidone) and depression (for example, the
tricyclic agents, clorimipramine and mianserin) (Sections
4.4 and 4.5), further exploration of the significance of
5-HT2A receptors in the control of anxious states would
appear of some importance (Brunello et al., 1995; Sperling
and Demling, 1997; Meltzer, 1999; Millan et al., 2000a,c;
Ninan et al., 2002).
4.3.4.3. 5-HT2B receptors. The low level of 5-HT2B sites
in the CNS as compared to peripheral tissues has discour-
aged interest in their potential role in the control of anx-
ious states. However, they have been detected in the amyg-
dala, lateral septum and hypothalamus (Duxon et al., 1997a;
Russel et al., 2002), and anxiolytic actions of the 5-HT2B
receptor agonist, BW723C86, have been observed in several
experimental models (Kennett et al., 1996a; Duxon et al.,
1997b). Further, anxiogenic properties of the 5-HT2B/2C
agonist, Ro60,0175, at 5-HT2C receptors (Section 4.3.4.4)
were revealed in the presence of selective 5-HT2B recep-
tor antagonists to mask an anxiolytic component of activity
mediated by these sites (Lightowler et al., 2000). Microin-
jection studies indicate that 5-HT2B sites in the (medial)
amygdala transduce the anxiolytic actions of BW723C86
in the social interaction procedure (Hascoët et al., 2000).
In the VCT, robust, dose-dependent and specific increases
in responses were reported upon systemic administration of
BW723C86: significantly, in light of its limited selectivity,
selective antagonists at 5-HT2B receptors abolished its anxi-
olytic properties (Table 14) (Kennett et al., 1998). However,
the population of 5-HT2B sites which mediates anxiolytic
actions of BW723C86 in the VCT is not located in the amyg-
dala, and remains to be identified (Duxon et al., 1997b).
134 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Selective antagonists at 5-HT2B receptors are inactive in the
VCT and several other procedures (Kennett et al., 1996a;
Brocco et al., 1998; Lightowler et al., 2000).
4.3.4.4. 5-HT2C receptors. 5-HT2C receptors are enriched
in the FCX, hippocampus, amygdala, nucleus accumbens,
hypothalamus, PAG and septum, offering an anatomical
foundation for their major role in the control of anxious
states (Wright et al., 1995; Sharma et al., 1997; Clemett
et al., 2000; Lopez-Giménez et al., 2001; Anderson et al.,
2002). Though 5-HT2C receptors (probably in the raphe
nuclei) may exert a modulatory influence upon serotonergic
transmission under certain conditions, the functional sig-
nificance of this action remains unclear (Barnes and Sharp,
1999; Clemett et al., 2000; Gobert et al., 2000; Millan
et al., 2000d). Via activation of GABAergic interneurones,
5-HT2C receptors exert an indirect, inhibitory influence
upon the tonic and stress-induced activity of corticolimbic
noradrenergic and mesocortical dopaminergic projections
(Gobert et al., 2000; Millan et al., 2000d; Di Giovanni et al.,
2001; Di Matteo et al., 2001; Pozzi et al., 2002). Conse-
quently, the activity of these pathways is powerfully sup-
pressed and enhanced by 5-HT2C agonists and antagonists,
respectively, actions which may well influence their control
of anxious states (see below). In limbic structures, activa-
tion of 5-HT2C receptors, via a protein kinase C-dependent
mechanism, interferes with the operation of colocalized
GABAA receptors, providing a mechanism for expression
of their anxiogenic properties (Huidobro-Toro et al., 1996).
Historically, there has been a tendency to attribute anxio-
genic actions of the clinical, serotonergic probe and “5-HT2 ”
agonist, mCPP (Section 4.3.4.1), in animals and man to the
engagement of 5-HT2C receptors, whereas the (generally)
anxiolytic actions of the “5-HT2 ” receptor antagonist, ri-
tanserin (see below), are considered to reflect their block-
ade (Brocco et al., 1990; Kahn and Wetzler, 1991; Anderson
et al., 2002). Subsequent studies of more selective ligands,
the focus of the following comments, largely support this
assumption.
Anxiogenic actions of mCPP and preferential 5-HT2C re-
ceptor agonists, such as Ro60,0175, have generally been re-
ported for tests based on spontaneous behavioural responses.
In studies where anxiogenic effects were absent, this may
reflect their confounding actions at other classes of recep-
tor (notably, anxiolysis-mediating 5-HT2B receptors, Section
4.3.4.3), and their 5-HT2C receptor-mediated sedative and
hypophagic properties (Kennett et al., 1989; Gibson et al.,
1994; Onaivi et al., 1995; Mora et al., 1997; Martin et al.,
1998; Setem et al., 1999; Kennett et al., 2000). Interestingly,
mCPP displayed mutual cross-generalization to the anxio-
genic agent, pentylenetetrazol (which acts as an antagonist
at the picrotoxin-sensitive site of GABAA receptors), in a
drug-discrimination procedure (Wallis and Lal, 1998). In ac-
cordance with anxiogenic actions of agonists, the 5-HT2C re-
ceptor antagonists, SB206,553, SB242,084 and SB243,213,
display robust anxiolytic actions in models such as the social
interaction procedure (Gacsalyi et al., 1997; Griebel et al.,
1997a; Mora et al., 1997; Graeff et al., 1998; Dekeyne et al.,
2000b; Millan et al., 2001a) and various conflict paradigms
(Chopin and Briley, 1987; Brocco et al., 1990, 1998; Kennett
et al., 1995, 1996b, 1997a; Wood et al., 2001; Martin et al.,
2002a). Similarly, these and other 5-HT2C receptor antago-
nists enhance punished responses in the VCT (Table 14 and
Fig. 7) (Stefański et al., 1992; Gacsalyi et al., 1997; Griebel
et al., 1997a; Dekeyne et al., 2000b; Millan et al., 2001a).
Such observations coincide with reports suggestive of di-
minished anxiety in mice lacking 5-HT2C receptors (Heisler
et al., 1998a; Rocha et al., 2002). Further, anxiolytic actions
of ritanserin and a further “5-HT2 ” receptor antagonist, me-
tergoline, have been seen: (1) in patients with GAD and (2)
in healthy probands subjected to protocols of conditioned
or anticipatory fear (Ceulemans et al., 1985; Graeff et al.,
1985; Hensman et al., 1991; Katz et al., 1993). Finally, a
progressive reduction in the density of 5-HT2C receptors in
the frontal cortex, amygdala and hippocampus likely con-
tributes to the delayed onset of anxiolytic actions of SS-
RIs and other classes of antidepressant agent (Section 4.4.2)
(Deakin, 1988, 1991; Rocha et al., 1994; Bristow et al.,
2000; Dekeyne et al., 2000a; Van Oekelen et al., 2003).
It is, thus, possible to marshall an impressive array of
data in support of anxiolytic properties of 5-HT2C receptor
antagonists. Nevertheless, in a clinical model of uncon-
ditioned fear (simulated public-speaking), ritanserin and
metergoline were found to potentiate anxiety, whereas
anxiolytic effects were acquired with 5-HT releasers and
a selective 5-HT2C receptor agonist (Graeff et al., 1985;
Guimarães et al., 1997; Connell et al., 1998). Further, meter-
goline abrogated the (rapid) relief by SSRIs by premenstrual
dysphoric disorder (Roca et al., 2002), while 5-HT2C recep-
tor antagonists may aggravate panic attacks (Den Boer and
Westenberg, 1990; Graeff et al., 1993, 2001). These observa-
tions can be assimilated into a framework whereby, in con-
trast to anxiogenic actions (for conditioned fear, GAD and
phobias, etc.) mediated by 5-HT2C receptors in the amyg-
dala and/or hippocampus (Hodges et al., 1987), 5-HT2C
receptors in the dorsomedial hypothalamus and the dorsal
PAG suppress—or fail to effect—non-conditioned, aversive
stimuli (Deakin and Graeff, 1991; Graeff et al., 1996b,
2001; Guimaraes et al., 1997; Zangrossi et al., 2001; Jacob
et al., 2002; Blanchard et al., 2003). By analogy, 5-HT2C ag-
onists rather than antagonists generally reduce the aversive
effects of PAG stimulation in rats (Jenck et al., 1989, 1990,
1998; Mora et al., 1997; Graeff, 2002), a model thought
to be related to panic attacks. Furthermore, in a procedure
of fear-induced ultrasonic vocalizations which has likewise
been related to panic disorders in man, this response is simi-
larly resistant to 5-HT2C receptor antagonists, yet attenuated
by agonists (Molewijk et al., 1995b; Dekeyne et al., 2000b;
Millan et al., 2001a). The above-mentioned inhibitory and
facilitatory influence of 5-HT2C agonists and antagonists,
respectively, upon corticolimbic noradrenergic transmission
may be relevant to these findings, inasmuch as the triggering
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
of panic attacks has been imputed to a hyperactivation of
noradrenergic pathways (Gorman et al., 1989, 2000;
Zacharko et al., 1995; Lovick, 2000; Millan et al., 2000d).
Nevertheless, not all observations are consistent with the
above scenario and both experimental and clinical evidence
that engagement of 5-HT2C receptors favors even uncondi-
tioned fear and panic-like states is available (Charney et al.,
1987; Benjamin et al., 1999; Kennett et al., 2000; Jones
et al., 2002a). There is, thus, a need for further study of
the role(s) of 5-HT2C receptors in the control of panic-like,
unconditioned, PAG-integrated, anxious states.
To summarize, despite the robust and clinically-relevant
anxiolytic actions of 5-HT2C receptor antagonists in the VCT
and several other models, it appears that 5-HT2C receptors
do not fulfil a unitary role in the control of anxious states.
Their clinical exploitation must be undertaken with this in
mind. Definitive resolution of the therapeutic significance of
5-HT2C receptors to the control of anxiety will only come
upon eagerly-awaited trials of genuinely-selective 5-HT2C
receptor antagonists (and agonists) (Fitzgerald and Ennis,
2002).
4.3.5. 5-HT3 receptors
4.3.5.1. Coupling, localization and interactions. 5-HT3
receptors may be distinguished from all other classes of
5-HT receptor in that they comprise ligand-gated, pen-
tameric ion channels structurally homologous to GABAA
receptors (Section 2.2) but functionally distinct in that they
are primarily permeable to cations. Activation of 5-HT3
receptors has been shown to engage phospholipase C and
thereby elevate intracellular concentrations of Ca2+ , rein-
forcing their excitatory influence upon neuronal activity
(Dubin et al., 1999; Millan, 2002a). Two subunits of 5-HT3
receptors have been cloned. In contrast to 5-HT3A sub-
units, heterologous expression of 5-HT3B subunits alone
does not yield functional receptors. Rather, they confer
distinctive biophysical (current-gating) properties upon
5-HT3A /5-HT3B heteromers as compared to pure 5-HT3A
homomers (Davis et al., 1999; Dubin et al., 1999; Hanna
et al., 2000; Brady et al., 2001). The suspicion that, by
analogy to structurally-related GABAA (Section 2.2) and
nicotinic (Section 6.2) receptors, 5-HT3 receptors may pos-
sess modulatory sites was recently afforded a concrete basis
with the identification of an inhibitory, allosteric site re-
sponsive to cannabinoids (Section 8.1). 5-HT3 receptors are
expressed in the entorhinal cortex, hippocampus, septum,
amygdala and hypothalamus (Doucet et al., 2000; Miquel
et al., 2002). Though mRNA encoding 5-HT3B subunits has
been detected in human brain, it has been suggested that
CNS-localized (as compared to peripheral) neurones in the
rat synthesize exclusively 5-HT3A subunits—conceivably
in addition to other, as yet undescribed, subunits (Dubin
et al., 1999; Morales and Wang, 2002).
Though initial studies indicated a facilitatory influence of
5-HT3 receptors upon dopaminergic and noradrenergic path-
135
ways, the specificity of these effects has been questioned and
selective 5-HT3 receptor antagonists do not modify extra-
cellular level of DA, NA or 5-HT in cortical or sub-cortical
structures (Barnes and Sharp, 1999; Millan et al., 2000d;
Morales and Wang, 2002). The detection of 5-HT3 receptors
on a subset of GABAergic neurones in the amygdala, hip-
pocampus and FCX (Morales and Bloom, 1997; Jakab and
Goldman-Rakic, 2000) provides an anatomical substrate for
an enhancement of GABA release in these structures (Ashby
et al., 1991; Ropert and Guy, 1991; Diez-Ariza et al., 1998;
Shen and Andrade, 1998; Stutzmann and LeDoux, 1999;
Zhou and Hablitz, 1999; Koyama et al., 2000, 2002). Such
an influence would be consistent with an anxiolytic role of
5-HT3 receptors, though no evidence to support this possibil-
ity has been forthcoming. On the other hand, the observation
that stimulation of 5-HT3 receptors augments cortical re-
lease of CCK (Paudice and Raiteri, 1991; Raiteri et al., 1993;
Morales and Bloom, 1997) is compatible with an anxiogenic
role of 5-HT3 receptors “upstream” of CCK-containing neu-
rones. Contrariwise, the reduction of CCK-induced panic
attacks in human subjects by pre-treatment with 5-HT3 re-
ceptor antagonists (Dépôt et al., 1999) situates 5-HT3 sites
“downstream” of CCK receptors. The interrelationship of
5-HT3 receptors and CCK in the modulation of anxious
states awaits, thus, further clarification.
4.3.5.2. Control of anxious states. By analogy to the
low-anxiety shown by mice genetically lacking 5-HT3A
receptor subunits (Kelley et al., 2003), 5-HT3 receptor an-
tagonists generally exert positive effects in models based on
exploratory behaviour, such as the plus-maze and the mouse
light–dark (two-compartment) box though—bizarrely—
in the latter instance at virtually “homeopathic” doses
(Malgorzata et al., 1992; Bentley and Barnes, 1995; Costall
and Naylor, 1997; Greenshaw and Siverstone, 1997; Olivier
et al., 2000; Bourin and Hascoët, 2003; Prut and Belzung,
2003). Their actions in paradigms of conditioned fear, in-
cluding the VCT, are less striking, usually being expressed
in a drug-dependent fashion, over a limited dose range and
primarily when parameters are adjusted to elicit only a
modest level of response suppression (Nevins and Anthony,
1994; Greenshaw and Siverstone, 1997; Olivier et al.,
2000). Indeed, it remains unclear as to why certain 5-HT3
receptor antagonists but not others are effective in these
paradigms (Table 15) (Jones et al., 1988; Piper et al., 1988;
Filip et al., 1992; Malgorzata et al., 1992; Stefański et al.,
1992, 1993b; Artaiz et al., 1995; Greenshaw and Siverstone,
1997; Olivier et al., 2000; Sanchez, 2003). Studies of con-
flict and other procedures indicate that 5-HT3 sites in the
hippocampus, nucleus accumbens and amygdala (though
not for the VCT) transduce the anxiolytic properties of
5-HT3 receptor antagonists (Table 15 and Fig. 8) (Costall
et al., 1989; Higgins et al., 1991; Stefański et al., 1993b;
Gargiulo et al., 1996). The modest and idiosyncratic effects
of various 5-HT3 receptor antagonists in the VCT and other
experimental models resemble their lack of reproducible
136 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Table 15
Influence of drugs interacting with 5-HT3 receptor ligands upon behaviour in the Vogel Conflict Test
Drug Class Species Route (structure) Effect Active dose range Maximum Reference
(strain) change (%)
Ondansetron 5-HT3 Ant Rat (W) i.p. + 0.1 and 0.3 mg/kg +465 Filip et al. (1992)
Rat (W) i.p. + 1.5 mg/kg +34 Stefanski et al. (1992)
Rat (W) i.p. + 0.05–1.6 +117 Jones (1988)
Rat (W) s.c. IA >0.63 mg/kg IA Brocco (unpublished
observations)
Rat (W) i.c. (hippocampus) + 1 and 2.5 ␮g +69 Stefanski et al. (1993b)
Rat (W) i.c. (N. accumbens) IA 0.01 and 15 ␮g IA Stefanski et al. (1993b)
Rat (LH) i.c. (amygdala) − 0.001–1.0 ␮g NI Higgins et al. (1991)
Granisetron 5-HT3 Ant Rat (W) i.p. + 0.1 mg/kg +92 Filip et al. (1992)
Rat (W) i.p. + 0.1 mg/kg +92 Aertaiz et al. (1995)
Tropisetron 5-HT3 Ant Rat (W) i.p. + 0.01 mg/kg +430 Filip et al. (1992)
Rat (W) i.p. + 0.25 and 0.5 mg/kg +430 Artaiz et al. (1995)
Rat (W) i.p. + 0.001–0.01 mg/kg +36 Stefanski et al. (1992)
Rat (W) i.c. (hippocampus) + 0.005 and 0.01 ␮g +125 Stefanski et al. (1993b)
Rat (W) i.c. (N. accumbens) + 0.01 and 0.25 ␮g +76 Stefanski et al. (1993b)
Rat (LH) i.c. (amygdala) − 0.001–0.1 ␮g NI Higgins et al. (1991)
MDL72,222 5-HT3 Ant Rat (W) i.p. IA 0.01–3.0 mg/kg IA Filip et al. (1992)
DAU6215 5-HT3 Ant Rat (W) s.c. IA 0.01–3.0 mg/kg IA Filip et al. (1992)
VA21B7 5-HT3 Ant Rat (W) i.p. + 1 and 2 mg/kg +85 Artaiz et al. (1995)
Zacopride 5-HT3 Ant Rat (W) i.p. + 0.1 and 1.0 mg/kg +215 Filip et al. (1992)
Abbreviations—N. accumbens: nucleus accumbens and IA: no significant change (inactive). For other abbreviations, see Table 2.

and convincing efficacy in clinical trials of GAD and panic
attacks (see Greenshaw and Siverstone, 1997; Olivier et al.,
2000).
4.3.6. Other classes of 5-HT receptor
4.3.6.1. 5-HT4 receptors. The presence of 5-HT4 recep-
tors (which engage adenylyl cyclase via Gs) in the hip-
pocampus and habenula in high levels, and in the septum and
amygdala (of rodents) in more modest densities, is consis-
tent with a role in the modulation of anxious states (Jakeman
et al., 1994; Waeber et al., 1994; Bonaventure et al., 2000).
Though their influence upon GABAergic transmission in
subcortical structures does not appear to have been defined,
5-HT4 receptors exert a complex, bi-modal influence upon
GABAA receptor-mediated currents in frontocortical pyra-
midal neurones: that is, GABAergic inhibition is accentuated
in certain cells and relieved in others. This bi-directional ef-
fect reflects a protein kinase A-dependent phosphorylation
of ␤1 (reduction) and ␤3 (enhancement) subunits, respec-
tively (Cai et al., 2002a; Yan, 2002).
5-HT4 receptors appear to exert a facilitatory influence
upon DRN-derived serotonergic neurones. However, the
contribution of direct and indirect mechanisms to this ac-
tion, and the conditions under which it is expressed, remain
to be determined (Jakeman et al., 1994; Ge and Barnes,
1996; Lucas and Debonnel, 2002). Inhibition of seroton-
ergic transmission might be related to reports that 5-HT4
receptor antagonists display anxiolytic properties in mod-
els based on spontaneous exploratory behaviour (Silvestre
et al., 1996; Kennett et al., 1997b; Menard and Treit, 1999).
However, their effects are not spectacular and 5-HT4 re-
ceptor antagonists were found to be inactive in a conflict
paradigm (Kennett et al., 1997b). Further, it has been re-
ported that 5-HT4 receptor antagonists interfere with the
actions of BZPs and other drug classes in exploratory mod-
els of anxiolytic activity, suggesting that 5-HT4 receptors
may participate in mechanisms inhibitory to anxious states.
Correspondingly, it was recently reported that the genetic
ablation of 5-HT4 receptors is associated with an anxio-
genic phenotype (Cheng et al., 1994; Costall and Naylor,
1997; Gazzara et al., 2002). On the other hand, 5-HT4 re-
ceptor antagonists did not modify the anxiolytic effects of
SSRIs in a model of fear-induced ultrasonic vocalization
(Schreiber et al., 1998).
In view of this contradictory pattern of data, further ex-
ploration of the potential influence of 5-HT4 receptors upon
anxious states is necessary before definitive conclusions can
be made concerning their—currently equivocal—role.
4.3.6.2. 5-HT5 receptors. Of the two subtypes of 5-HT5
receptor, 5-HT5A and 5-HT5B , only the former is present in
human CNS (Grailhe et al., 2001). Activation of 5-HT5A re-
ceptors has been shown to inhibit adenylyl cyclase activity
and to promote K+ -currents, though the question of their
principle mode of intracellular coupling is incompletely re-
solved (Francken et al., 1998; Graı̈lhe et al., 2001; Millan,
2002a). Though they have been largely neglected to date,
5-HT5A receptors are of special note in view of their high
concentration in the hippocampus, cortex, septum, habenula,
amygdala and the PAG, as well as the LC and raphe nuclei, of
both rodent and human brain (Pasqualetti et al., 1998; Oliver
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
et al., 2000; Kinsey et al., 2001). Mice lacking 5-HT5A sites
showed no clear alterations in behaviour in several models of
anxiety (Grailhe et al., 1999), but the distinctive anatomical
organization of 5-HT5 sites in corticolimbic structures sup-
ports further exploration with the VCT and other paradigms
of their potential implication in the modulation of anxious
states.
4.3.6.3. 5-HT6 receptors. 5-HT6 receptors, which are
positively coupled to adenylyl cyclase via Gs (Boess
et al., 1997), are abundant in the hippocampus, nucleus
accumbens, amygdala, frontal cortex and entorhinal cortex
(Yoshioka et al., 1998; Hamon et al., 1999; Kinsey et al.,
2001; Millan, 2002a; Roberts et al., 2002b). There are sev-
eral indications that their blockade may favor anxious states.
Thus, mice lacking 5-HT6 receptors present an anxiogenic
phenotype (Tecott et al., 1998), while antisense probes neu-
tralizing 5-HT6 receptors exerted anxiogenic properties in
rats (Hamon et al., 1999; Otano et al., 1999). Further, it
has been reported that selective 5-HT6 antagonists accel-
erate hippocampal and frontocortical release of glutamate,
NA and/or DA, though contradictory data have been ob-
tained (possibly reflecting differences amongst rat strains)
(Matsumoto et al., 1999; Dawson et al., 2000, 2001; Frantz
et al., 2002; Gobert and Millan, unpublished observation).
On the other hand, there is some (albeit inconclusive) evi-
dence for 5-HT6 receptor expression in raphe nuclei (Gérard
et al., 1996; Kinsey et al., 2001). These findings may be
related to the ability of antisense probes against 5-HT6
receptors to attenuate the fear-induced release of 5-HT in
FCX (Gérard et al., 1996; Yoshioka et al., 1998), though
selective 5-HT6 receptor antagonists do not affect basal
cerebral release of 5-HT (Dawson et al., 2000, 2001; Gobert
and Millan, unpublished observations). Recently-described,
selective antagonists at 5-HT6 receptors (Slassi et al., 2002)
could instructively be employed in the VCT and other pro-
cedures for further elucidation of their currently-ambiguous
role in the control of anxious states.
4.3.6.4. 5-HT7 receptors. 5-HT7 sites potentiate the ac-
tivity of adenylyl cyclase via recruitment of Gs (Hagan
et al., 2000). They are well-represented in the hippocam-
pus, cortex, lateral septum, hypothalamus and amygdala
(Hagan et al., 2000; Kinsey et al., 2001; Neumaier et al.,
2001). It has been suggested that 5-HT7 receptors operate
as autoreceptors on serotonergic perikarya. Though these
populations are of comparatively minor significance as
compared to dendritic 5-HT1A receptors (Section 4.3.2.1)
and terminal-localized 5-HT1B receptors (Section 4.3.3.1)
(Roberts et al., 2001, 2002a; Bonaventure et al., 2002),
5-HT7 receptors may exert an indirect inhibitory influence
upon DRN-localized serotonergic perikarya via the acti-
vation of local GABAergic interneurones (Roberts et al.,
2002a). This configuration is coherent with a role of 5-HT7
receptors in the modulation of anxiety via an interaction
with GABAergic and serotonergic mechanisms. However,
137
data concerning the actions of antisense probes directed
against 5-HT7 receptors and of selective antagonists remain
fragmentary and offer little support for such a possibility
(Clemett et al., 1998; Vanhoenacker et al., 2000). Thus, a
more thorough evaluation of the potential significance of
5-HT7 receptors in the control of anxions states is required
before concrete conclusions can be reached.
4.4. Antidepressant agents
4.4.1. Clinical actions of antidepressant agents in the
treatment of anxious states
Evaluation of the influence of antidepressant agents upon
anxious states is of considerable interest inasmuch as: (1)
genetic variation (polymorphisms) in the human 5-HT trans-
porter (reuptake site) is associated with an altered response
of the amygdala to fear (Lesch et al., 1996; Hariri et al.,
2002a,b); (2) mice lacking 5-HT transporters show increased
anxiety (Wichems et al., 2000); (3) a substantial proportion
of depressed patients display co-morbid anxious symptoms
(Nutt, 2000; Zimmerman et al., 2000) and (4) antidepressant
agents are increasingly employed in the long-term treatment
of diverse anxious states—despite their tendency to exacer-
bate symptoms upon commencing treatment (Sramek et al.,
2002).
In the latter respect, both SSRIs (Van Der Linden et al.,
2000; Kasper and Resinger, 2001; Millan et al., 2001c,d;
Kent et al., 2002a,b; Liebowitz et al., 2002; Roca et al., 2002;
Varia and Rauscher, 2002; Wagstaff et al., 2002) and mixed
5-HT/NA reuptake inhibitors, such as venlafaxine and du-
loxetine (Sasson et al., 1999; Allgulander et al., 2001; Millan
et al., 2001c,d; Goldstein et al., 2002; Montgomery et al.,
2002), have proven clinically effective against a broad range
of anxiety disorders. Indeed, together with BZPs and 5-HT1A
agonists (both effective in the VCT), SSRIs represent the
cornerstone of therapy for patients with GAD (Vetulani and
Nalepa, 2000; Gorman, 2002; Sramek et al., 2002). More-
over, selective NA reuptake inhibitors also express clinical
anxiolytic properties upon sustained administration suggest-
ing that therapeutic efficacy can be achieved independently
of serotonergic mechanisms (Sasson et al., 1999; Millan
et al., 2001c,d; Stahl et al., 2002; Versiani et al., 2002). The
clinical utility of such reuptake inhibitors is shared by agents
which behave as antagonists at 5-HT2C receptors including:
(1) mianserin—which also inhibits NA reuptake (Bjertnaes
et al., 1982; Jenck et al., 1994); (2) mirtazapine, a potent
5-HT2C receptor (and ␣2 -AR) antagonist devoid of activ-
ity at reuptake sites (Sperling and Demling, 1997; Feighner,
1999; Millan et al., 2000c,d) and (3) nefazodone—which
also inhibits 5-HT reuptake (Silva et al., 2001; Ninan et al.,
2002). Interestingly, by analogy to the 5-HT2 receptor antag-
onists, ritanserin and metergoline (Section 4.3.4), blockade
of 5-HT2C sites was specifically implicated in the ability of
nefazodone to blunt conditioned (but not unconditioned) fear
in normal human subjects (Nutt, 1996; Graeff et al., 2001;
Silva et al., 2001). Nefazodone has also revealed anxiolytic
138 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
activity in patients with social phobia or with co-morbid
anxiety and depression and it reduces anxious symptoms
in individuals undergoing marijuana withdrawal (Zajecka,
1996; Van Ameringen et al., 1999; Haney et al., 2003).
4.4.2. SSRIs and mixed 5-HT/NA reuptake inhibitors:
long-term, adaptive actions
In analogy to 5-HT2C receptor agonists (Section 4.3.4.4),
and reflecting indirect activation of 5-HT2C sites by an in-
crease in extracellular levels of 5-HT, acute application of
SSRIs and tricyclic agents moderates the aversive effects of
PAG stimulation in rodents (Jenck et al., 1998; Schenberg
et al., 2002), a model of especial pertinence to unconditioned
fear and panic-like states (Section 1.5.3.2). A progressive
sensitisation of 5-HT2A/2C and 5-HT1A receptors in the
PAG was, further, proposed to account for the long-term,
beneficial actions of antidepressants drugs in unconditioned
(panic-like) anxiety states in man (Borsini et al., 2002;
Graeff, 2002; Jacob et al., 2002; Castro et al., 2003).
This hypothesis remains, however, to be reconciled with
evidence discussed below that prolonged antidepressant
exposure down-regulates levels of 5-HT2A/2C receptors in
corticolimbic structures.
In patients suffering from GAD or phobias, anxiety is
initially aggravated by treatment with antidepressant agents
(Section 4.4.1). Correspondingly, acute application of SS-
RIs and of 5-HT/NA reuptake inhibitors elicits anxiogenic
effects in the rodent social interaction test. Though activa-
tion of postsynaptic 5-HT1A sites has been incriminated,
this is debatable (Schreiber et al., 1998; Duxon et al., 2000;
File et al., 2000; Kõks et al., 2001a; Li et al., 2001b) and the
indirect engagement of 5-HT2C receptors (by 5-HT) appears
to be primarily involved (Bristow et al., 2000; Dekeyne
et al., 2000a; Bagdy et al., 2001; Kõks et al., 2001a;
Allikmets et al., 2002). Upon long-term administration of
SSRIs, their anxiogenic effects wane and there may be a
gradual transition to anxiolytic actions (Bodnoff et al., 1989;
Griebel et al., 1994; Beaufour et al., 1999; Skrebuhkova
et al., 1999; Bristow et al., 2000; Duxon et al., 1997a; Silva
and Brandao, 2000; Li et al., 2001c; Borsini et al., 2002;
Jones et al., 2002b) paralleling the delayed onset of clinical
anxiolytic, panicolytic (and antidepressant) properties in
man.
This time-dependent institution of anxiolytic properties
may involve a progressive inactivation of the response of
raphe-derived serotonergic and/or LC-derived noradrenergic
neurones to stress: however, neurochemical studies have not
led to a consensus in this regard (Page and Abercrombie,
1997; Anthony et al., 2000; Szabo et al., 2000; Dazzi
et al., 2002; Page and Lucki, 2002). Further, owing to
down-regulation of inhibitory 5-HT1A and 5-HT1B autore-
ceptors (Sections 4.3.2 and 4.3.3), as well as ␣2 -AR hetero-
ceptors (Linner et al., 1999; Mateo et al., 2001), “resting”
monoaminergic transmission is actually enhanced. It is
more likely, then, that the decisive events occur downstream
of monoaminergic neurones, including a 5-HT-mediated
down-regulation/uncoupling of postsynaptic, corticolimbic
populations of 5-HT2C and, possibly, 5-HT1A and 5-HT2A
receptors mediating anxiety (Sections 4.3.2 and 4.3.4)
(Hollander et al., 1991; Kennett et al., 1994; Maj et al.,
1996; Skrebuhhova et al., 1999; Bristow et al., 2000; File
et al., 2000; Berg et al., 2001; Kagaya et al., 2001; Millan
et al., 2001c,d; Hensler, 2002; Shen et al., 2002; Stout et al.,
2002; Castro et al., 2003; Van Oekelen et al., 2003).
Other changes may also be implicated in the long-term
anxiolytic actions of drugs which suppress 5-HT (and
5-HT/NA) reuptake: a reduction in NPY, CCK, CRF, VP
and glucocorticoid-mediated mechanisms of anxiety, modu-
lation of GABA and neurosteroid production (Section 2.2.3),
and changes in the responsiveness of the hypothalamo-corti-
cotropic axis (Barden et al., 1995; Montkowski et al., 1995;
Duncan et al., 1998; To et al., 1999; To and Bagdy, 1999;
Makino et al., 2000, 2002a,b; Sanacora et al., 2002; Yau
et al., 2002).
With one exception in mice (Hascoët et al., 2000), acute
administration of SSRIs or 5-HT/NA reuptake inhibitors
has proven to be inffective or to increase anxiety in the VCT
and other conflict procedures, mirroring above-mentioned
clinical and experimental observations (Table 16 and Fig. 7)
(Mason et al., 1987; Fontana and Commissaris, 1988;
Fontana et al., 1989a; Kostowski et al., 1994; Beaufour et al.,
1999; Borsini et al., 2002). In certain conflict paradigms, it
has been shown that chronic treatment is accompanied by
the progressive induction of anxiolytic effects (Fontana and
Commissaris, 1988; Fontana et al., 1989a; Beaufour et al.,
1999; Borsini et al., 2002) and, assuming its appropriate
manipulation to detect acute anxiogenic actions of SSRIs
and 5-HT/NA reuptake inhibitors, such studies would be of
interest to undertake with the VCT.
4.4.3. Selective NA reuptake inhibitors
Selective inhibitors of NA reuptake, such as reboxetine,
mimic the anxiogenic effects of SSRIs upon acute admin-
istration in the social interaction protocol ((Hascoët et al.,
1994); Dekeyne and Millan, unpublished observation).
Though their long-term effects in this procedure remain
to be evaluated, chronic (as compared to acute) admin-
istration induced a gradual anxiolytic effect in a conflict
model (Fig. 6) (Beaufour et al., 1999; Lacerra et al., 1999).
Interest in NA reuptake inhibitors it underpinned by their
therapeutic efficacy in the control of GAD and other anxiety
disorders (Section 4.4.1) and by the following observations:
(1) mice genetically deprived of NA transporters reveal
sustained alterations in emotional behaviour (Haller et al.,
2002a); (2) selective NA reuptake inhibitors are more effec-
tive than SSRIs in moderating the behavioural symptoms of
BZP withdrawal Lacerra et al. (1999) and (3) NA reuptake
inhibitors suppress the response of noradrenergic pathways
to stress (Valentino et al., 1990; Durand et al., 2000). It is
possible that prolonged exposure to NA reuptake inhibitors
induces adaptive processes simular to those engendered
by other antidepressant agents (Secton 4.4.2). However,
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 139

Table 16
Influence of antidepressant agents upon behaviour in the Vogel Conflict Test
Drug Class Species Route Effect Active dose Maximum Reference
(strain) (structure) range (mg/kg) change (%)
Citalopram SSRI Rat (W) s.c. IA 0.63–40.0 IA Brocco (unpublished observations)
Fluoxetine SSRI Rat (W) s.c. IA 0.63–40.0 IA Brocco (unpublished observations)
Maprotiline NARI Rat (SD) s.c. IA 3.0–30.0 IA Mason et al. (1987)
Reboxetine NARI Rat (W) i.p. IA 0.63–10.0 IA Brocco (unpublished observations)
Venlafaxine SNRI Rat (W) s.c. IA >10.0 IA Brocco (unpublished observations)
S33005 SNRI Rat (W) s.c. IA 0.16–10.0 IA Brocco (unpublished observations)
AS-8 SNRI Rat (W) i.p. IA 50–100 IA Kostowski et al. (1994)
Trazodone SSRI/5-HT2 Ant Rat (SD) s.c. + 0.1–10.0 +320 Mason et al. (1987)

Mianserin NARI/5-HT2A/2C Ant Rat (SD) s.c. + 3.0 +90 Mason et al. (1987)
Rat (SD) s.c. + 10.0 +290 Griebel et al. (1997a,b)
Rat (W) s.c. + 2.5 and 10.0 +90 Brocco (unpublished observations)
Mirtazapine 5-HT2A/2C Ant Rat (W) s.c. + 0.63–40.0 +230 Brocco (unpublished observations)
Abbreviations—SSRI: selective serotonin reuptake inhibitor; NARI: noradrenaline reuptake inhibitor; SNRI: serotonin and noradrenaline reuptake inhibitor
and IA: no significant change (inactive). For other abbreviations, see Table 2.

the neuronal mechanisms underlying the long-term, (and 5-HT2A ) receptors appears to more than compensate
therapeutic and experimental anxiolytic properties of NA for its inhibition of 5-HT reuptake (Table 16) (Mason et al.,
reuptake inhibitors remain obscure. 1987; Griebel et al., 1997a, Griebel et al., 1997).

4.4.4. Antidepressant agents possessing 5-HT2A/2C 4.4.5. Monoamine oxidase inhibitors

antagonist properties
In distinction to SSRIs and other agents which interact
with 5-HT transporters, the antidepressants, mianserin and
mirtazapine, are devoid of activity at these sites and share po-
tent antagonist properties at 5-HT2C receptors (Jenck et al.,
1994; Sperling and Demling, 1997; Millan et al., 2000c,d).
In each case, they elicit robust and dose-dependent anxi-
olytic actions in the VCT (Table 16) (Brocco and Millan,
unpublished observations). These observations suggest that
their clinical relief of anxious states might be more rapidly
expressed than in the case of SSRIs, though this remains
to be rigorously demonstrated by well-designed, compara-
tive therapeutic trials (Feighner, 1999; Van Hensbeek et al.,
2000; Quitkin et al., 2001; Borsini et al., 2002; Van Veen
et al., 2002). Mianserin and mirtazapine also show pro-
nounced anxiolytic actions in non-conflict paradigms sensi-
tive to 5-HT2C antagonists and, in such models, their actions
are generally more pronounced upon long-term application
(Chopin and Briley, 1987; Bodnoff et al., 1989; Benjamin
et al., 1992; Dazzi et al., 2001). The latter finding coincides
with their ability (upon chronic treatment) to attenuate the re-
sponse of FCX pools of NA to stress (Dazzi et al., 2002) and
to down-regulate 5-HT2C and 5-HT2A sites, notably in the
amygdala (Zohar et al., 1988; Sanders-Bush, 1990; Rocha
et al., 1994; Anji et al., 2000; Van Oekelen et al., 2003).
This desensitization of 5-HT2A or 5-HT2C receptors, an ef-
fect common to SSRIs (Sections 4.4.1 and 4.4.2), appears
to be of key significance to the long-term control of anxious
states and manifestly does not necessitate their direct acti-
vation (Van Oekelen et al., 2003). Inasmuch as trazodone
which is structurally related to nefazodone (Section 4.4.1),
exerts anxiolytic actions in the VCT, its blockade of 5-HT2C
The mitochondrial enzyme, monoamine oxidase (MAO
A), is principally located in catecholaminergic neurones and
in astrocytes. It displays high affinity for all monoamines
including 5-HT and catalyses their degradation by oxida-
tive deamination. Mice genetically deprived of MAO A
(or B) display elevated levels of 5-HT, NA and DA (or
␤-phenylethylamine, a trace amine) together with an en-
hanced reactivity to stress, though specific and consistent al-
terations in anxious behavior have not been reported (Cases
et al., 1995; Grimsby et al., 1997; Kim et al., 1997; Shih
et al., 1999). Inhibitors of monoamine oxidase A are of clini-
cal utility in the long-term administration of management of
anxious disorders, such as phobias and panic attacks (Buller,
1995; Feighner, 1999; Shih et al., 1999; Schneier, 2001;
Blanchard et al., 2001b; Borsini et al., 2002). Accordingly,
chronic administration of MAO A inhibitors generally elic-
its anxiolytic actions in conflict (and defensive behaviour)
paradigms, though no information is currently available for
the VCT (Chopin and Briley, 1987; Fontana et al., 1989a;
Paslawski et al., 1996; Griebel et al., 1998a; Maki et al.,
2000; Bonnet, 2002; Blanchard et al., 2003). Their pro-
longed treatment also initiates adaptive events at pre- and
postsynaptic monoaminergic receptors (and in the response
of monoaminergic pathways to stress) resembling those
instigated by other classes of antidepressant agents which
act at 5-HT2C receptors and/or 5-HT transporters (Sections
4.4.2 and 4.4.4) (Twist et al., 1990; Miura et al., 1996;
Haddjeri et al., 1998; Bonnet, 2002). Such mechanisms are,
presumably, involved in the development of their anxiolytic
properties. Further, an increase in the activity of cortical
populations of GABAB receptors has been reported upon
sustained exposure to MAO inhibitors (Sands et al., 2003).
140 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Catecholamines are also subject to catabolism by
catechol-O-methyltransferase. Male mice genetically de-
prived of this enzyme showed a pronounced augmenta-
tion in DA levels and enhanced aggression, though they
displayed no propensity for alterations in anxious be-
haviour (Gogos et al., 1998). Contrariwise, notwithstand-
ing comparatively modest neurochemical changes, female
conspecifics manifested an anxiogenic phenotype. This
distinction pleads for interactions between hormones and
catechol-O-methyltransferase in the modulation of anxious
behaviour, and anticipates a consideration in Section 12.3 of
marked gender differences in the emotional response to fear.
4.5. Antipsychotic agents
Inasmuch as anxiety is frequently a co-morbid symptom
of schizophrenia, it is important to evaluate the influence of
antipsychotic agents upon anxious states (Penn et al., 1994;
Emsley et al., 1999; Braunstein-Bercovitz, 2000; Fenton,
2001).
Despite some early clinical reports (Raymond et al., 1957;
Finnerty et al., 1976) that conventional neuroleptics, such as
haloperidol, relieve anxious symptoms in “psychoneurotic
patients”, they are essentially ineffective in alleviating anx-
ious symptoms of psychotic subjects: indeed, anxiety may
even be secondarily exacerbated by their extrapyramidal and
dysphoric side-effects (Meltzer, 1995, 1999; Millan, 2000).
Correspondingly, with few exceptions (Pich and Samanin,
1986), haloperidol has generally preven to be devoid of anx-
iolytic properties in experimental models, including conflict
procedures such as the VCT: indeed, it may even elicit anx-
iogenic effects (Section 4.2.3.3) (Table 17) (Spealman et al.,
1983; Mansbach et al., 1988; Wiley et al., 1993; Moore
et al., 1994; Szewczak et al., 1995; Ninteman et al., 1996;
Bartoszyk, 1998; Millan et al., 1999a; Corbin et al., 2000;
Siemiatkowski et al., 2001).
The “atypical” antipsychotic, clozapine, differs to
haloperidol (essentially a dopaminergic D2 /D3 /D4 receptor
antagonist) in recognizing multiple classes of monoaminer-
gic receptor, a distinctive profile which underlies its lesser
propensity to provoke extrapyramidal side-effects (Corbett
et al., 1993; Brunello et al., 1995; Millan et al., 1998, 2000a;
Millan, 2000). Clozapine reveals anxiolytic properties in
several experimental models, including conflict paradigms
(Spealman et al., 1983; Bruhwyler et al., 1990; Wiley et al.,
1993; Moore et al., 1994; Szewczak et al., 1995;
Siemiatkowski et al., 2001; Manzaneque et al., 2002;
Rademacher et al., 2002; Bourin and Hascoët, 2003), though
it shows only borderline activity in the VCT (Table 17)
(Millan et al., 1999a; Corbin et al., 2000). Amongst its many
receptorial interactions, clozapine is a potent antagonist at
5-HT2A and 5-HT2C receptors (Millan et al., 1998; Cussac
et al., 2000, 2002b). Their acute blockade and longer-term
down-regulation likely contribute to its anxiolytic proper-
ties (Kuoppamaki et al., 1995; Burnet et al., 1996; Meltzer,
1999; Van Oekelen et al., 2003), in analogy to a further,
structurally-distinct, multireceptorial antipsychotic, S18327,
which does exert significant anxiolytic agents in the VCT
(Millan et al., 2000a). 5-HT2A and 5-HT2C receptor antago-
nism also likely accounts for the anxiolytic effects of other
antipsychotics with marked affinity for these sites, such as
olanzapine, in the VCT and other conflict models (Table 17)
(Engel et al., 1989; Moore et al., 1994; Benvenga and
Leander, 1995; Millan et al., 2000a; Rademacher et al.,
2002). Since sertindole likewise is a potent antagonist at
5-HT2A and 5-HT2C receptors, any potential activity in
the VCT may be compromised by its pronounced sedative
properties (Table 17) (Sanchez et al., 1995).
Clozapine also possesses partial agonist actions at
5-HT1A receptors, an action reinforced in several other (po-
tential) antipsychotic agents (Bantock et al., 2001; Millan,
2000; Cussac et al., 2002a). Notably, the mixed dopamine
D2 /5-HT1A receptor partial agonist, PD158,778, and the
dopamine D2 /5-HT2A /5-HT2C receptor antagonist/5-HT1A
receptor agonist, S16924, both of which manifest robust
anxiolytic actions in the VCT (Table 17) (Ninteman et al.,
1996; Millan et al., 1999a; Cussac et al., 2002a). Indeed,
the broad anxiolytic profile of S16924 across numerous
procedures can largely be ascribed to its stimulation of
5-HT1A receptors—though blockade of 5-HT2C sites may

Table 17
Influence of antipsychotic agents upon behaviour in the Vogel Conflict Test
Drug Class Species Route Effect Active dose Maximum Reference
(strain) (structure) range (mg/kg) change (%)
Haloperidol Neuroleptic Rat (W) s.c. IA 0.01–0.16 IA Millan et al. (1999a,b)
Rat (SD) i.p. IA >0.25 IA Corbin et al. (2000)
Clozapine “Atypical” Rat (W) s.c. IA 0.63–5.0 IA Millan et al. (1999a,b)
Rat (SD) i.p. IA >10.0 IA Corbin et al. (2000)
Amperozide 5-HT2 Ant Rat (SD) s.c. + 0.4 +60 Engel et al. (1989)
Sertindole 5-HT2 /␣1 Ant Rat (?) s.c. IA >2.5 IA Sanchez et al. (1995)
S18327 5-HT2 /␣2 Ant Rat (W) s.c. + 2.5 +260 Millan et al. (2000a)
S16924 5-HT1A agonist/5-HT2 Ant Rat (W) s.c. + 0.04 and 0.16 +320 Millan et al. (1999a,b)
PD158,778 5-HT1A PAGO Rat (SD) i.p. + 1.0 and 2.0 +550 Ninteman et al. (1996)
All drugs possess antagonist properties at dopamine D2 receptors. PAGO: partial agonist and IA: no significant change (inactive). For other abbreviations,
see Table 2.
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
also contribute (Millan et al., 1998, 1999a). An additional
antipsychotic which acts, albeit less markedly, by engage-
ment of 5-HT1A receptors is ziprasidone (Newman-Tancredi
et al., 1998; Sprouse et al., 1999; Rollema et al., 2000;
Cussac et al., 2002a). Though potential anxiolytic effects
of ziprasidone in the VCT remain to be described, it allevi-
ates anxious symptoms in psychotic patients (Schooler and
Siu, 2000).
Anxiolytic actions of antipsychotic agents are an impor-
tant feature of their clinical profiles (Tollefson et al., 1998;
Schooler and Siu, 2000; Adityanjee and Schulz, 2002;
Barnett et al., 2002) which can be well-characterized em-
ploying the VCT. The application of this procedure to
novel antipsychotic drugs acting as 5-HT1A receptor ago-
nists and/or as 5-HT2A/2C receptor antagonists—and which
display anxiolytic actions in other models (Barnes et al.,
1991; Szewczak et al., 1995; Ishida-Tokuda et al., 1996;
Sakamoto et al., 1998)—would be of considerable interest.
Finally, by mechanisms which remain to be elucidated—
and in contrast to haloperidol—clozapine increases cortical
levels of allopregnanolone in rodents suggesting that neuros-
teroids (Section 2.2.3) may be implicated in its distinctive
anxiolytic properties (Marx et al., 2003).
5. Histamine
5.1. Coupling, localization and interactions
Histaminergic projections derived from the tuberomam-
millary hypothalamus heavily innervate corticolimbic struc-
tures, including the septum, hippocampus, PAG and amyg-
dala, as well as monoaminergic cell clusters. Interestingly,
there is extensive colocalization of GABA with histamine in
this network of neurones (Panula et al., 1989; Millan, 2002a;
Trottier et al., 2002; Haas and Panula, 2003). The activity of
histaminergic pathways subserving corticolimbic structures
is enhanced in response to fear-evoking and other stressful
stimuli (Ito et al., 1999; Brown et al., 2001; Cangioli et al.,
2002; Westerink et al., 2002).
At least three classes of receptor for histamine have been
identified in the CNS. Histamine H1 receptors activate phos-
pholipase C via Gq and may also stimulate phospholipase
A2 , whereas H2 receptors couple positively to adenylyl cy-
lase via Gs. In contrast to H1 and H2 sites, inhibitory H3 re-
ceptors are coupled negatively via Gi to adenylyl cylase and
they also suppress Ca2+ -currents (Hill et al., 1997; Hough,
2001; Haas and Panula, 2003) (A fourth (H4 ) receptor, which
is virtually absent from CNS tissue (Hough, 2001; Gantner
et al., 2002), is not considered herein).
Histamine H1 and H2 receptors share high densities in
the hippocampus, amygdala, DRN and LC, and H1 sites
are also prominent in the septum and cortex (Brown et al.,
2001; Barbara et al., 2002; Haas and Panula, 2003). His-
tamine H3 receptors display a more restricted distribution.
However, recent work has demonstrated H3 receptors in the
141
amygdala, PAG, septum, nucleus accumbens, cortex and hip-
pocampus: in addition, they are produced by monoaminer-
gic and GABAergic perikarya. Of particular note is the lo-
calization of inhibitory H3 autoreceptors on histaminergic
neurones (Leurs et al., 1998; Brown et al., 2001; Chazot
et al., 2001; Drutel et al., 2001; Pillot et al., 2002; Haas and
Panula, 2003). Histaminergic pathways exert a direct facil-
itatory influence, via H1 and, less markedly, H2 receptors
upon the activity of serotonergic and noradrenergic neurones
originating in the DRN and LC, respectively—though it was
recently suggested that, via recruitment of GABAergic in-
terneurones, H1 receptors may indirectly inhibit serotoner-
gic transmission in mice (Brown et al., 2001, 2002; Son
et al., 2001; Barbara et al., 2002; Millan, 2002a). In rats,
in contrast to H1 /H2 sites, histamine H3 receptors exert a
suppressive influence upon serotonergic and noradrenergic
pathways (Brown et al., 2001; Millan, 2002a).
5.2. Control of anxious states
The foregoing observations provide a neuroanatomical
substrate for several reports, employing models of sponta-
neous behaviours, of anxiolytic effects of: (1) lesions of
histaminergic pathways; (2) genetic deletion of H1 recep-
tors in mice and (3) administration of H1 receptor antag-
onists (Imaizumi and Onodera, 1993; Frisch et al., 1998;
Privou et al., 1998; Yanai et al., 1998; Hasenöhrl et al., 1999;
Malberg-Aiello et al., 2002; Sanchez, 2003). Contrariwise,
increases in endogenous levels of histamine and the admin-
istration of H1 receptor agonists are accompanied by an en-
hancement of anxious behaviour (Imaizumi and Onodera,
1993; Yuzurihara et al., 2000; Malberg-Aiello et al., 2002).
A clinical correlate of these findings is provided by con-
trolled, short- and long-term studies demonstrating efficacy
and safety of the preferential H1 receptor antagonist, hy-
droxyzine, in the management of GAD. Its effects were ex-
pressed in the absence of a withdrawal syndrome following
its abrupt discontinuation. Moreover, this agent was partic-
ularly efficacious against the psychic symptoms of anxious
states (Lader and Scotto, 1998; Llorca et al., 2002).
Though the significance of H2 sites is less well-defined,
they may fulfil an anxiolytic role opposite to that of H1
receptors (Imaizumi and Onodera, 1993; Yuzurihara et al.,
2000; Malberg-Aiello et al., 2002).
In the majority of studies, H3 receptor antagonists have
revealed anxiogenic actions which may be explained by: (1)
an increase in histamine release (which engages postsynap-
tic H1 sites) and (2) blockade of inhibitory H3 sites on the
terminals of LC- and DRN-derived noradrenergic and sero-
tonergic projections, thereby accelerating corticolimbic re-
lease of NA and 5-HT, respectively (Imaizumi and Onodera,
1993; Leurs et al., 1998; Pérez-Garcia et al., 1999;
Yuzurihara et al., 2000; Malberg-Aiello et al., 2002;
Westerink et al., 2002).
In light of this intriguing pattern of data, further exami-
nation of the influence of histaminergic mechanisms upon
142 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
anxious states could profitably be undertaken with the VCT
and other models.
6. Acetylcholine
6.1. Cholinergic pathways and their modulation
Cholinergic pathways, which fulfil a pivotal role in the
control of arousal, motivation and cognitive-attentional func-
tion, ramify extensively in the hippocampus, amygdala, sep-
tum, frontal cortex and several other limbic regions: therein,
they reciprocally interact with monoaminergic, GABAergic
and glutamatergic pathways and modulate the activity of the
hypothalamo-corticotropic axis (Wonnacott, 1997; Bugajski
et al., 1998; Picciotto, 1999; Paterson and Nordberg, 2000;
Li et al., 2001b; Araki et al., 2002; Hajszan and Zabroszky,
2002; Seth et al., 2002; Gobert et al., 2003).
The activity of frontocortical, hippocampal and lateral
septal cholinergic pathways is enhanced in response to anx-
iogenic and stressful stimuli, and it has been proposed that
an overactivity of cholinergic input to the FCX may con-
tribute to anxious states while septal cholinergic mecha-
nisms participate in the pressor response to stress (Miczek
and Lau, 1975; Gilad, 1987; Acquas et al., 1996; Berntson
et al., 1998; Ceccarelli et al., 1999; Hart et al., 1999; Sarter
and Bruno, 1999; Giovannini et al., 2001; Ichikawa et al.,
2002; Kubo et al., 2003). Further, under conditions of stress,
this anxiogenic role of ACh may involve the generation of
a distinct isoform of acetylcholinesterase (AChE-R, where
“R” stands for “read through”) which accumulates intracel-
lularly to interact with protein kinase C␤ (isoform II): this
kinase is concentrated in the amygdala, hippocampus and
cortex and is implicated in the induction of anxious states
(Weeber et al., 2000; Birikh et al., 2003).
However, cholinergic pathways do not fulfil a uniform
role in the control of anxious states (see below) and, in op-
posite fashion, an overall enhancement of cholinergic trans-
mission in the hippocampus (elicited by local injection of
acetylcholinesterase inhibitors) was accompanied by anx-
iolytic properties (File et al., 1998; Degroot et al., 2001;
Degroot and Treit, 2002).
6.2. Nicotinic receptors
6.2.1. Localization and interactions
Neuronal nicotinic receptors consist of ligand-gated, pen-
tameric, cation-permeable channels assembled from ␣ and
␤-subunits, of which, respectively, nine and three isoforms
exist in the CNS. The most prevalent central isoforms are
the ␣4 ␤2 heteromer and (less prominently) the ␣7 homo-
mer, the latter of which is highly permeable to Ca2+ and
displays distinctively rapid kinetics (Picciotto, 1999; Lloyd
and Williams, 2000; Paterson and Nordberg, 2000; Dani,
2001; Araki et al., 2002; Lax et al., 2002; Mihailescu et al.,
2002). ␣4 , ␤2 , ␣7 and other nicotinic subunits are broadly
distributed in corticolimbic structures, notably in the FCX,
hippocampus (wherein ␣7 sites are dominant) and septum.
Their co-existence as excitatory receptors on serotonergic
and noradrenergic cell bodies and, in the latter case, termi-
nals deserves emphasis in the present context (Ribeiro et al.,
1993; Clark and Reuben, 1996; Wonnacott, 1997; Picciotto,
1999; Bitner et al., 2000; Paterson and Nordberg, 2000;
Bitner and Nikkel, 2002; Pradhan et al., 2002; Seth et al.,
2002; Woo et al., 2002; Yasuda et al., 2002; Vincler and
Eisenach, 2003).
In monoaminergic cell clusters and in limbic regions, ex-
citatory ␣7 nicotinic receptors are both localized on, and
postsynaptic to, GABAergic neurones (Yang et al., 1996;
Frazier et al., 1998; Lu et al., 1998; Alkondon et al., 2000;
Dani, 2001; Bitner and Nikkel, 2002; Kawai et al., 2002;
Mihailescu et al., 2002; Vincler and Eisenach, 2003). Fur-
ther, there is considerable evidence for an excitatory in-
fluence of ␣7 and other classes of nicotinic receptor upon
mesocortical and mesolimbic dopaminergic neurones. Their
actions are mediated both directly and via multisynaptic
circuits involving other transmitters (Pontieri et al., 1996;
Wonnacott, 1997; Schilström et al., 1998, 2003; Cohen et al.,
2002; George et al., 2001). Interestingly, in contrast to the ef-
fects of acute stimulation of nicotinic receptors, their chronic
activation (presumably reflecting desensitisation) attenuates
the induction of DA release in the FCX and nucleus accum-
bens by conditioned fear (Schilström et al., 1998; George
et al., 2000, 2001).
6.2.2. Influence upon anxious states
Zicotine elicits a bewilderingly complex pattern of anx-
iogenic and anxiolytic effects reflecting: diverse sites of
action in various corticolimbic structures (File et al., 1998;
Kenny et al., 2000); interactions with glutamatergic (Perez
De La Mora et al., 1991; Wonnacott, 1997), monoaminergic
(Section 6.2.1) and GABAergic (Section 6.2.1) pathways;
modulation of corticolimbic levels of various neurosteroids;
the differential involvement of ␣4 ␤2 versus ␣7 receptor sub-
types (Araki et al., 2002; Seth et al., 2002); procedural as-
pects, such as the time of testing, drug dose and duration of
administration; “basal” levels of anxiety; housing conditions
and the experimental model employed (Vale and Green,
1986; Picciotto, 1999; Paterson and Nordberg, 2000; Cheeta
et al., 2001a; Dani, 2001; George et al., 2001; Szyndler
et al., 2001; Araki et al., 2002; File et al., 2002 and Seth
et al., 2002; Porcu et al., 2003). Both anxiogenic and anx-
iolytic properties of nicotine have likewise been detected in
human subjects (Parrott, 1995; Netter et al., 1998; Picciotto,
1999; Paterson and Nordberg, 2000). Not surprisingly,
recruitment of GABAergic neurones has been strongly im-
plicated in the anxiolytic properties of nicotinic agonists,
whereas serotonergic mechanisms (in particular, involving
postsynaptic 5-HT1A receptors, Section 4.3.2) are involved
in their anxiolytic and anxiogenic actions (op. cit.). Studies
of knock-out mice indicate a specific role for ␣7 recep-
tors in mediating the anxiolytic actions of nicotine, and of
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
their ␣4 ␤2 counterparts in transducing both anxiogenic and
anxiolytic effects, though their precise significance remains
rather nebulous (Paylor et al., 1998; Picciotto, 1999; Ross
et al., 2000; Cheeta et al., 2001a; Labarca et al., 2001;
Salas et al., 2002). Reconciliation of competing claims of
anxiogenic versus anxiolytic roles for nicotinic receptors
will likely be aided not only by studies of mice genetically
deprived of individual nicotinic receptor subunits, but also
by use of pharmacological agents discriminating specific
cerebral isoforms.
It is important to note that the above-described patterns of
data were exclusively acquired in models employing natural
behaviours, such as the social interaction and plus-maze tests
(Brioni et al., 1994; Ouagazzal et al., 1999; Picciotto, 1999;
Cheeta et al., 2000, 2001a; Kenny et al., 2000; Irvine et al.,
2001). Indeed, with the exception of one (very dated) report
(Morrison, 1969), studies of the influence of nicotinic mech-
anisms upon anxious states employing conflict paradigms
are conspicuous by their absence. For an improved apprecia-
tion of the broad pathophysiological and clinical pertinence
of nicotinic mechanisms in the control of anxious states it
would, then, appear imperative to undertake studies with
conflict procedures.
Though tricyclic antidepressants, fluoxetine and several
other SSRIs behave as reversible, non-competitive inhibitors
of nicotinic receptors, there is currently no evidence that
this mechanism participates in their control of anxious states
(Section 4.4) (Paterson and Nordberg, 2000).
6.3. Muscarinic receptors
Of the five classes of muscarinic receptor known, three
(M1 , M3 and M5 ) are primarily coupled to phospholipase
C via Gq underlying an excitatory influence upon neuronal
activity, whereas two (M2 and M4 ) are inhibitory, reflect-
ing their Gi -mediated inhibition of adenylyl cyclase and
an enhancement of K+ -currents (McKinney, 1993; Wess,
1996; Porter et al., 2002). Muscarinic M2 receptors are lo-
calized presynaptically as inhibitory autoreceptors on the
terminals of corticolimbic cholinergic neurones in the cor-
tex, hippocampus and other structures (Kitaichi et al., 1999;
Ichikawa et al., 2000, 2002; Zhang et al., 2002).
Little is known concerning the potential roles of multi-
ple classes of muscarinic receptor in the response to, and
the control of, anxious states, despite their (M1 –M4 ) broad
and differential occurrence in corticolimbic structures such
as the FCX, hippocampus and amygdala, wherein M1 sites
are especially prominent (Brann et al., 1988; Buckley et al.,
1988; Levey et al., 1991; Gomeza et al., 1999; Piggott et al.,
2002). It has been proposed that postsynaptic muscarinic
(M1 ) sites in the infralimbic region of the cortex partici-
pate in the induction of anxiety by cholinergic pathways
(Wall et al., 2001; Wall and Messier, 2002), and muscarinic
mechanisms in the amygdala may facilitate (unconditioned)
fear (Power and McGaugh, 2002). Further, the excitatory
influence of muscarinic receptors upon LC-derived nora-
143
drenergic pathways may favor anxious (panic-like) states
(Pudovkina et al., 2002). On the other hand, under certain
conditions, muscarinic mechanisms counter anxiety via ac-
tions in the hippocampus, possibly reflecting the modulation
of GABAergic transmission (Rodgers and Cole, 1995; File
et al., 1998, 2000; Smythe et al., 1998; Wu et al., 2000). Fi-
nally, muscarinic (M1 /M3 ) sites in the lateral septum have
been implicated in the pressor response to stress (Kubo et al.,
2003).
All of the above observations were derived from proce-
dures, such as the plus-maze, which employ exploratory be-
haviours, and studies of the role of muscarinic mechanisms
in the control of behaviour in the VCT and other conflict
models remain to be undertaken. Moreover, though mice
lacking specific muscarinic receptor subtypes have been gen-
erated, and M2 receptors demonstrated to facilitate corticos-
terone secretion, there appear to be no reports specifically
focussing on their response to stress or anxious behaviour
(Gomeza et al., 1999; Hemrick-Lubecke et al., 2002).
7. Adenosine
7.1. Generation, localization and coupling to multiple
receptor subtypes
Adenosine can, in principle, be produced throughout the
CNS by both neuronal and non-neuronal elements, and its
formation is interlinked with the generation of adenosine
triphosphate and energy balance. As outlined elsewhere
(Latini and Pedata, 2001; Millan, 2002a), adenosine is
formed in neurones primarily by hydrolysis (catalysed by
5-nucleotidase) of 5-adenosine monophosphate. It is subse-
quently released by a bi-directional, Na+ -dependent nucle-
oside carrier. In addition to this pool of secreted adenosine,
it can be directly produced extracellularly from various
sources, of which its cleavage from adenosine monophos-
phate via an ecto-5-nucleotidase is the most familiar mech-
anism. Neuronal (and glial) transporters capture adenosine
from the extracellular space and metabolise it (by adenosine
deaminase) into inosine which is eventually re-transformed
into adenosine triphosphate. Studies of the cerebral dis-
tribution of adenosine, adenosine deaminase and other
markers have revealed maximal concentrations in the cor-
tex (frontal and parietal), lateral septum and hippocampus,
as well as high levels in the amygdala, nucleus accumbens
and PAG (Braas et al., 1986; Nagy et al., 1990). Further,
adenosine fulfils a co-transmitter role with NA—and pos-
sibly GABA—in the hippocampus and other supraspinal
structures (Manzoni et al., 1994; Poelchen et al., 2001).
Adenosine exerts its actions via A1 , A2A , A2B and A3
receptors (Olah and Stiles, 1985, 1995; Impagnatiello et al.,
2000; Fredholm et al., 2001; Millan, 2002a). Although
A2B receptor subtypes are found in the hippocampus at
modest levels, they are not specifically implicated in the
control of anxious states, and the apparent presence of A3
144 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

sites in supraspinal structures awaits further verification
(Impagnatiello et al., 2000; Rivkees et al., 2000). Thus, the
ensuing discussion focuses on A1 and A2A receptors.
7.2. Adenosine A1 receptors
Adenosine A1 sites are enriched in the hippocampus, sep-
tum and cortex (Rivkees et al., 1995; Swanson et al., 1995;
Dixon et al., 1996; Ralevic and Burnstock, 1998; Ochiishi
et al., 1999). They interact via Gi/o with adenylyl cyclase
(inhibition), K+ -currents (potentiation) and VDCCs (reduc-
tion of Ca2+ -currents), actions accounting for the inhibitory
influence of adenosine upon corticolimbic glutamatergic,
dopaminergic, serotonergic and other modes of transmission
(Impagnatiello et al., 2000; Johansson et al., 2001; Nikbakht
and Stone, 2001; Okada et al., 2001; Abrams et al., 2002;
Masino et al., 2002; Solinas et al., 2002). Mice lacking A1
receptors display enhanced anxiety (Johansson et al., 2001;
Giménez-Llort et al., 2002) and the anxiogenic actions of
adenosine antagonists, such as caffeine, in animals and man
have generally been attributed to blockade of A1 sites (Uhde
et al., 1984a; Loke et al., 1985; File et al., 1988; Baldwin
and File, 1989; McCloskey et al., 1990; Nickell and Uhde,
1994; Jain et al., 1995; Fredholm et al., 1999). Indeed,
studies employing models based on exploratory behaviour
indicate that selective stimulation and antagonism of A1 re-
ceptors is associated with anxiolytic and anxiogenic actions,
respectively (Baldwin and File, 1989; Jain et al., 1995; Florio
et al., 1998).
However, conflict paradigms in rodents and primates
have not invariably yielded evidence in favour of a specific
anxiolytic role of A1 sites (Coffin and Spealman, 1985;
Commissaris et al., 1990; Haraguchi and Kuribara, 1991;
Thiébot et al., 1991). Moreover, caffeine was reported to
either act anxiolytically, or to be ineffective, in the VCT, a
result at variance with human experience (Table 18) (Beer
et al., 1972; Baldwin et al., 1989; Fredholm et al., 1999).
This puzzling incoherence between the VCT and the clini-
cal effects of A1 receptor blockade may reflect one or more
of the following factors: (1) a lack of sensitivity of the
VCT to the relatively weak anxiogenic properties of caf-
feine; (2) the fact that high doses of caffeine are needed to
elicit anxiety in man as compared to the relatively modest
doses employed experimentally; (3) a role of A2A receptor
blockade (see below) in the anxiogenic actions of caffeine;
(4) induction by caffeine in man of an (un-conditioned)
anxious state qualitatively different to that reproduced by
the VCT in rodents and (5) actions of caffeine expressed
independently of adenosine receptors (Foukas et al., 2002).
Additional studies with more potent and selective A1 re-
ceptor antagonists would be desirable to resolve this issue
since the lack of anxiogenic properties of caffeine in the
VCT represents an apparently major discrepancy between
this model and results in human subjects.
7.3. Adenosine A2A receptors
Counterbalancing the neuronal actions of inhibitory A1
sites, excitatory A2A receptors are positively coupled via Gs
to adenylyl cyclase and (via protein kinase A) to VDCCs
(Ralevic and Burnstock, 1998; Impagnatiello et al., 2000).
Adenosine A2A receptors are concentrated in the basal gan-
glia and the nucleus accumbens. Though they have also
been detected in the LC, DRN, hippocampus, cortex and
amygdala (Olah and Stiles, 1995; Dixon et al., 1996; Rosin
et al., 1998; Impagnatiello et al., 2000; Fredholm et al.,
2001; Phillis, 2001; DeMet and Chicz-DeMet, 2002), and
appear to share the localization of A1 sites on serotoniner-
gic, glutamatergic and GABAergic neurones (Impagnatiello
et al., 2000; Nikbakht and Stone, 2001), the quantitative

Table 18
Influence of adenosine receptor ligands, of melatonin and testosterone, of NO synthase inhibitors, of calcium channel blockers, and of sigma ligands
upon behaviour in the Vogel Conflict Test
Drug Class Species Route Effect Active dose Maximum Reference
(strain) (structure) range (mg/kg) change (%)
Theophylline A1/2 Ant Rat (?) i.p. + 75 and 100 + 400 Beer et al. (1972)
Caffeine A1/2 Ant Rat (?) i.p. + 25–100 + 800 Beer et al. (1972)
Rat (LH) i.p. IA 40.0 IA Baldwin et al. (1989)
Dibutyryl cyclic AMP A1/2 Ant Rat (?) i.p. + 100–400 +450 Beer et al. (1972)
Melatonin Melatonin agonist Rat (W) s.c. IA 0.63–80.0 IA Millan et al. (2002)
Testosterone Androgen Rat (W) s.c. + 5 + 102 Bing et al. (1998)
l-NAME NO (synth. inhib.) Rat (?) i.v. + 54.8 and 100 NI Dunn et al. (1995)
l-NOARG NO (synth. inhib.) Rat (?) i.v. + 30 NI Dunn et al. (1995)
Flunarizine Ca2+ channel Ant Rat (W) i.p. + 10 and 20 +70 Matsumoto et al. (1994)
Verapamil Ca2+ channel Ant Rat (W) i.p. + 20 +95 Matsumoto et al. (1994)
Nicardipine Ca2+ channel Ant Rat (W) i.p. + 20 +90 Matsumoto et al. (1994)
PD144418 Sigma1 “Ago” Rat (W) i.p. IA 5 and 15 IA Akunno et al. (1997)
Cyclazocine Sigma1 “Ago” Mouse (ICR) s.c. IA 0.1–3 IA Umezi (1999)
Siramesine Sigma2 “Ago” Rat (W) i.p. + 10 and 22 +65 Sanchez et al. (1997)
Abbreviations—l-NAME: N(G)-nitro-l-arginine methyl ester; l-NOARG: N(G)-nitro-l-arginine; A: adenosine; NO (synth. inhib.): nitric oxide synthase
inhibitor; IA: no significant change (inactive) and NI: not indicated. For other abbreviations, see Table 2.
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
distribution, precise identity and functional status of
extra-striatal A2A sites remains controversial. Irrespective of
this uncertainty, there is evidence that A2A receptors exert a
facilitatory influence upon GABA release in the septum and
hippocampus, actions which may be related to the observa-
tion that mice genetically lacking A2A receptors show an
exaggerated response to anxiogenic stimuli. However, A2A
receptors are also excitatory to 5-HT and glutamate release
in the hippocampus (Popoli et al., 1995; Impagnatiello et al.,
2000; Okada et al., 2001) and no consistent evidence for
anxiolytic effects of A2A receptor stimulation has, to date,
been obtained (Baldwin and File, 1989; Griebel et al., 1991;
Jain et al., 1995; Ledent et al., 1997). Unfortunately, infor-
mation from the VCT concerning the potential significance
of A2A sites in the control of anxious states is unavailable.
In light of the above comments, there is a need for a
thorough and interdisciplinary reappraisal of the role(s) of
adenosine in the modulation of anxious states employing
ligands highly-selective for specific adenosine receptor sub-
types, as well as agents modulating its synthesis and degra-
dation (Impagnatiello et al., 2000; Millan, 2002a).
7.4. Purinoceptors
As mentioned above (Section 7.1), one source of neu-
ronal pools of adenosine is adenosine triphosphate which
itself acts via ionotropic P2X and metabotropic P2Y recep-
tors (Ralevic and Burnstock, 1998). Though their influence
upon anxious states remains to be defined, in light of their
occurrence in corticolimbic regions and their modulatory in-
fluence upon monoaminergic pathways—for example, P2X
sites are excitatory to noradrenergic perikarya—this issue
would be of interest to explore (Ralevic and Burnstock,
1998; Sansum et al., 1998; Williams and Jarvis, 2000).
8. Cannabinoids
8.1. Generation and coupling to CB1 receptors
Cannabinoids comprise a family of lipids, including
anandamide and 2-arachidonylglycerol, which are phasi-
cally generated from phospholipids in an activity-dependent
fashion (Piomelli et al., 2000; Giuffrida et al., 2001;
Stella and Piomelli, 2001; Millan, 2002a). Following their
(non-vesicular) release, they are rapidly taken up into neu-
rones and glia and catabolized by the microsomal enzyme,
fatty acid amide hydrolase (amidohydrolase) and by the ser-
ine hydrolase, monogluceride lipase (Piomelli et al., 2000;
Giuffrida et al., 2001; Stella and Piomelli, 2001; Bracey
et al., 2002; Dinh et al., 2002; Millan, 2002a). Interestingly,
cannabinoids exert actions both anterogradely (conven-
tional transmission) and, in analogy to NO (Section 14)
and neurotrophins (Section 15), retrogradely at presynaptic
terminals (Ohno-Shosaku et al., 2001; Tao and Poo, 2001;
Alger, 2002; Millan, 2002a).
145
Currently, it appears that cannabinoids exert their cere-
bral actions solely via CB1 receptors, though the poten-
tial existence of additional CB sites remains under discus-
sion, not least in view of the preservation of several func-
tional actions of “selective” CB1 receptor antagonists in
mice lacking these sites (Pertwee, 1997, 2000; DiMarzo
et al., 2000; Breivogel et al., 2001; Haller et al., 2002b;
Millan, 2002a). Furthermore, actions of anandamide at sites
other than CB1 receptors, such as vanilloid receptors, VD-
CCs (T-type) and muscarinic receptors, should be borne in
mind (Chemin et al., 2001; Millan, 2002a) and it was re-
cently reported that anandamide non-competitively reduces
the operation (cation-conductance) of 5-HT3 receptors by
actions at a novel, allosteric site refractory to selective CB1
receptor antagonists (Section 4.3.5) (Barann et al., 2002;
Molderings-Godlewski et al., 2002). Though CB1 receptors
can engage various intracellular mediators, their inhibition
of adenylyl cyclase via Gi/o and their suppression and po-
tentiation of Ca2+ -currents and K+ -currents, respectively,
provide a substrate for their generally inhibitory influence
upon neuronal excitability (Pertwee, 1997).
8.2. Influence upon anxious states
Though comparatively little information is available, the
following observations support a role of CB1 receptors in
the modulation of anxious states.
First, cannabinoids are produced throughout the brain and
CB1 receptors are particularly well-represented in the cor-
tex (entorhinal and cingulate), hippocampus, lateral septum,
nucleus accumbens, amygdala and PAG (Tsou et al., 1998;
Ameri, 1999; Katona et al., 1999; Davis et al., 2002).
Second, cannabinoids modulate the release of several
transmitters implicated in the control of anxious states.
They suppress the outflow of glutamate in the hippocampus
and PAG—possibly reflecting a retrograde action at presy-
naptic terminals—though glutamate release in the FCX is
(indirectly) enhanced by cannabinoids (Shen et al., 1996;
Robe et al., 2001; Stella and Piomelli, 2001; Tomasini
et al., 2002). Cannabinoids are inhibitory to corticolimbic
release of NA and DA (Schlicker et al., 1997; Schlicker and
Kathman, 2001), 5-HT (Nakazi et al., 2000; Schlicker and
Kathman, 2001; Hermann et al., 2002) and the anxiogenic
neuropeptides, CCK and CRF (Ameri, 1999; Rodriguez
de Fonseca et al., 1997; Schlicker and Kathman, 2001).
On the other hand, by presynaptic mechanisms, they in-
terfere with GABAergic transmission in the amygdala,
hippocampus, FCX and other regions (Katona et al., 1999,
2001; Hajos et al., 2000a; Hoffman and Lupica, 2000;
Ferraro et al., 2001; Schlicker and Kathman, 2001; Wilson
et al., 2001; Marsicano et al., 2002; Millan, 2002a; Pistis
et al., 2002). This interruption of GABAergic activity
may underlie their indirect disinhibition of cortical glu-
tamatergic and dopaminergic transmission pathways in
the FCX and nucleus accumbens (Navarro et al., 1993;
French, 1997; Ameri, 1999; Schlicker and Kathman, 2001;
146 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Cohen et al., 2002; Pistis et al., 2002; Tomasini et al.,
2002).
Third, probably reflecting this complex pattern of influ-
ence upon neurotransmitters known to divergently modu-
late anxious states, cannabinoids elicit dose-dependent and
environment-dependent anxiolytic and anxiogenic effects in
rodent models incorporating exploratory behaviour (Onaivi
et al., 1990; Rodriguez de Fonseca et al., 1996, 1997;
Navarro et al., 1997; Martin et al., 2002b). In line with
this broad spectrum of actions in experimental models, as
a function of personality and the precise circumstances of
testing, cannabinoids have been found to either relieve or
to induce anxiety in man (Ashton, 2001; Porter and Felder,
2001; Robson, 2001).
Fourth, notwithstanding this diverse pattern of experi-
mental and clinical observations with cannabinoid agonists,
CB1 receptor antagonists generally provoke an increase in
anxiety in rodents (Navarro et al., 1997; Arevalo et al., 2001;
Maccarone et al., 2002; Martin et al., 2002b). Correspond-
ingly, mice genetically lacking CB1 receptors reveal an anx-
iogenic profile (Haller et al., 2002b): however, in this study,
anxiolytic properties of CB1 receptor antagonists were, sur-
prisingly, observed. Moreover, their persistence in the CB1
knock-out population was interpreted as support for the no-
tion that an “anxiogenic” CB receptor exists (Haller et al.,
2002b). This hypothesis awaits verification and an alter-
native, more conservative, interpretation would be that the
antagonists in question recognize other non-cannabinoid
mechanisms mediating anxiety.
In addition to mice deficient in CB1 receptors, popula-
tions lacking fatty acid amide hydrolase have been generated
(Navarro et al., 1997; Cravatt et al., 2001; Maccarone et al.,
2002; Martin et al., 2002b). Moreover, chemical inhibitors of
this cannabinoid-degrading enzyme, modulators of cannabi-
noid transport, and selective agonists and antagonists at CB1
receptors are all available for exploitation in the VCT and
other models (Pertwee, 1997, 2000; Piomelli et al., 2000;
Giuffrida et al., 2001; Millan, 2002a). There is increasing
interest in the therapeutic use of cannabinoidergic agents for
the management of pain, schizophrenia and drug abuse, dis-
orders which display substantial comorbidity with anxiety
states (Pertwee, 1997, 2000; Porter and Felder, 2001; Millan,
2002a). A clarification of the poorly-understood role of
cannabinoidergic mechanisms in the modulation of anxious
states would, consequently, appear to be of some urgency.
9. Neuropeptides
9.1. Neuropeptides/receptors previously examined
by use of the VCT
9.1.1. Cholecystokinin
9.1.1.1. Localization and coupling to CCK1 and CCK2 sites.
Like the closely-related peptide, gastrin, CCK—which exists
in sulphated and non-sulphated forms of various length—
exerts its actions via excitatory CCK1 (CCKA ) and CCK2
(CCKB ) receptors, both of which activate phospholipase C
via Gq (Woodruff et al., 1991; Noble and Roques, 1999).
Together with CCK itself, CCK2 receptors are widespread
throughout the limbic system (including the amygdala and
hippocampus) and cortex. While the distribution of CCK1
sites is more restricted, their presence in the hypothalamus,
DRN, hippocampus and septum is of note in the present con-
text (Rehfeld and Nielsen, 1995; Van Megen et al., 1996;
Noble and Roques, 1999; Adell et al., 2002). These neu-
roanatomical observations, the responsiveness of cortical
and amygdala pools of CCK2 receptors and CCK to anxiety
and other stressful stimuli in rats (Harro et al., 1990; Del Bel
and Guimaraes, 1997; Becker et al., 1999, 2001), and func-
tional interactions amongst CCK-containing, monoaminer-
gic and GABAergic neurones (Boden et al., 1991; Woodruff,
1992; Bickerdike et al., 1995; Ferraro et al., 1999; Noble
and Roques, 1999; Hamilton et al., 2001; Kõks et al., 2001b;
Tanganelli et al., 2001; Adell et al., 2002; Siniscalchi et al.,
2003), collectively support a role of CCK in the modula-
tion of anxious states (Ravard and Dourish, 1990; Bradwejn,
1993; Wettstein et al., 1994; Van Megen et al., 1996; Bourin
et al., 1998; Daugé and Léna, 1998; Kõks et al., 2000;
Bradwejn and Koszycki, 2001).
9.1.1.2. Role of CCK2 sites in the control of anxious states.
CCK2 sites in several structures, including the nucleus
tractus solitarius, amygdala, nucleus accumbens, FCX,
hippocampus and DRN, have been implicated in the anx-
iogenic properties of CCK (Frankland et al., 1997; Noble
and Roques, 1999; Becker et al., 1999, 2001; Kõks et al.,
2000; Adell et al., 2002; Wunderlich et al., 2002). Ac-
cordingly, the anxiogenic (panicogenic) actions of CCK4
and the synthetic pentapeptide analogue, pentagastrin, in
animals and man are abolished by selective CCK2 recep-
tor antagonists (Singh et al., 1991; Bradwejn, 1993; Lines
et al., 1995; Bourin et al., 1998; Kõks et al., 2000; Geraci
et al., 2002). Such experimental studies, and complementary
work demonstrating intrinsic anxiolytic actions of CCK2
antagonists, have principally been successful upon employ-
ing models of exploratory behaviour, notably the elevated
plus-maze (Costall et al., 1991; Singh et al., 1991; Frankland
et al., 1997; Tsutsumi et al., 1999; Wunderlich et al., 2002;
Blanchard et al., 2003). Contrariwise, anxiolytic actions of
CCK2 (and CCK1 ) antagonists in conflict paradigms are
weak, inconsistent and rarely dose-dependent (Hendrie and
Dourish, 1990; Powell and Barrett, 1991; Singh et al., 1991;
Charrier et al., 1995; Dawson et al., 1995; Van Megen et al.,
1996; Griebel et al., 1997a,b). In line with these ambivalent
findings, in a study of the VCT, selective antagonists at
either CCK1 or CCK2 receptors were ineffective (Table 19)
(Griebel et al., 1997b). Moreover, mice lacking CCK2 (or
CCK1 ) receptors show at most modest alterations in anxious
behaviour, and may even reveal an anxiogenic phenotype
(Kobayashi et al., 1996; Nomoto et al., 1999; Chambers
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 147

Table 19
Influence of neuropeptide receptor ligands upon behaviour in the Vogel Conflict Test
Drug Class Species Route Effect Active dose Maximum Reference
(strain) (structure) range change (%)
Lorglumide CCK1 Ant Rat (SD) i.p. IA 0.3–1.0 mg/kg IA Griebel et al. (1997b)
PD135,158 CCK2 Ant Rat (SD) i.p. IA 0.01–1.0 mg/kg IA Griebel et al. (1997b)
LY288,513 CCK2 Ant Rat (SD) i.p. IA 0.3–10.0 mg/kg IA Griebel et al. (1997b)
CRF CRF1(2) agonist Rat (W) i.c.v. − 10 ␮g −40 Britton et al. (1985)
CRF9–41 CRF Ant Rat (?) i.c. (lateral + 0.25–0.5 ␮g NI Thomas et al. (2002)
septum)
CP154,526 CRF1 Ant Rat (W) i.p. + 80 mg/kg +400 Millan et al. (2001a)
Rat (W) i.p. IA 0.62–20 mg/kg IA Griebel et al. (1998a,b)
DMP695 CRF1 Ant Rat (W) i.p. + 40 mg/kg +300 Millan et al. (2001a)
SR125,543A CRF1 Ant Rat (SD) i.p. + 20 and 30 mg/kg +188 Griebel et al. (2002b)
SR149,415 VP1B Ant Rat (W) i.p. + 3 and 10 mg/kg +148 Serradiel-Gal et al. (2002)
GR205,171 NK1 Ant Rat (W) i.p. + 40 mg/kg +131 Brocco (unpublished
observations)
Neuropeptide Y Y1 agonist Rat (SD) i.c.v. + 0.2–5.0 nmol +320 Heilig et al. (1989)
Neuropeptide Y 13-36 Y2 agonist Rat (SD) i.c.v. IA 0.4 and 2.0 nmol IA Heilig et al. (1989)
Glucagon-like peptide Agonist Rat (SD) i.c.v. − 10 ␮g −74 Moller et al. (2002)
Galanin Agonist Rat (SD) i.c.v. + 3 nmol +95 Bing et al. (1993)
Rat (SD) i.c. (amygdala) − 0.2 and 0.6 nmol −50 Moller et al. (1999)
Morphine ␮ Opioid agonist Rat (W) ip IA 5–10 mg/kg IA Ågmo et al. (1995)
U50,488H ␬-Opioid agonist Mouse (ddY) sc + 1.0 mg/kg +117 Tsuda et al. (1996)
Naloxone Opioid Ant Rat (W) ip IA 2.5 and 20 mg/kg IA Ågmo et al. (1995)
Mouse (ddY) sc − 3.0 mg/kg −36 Tsuda et al. (1996)
OrphaninFQ ORL agonist Rat (SD) i.c.v. + 0.3–1.0 nmol NI Lu et al. (2002)
ACTH1–24 MC4 agonist Rat (SD) i.c.v. − 0.3–10 ␮g −80 Corda et al. (1990)
␣-MSH MC4 agonist Rat (SD) i.c.v. − 1.0–5.0 mg −84 Corda et al. (1990)
SNAP-7941 MCH1 Ant Rat (W) i.p. + 40 mg/kg +60 Brocco (unpublished
observations)
Angiotensin II AT1 /AT2 Ago Rat (W) i.c.v. − 0.1–0.5 ␮g −80 Georgiev et al. (1990)
Abbreviations—CCK: cholecystokinin; CRF: corticotropin releasing factor; VP: vasopressin; NK: neurokinin; ORL: orphan opioid receptor; MCH1 :
melanin concentrating hormone; AT: angiotensin; ACTH: adrenocorticotropic hormone; MC: melanocortin; IA: no significant change (inactive) and NI:
not indicated. For other abbreviations, see Table 2.

and Fletcher, 2000; Daugé et al., 2001; Kõks et al., 2001b;
Miyasaka et al., 2002; Noble and Roques, 2002).
These findings question the anxiolytic potential of CCK2
(and CCK1 ) receptor antagonists. Correspondingly, in clin-
ical studies, despite their ability to block the anxiogenic
(panicogenic) actions of CCK4 , CCK2 receptor antagonists
have not proven consistently efficacious as anxiolytic agents
(Kramer et al., 1995; Sramek et al., 1995, 2002; Van Megen
et al., 1996; Goddard et al., 1999; Pande et al., 1999b; Cham-
bers and Fletcher, 2000; Blanchard et al., 2001b; Radu et al.,
2003). Moreover, it is unlikely that appreciable amounts of
CCK4 or pentagastrin penetrate into CNS tissue upon i.v.
application: this suggests that the susceptibility of their ef-
fects to blockade by CCK2 antagonists reflects actions at
gastrointestinal or vagal, rather than cerebral, loci. The lack
of activity of CCK2 receptor antagonists in the VCT in ro-
dents is, then, mirrored by their limited efficacy in man.
9.1.2. Corticotropin releasing factor
9.1.2.1. CRF and related peptides: localization and cou-
pling to CRF1 and CRF2 receptors. The 41 amino acid
neuropeptide, CRF, is generated in numerous cerebral struc-
tures, including the cortex, amygdala, hippocampus and,
most prominently, the hypothalamus (Gray and Magnuson,
1992; Koob et al., 1994; De Souza, 1995; Steckler and Hols-
boer, 1999; Eckart et al., 2002). CRF exerts its actions via
CRF1 and (with less pronounced affinity) CRF2 receptors
which share positive coupling (via the activation of Gs) to
adenylyl cyclase: recruitment of phospholipase C via Gq has
also been demonstrated in neuronal tissue (De Souza, 1995;
Steckler and Holsboer, 1999; Dautzenberg and Hauger,
2002; Eckart et al., 2002; Blank et al., 2003a; Hauger et al.,
2003). Amongst several isoforms, CRF2␣ receptors pre-
dominate in supraspinal structures, while a CRF2␥ isoform
was recently isolated from human amygdala (Steckler and
Holsboer, 1999; Dautzenberg and Hauger, 2002; Hauger
et al., 2003). In mammalian brain, an additional CRF-related
peptide, urocortin, displays comparable affinity at CRF1 as
compared to CRF2 sites. Two further peptides, urocortin II
(also known as stresscopin-related peptide) and urocortin
III (or stresscopin)—both 38 amino acids in length—were
recently shown to behave as selective agonists at CRF2 ver-
sus CRF1 sites (Hsu and Hsueh, 2001; Lewis et al., 2001;
148 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Reyes et al., 2001; Dautzenberg and Hauger, 2002; Eckart
et al., 2002; Hauger et al., 2003). The pharmacology of CRF
is further complicated by the existence of a CRF-binding
protein which recognises (and neutralizes) CRF and uro-
cortin, though not urocortin II and III (Behan et al., 1995;
Seasholtz et al., 2001; Eckart et al., 2002).
CRF1 receptors mediate the facilitatory influence of CRF
upon ACTH secretion from the pituitary in response to
stressors and other stimuli (De Souza, 1995; Arborelius
et al., 2000; McElroy et al., 2002; Ohata et al., 2002;
Carrasco and Van de Kar, 2003) with CRF2 sites fulfilling
a more complex, modulatory and time-dependent role (Ma
et al., 1997; Coste et al., 2000, 2001; Kishimoto et al.,
2000b; Bale et al., 2002; Dautzenberg and Hauger, 2002;
Eckart et al., 2002; Gold and Chrousos, 2002; Reul and
Holsboer, 2002). Via actions at CRF1 (and CRF2 ) receptors
in the brain, CRF fulfills a more general role in regulating
the endocrine, cognitive, emotional and autonomic response
to stress, which is characterized by robust alterations in
levels of CRF in the amygdala and several other limbic
regions (Albeck et al., 1997; Hsu et al., 1998; Merali et al.,
1998; Makino et al., 1999, 2002a; Steckler and Holsboer,
1999; Bakshi and Halin, 2000; Gilligan et al., 2000; Gold
and Chrousos, 2002; Roozendaal et al., 2002).
9.1.2.2. CRF1 receptors. CRF1 receptors are particularly
concentrated in the paraventricular hypothalamus, cortex,
PAG, hippocampus and amygdala (Sanchez et al., 1991a;
Chalmers et al., 1995; Chen et al., 2000b). Further, they
mediate the excitatory influence of CRF upon LC-derived
noradrenergic pathways, an action implicated in their acti-
vation by psychological and other stressors (Valentino et al.,
1992; Arborelius et al., 2000; Kawahara et al., 2000; Mil-
lan et al., 2001a; Sauvage and Steckler, 2001; Valentino
and Van Bockstaele, 2001; Griebel et al., 2002b; Lejeune
and Millan, 2003). More tentative evidence for a facili-
tatory influence of CRF1 receptors upon (a subpopulation
of) DRN-localized serotonergic neurones has also been pre-
sented: however, there are conflicting data and the precise
nature of this interaction awaits clarification (Ruggiero et al.,
1999; Isogawa et al., 2000; Millan et al., 2001a; Hammack
et al., 2002, 2003; Linthorst et al., 2002a,b; Commons et al.,
2003; Roche et al., 2003; Temel et al., 2003; Thomas et al.,
2003). Similarly, while it has been conjectured that CRF1
receptors participate in the engagement of serotonergic path-
ways by stress, this hypothesis remains to be corroborated
(Arborelius et al., 2000; Hammack et al., 2002; Linthorst
et al., 2002a,b; Penalva et al., 2002).
The above observations may be related to alterations in
emotionality in mice lacking CRF1 receptors which man-
ifest an unambiguous anxiolytic phenotype in an array of
experimental procedures (Smith et al., 1998a; Timpl et al.,
1998; Contarino et al., 1999a,b; Contarino and Gold, 2002).
Notably, a reduction in circulating levels of glucocorticoids
could be dissociated from these changes. Moreover, a line
of “conditioned” knock-out mice deprived of corticolim-
bic as compared to hypothalamo-hypophyseal populations
of CRF1 receptors likewise revealed an anxiolytic pheno-
type: this finding underscores the importance of cerebral
populations of CRF1 receptors in the “direct” control of
mood as compared to “indirect” effects of populations
modulating activity of the hypothalamo-corticotropic axis
and, ultimately, glucocorticoid secretion (Section 11) (Reul
and Holsboer, 2002). As judged by behavioural and auto-
nomic criteria, mice overexpressing CRF centrally reveal
increased anxiety together with a dysregulation of the
hypothalamus–corticotropic axis: mice lacking CRF-binding
protein also show enhanced anxiety (Stenzel-Poore et al.,
1994; Heinrichs et al., 1997b; Holsboer, 1999; Karolyi et al.,
1999; Coste et al., 2001; Clément al., 2002; Dirks et al.,
2002; Groenink et al., 2002, 2003; Van Gaalen et al., 2002).
Paradoxically, mice deprived of CRF reveal few changes in
behaviour indicative of reduced anxiety or insensitivity to
stress (Dunn and Swiergiel, 1999; Weninger et al., 1999;
Muglia et al., 2001 see Groenink et al., 2003). However, in
interpreting these findings, it should be noted that urocortin
may compensate for decreases (or increases) in the activity
of CRF.
Particularly, under conditions of high stress, anxiogenic
properties of CRF itself, and anxiolytic actions of peptider-
gic and non-peptidergic CRF1 antagonists, are expressed in
several rodent and primate paradigms (De Fonseca et al.,
1996; Heinrichs et al., 1997b, 2002; Griebel et al., 1998b;
Habib et al., 2000; Okuyama et al., 1999a; Keck et al.,
2001; Millan et al., 2001a; Gehlert et al., 2002; McElroy
et al., 2002; Zorilla et al., 2002; Blanchard et al., 2003;
Blank et al., 2003b). Structures implicated in these ac-
tions include the amygdala and the interconnected bed
nucleus of the stria terminalis (Liebsch et al., 1995; Davis
and Shi, 1999; Sajdyk et al., 1999a; Sajdyk and Gehlert,
2000; Bakshi et al., 2002; Keim et al., 2002), the PAG
(Martins et al., 1997) and the lateral septum (Takahashi,
2001; Bakshi et al., 2002; Thomas et al., 2002). Consistent
with these observations, centrally-administered antisense
probes directed against CRF1 receptors display anxiolytic
properties expressed, at least partially, via actions in the
amygdala (Liebsch et al., 1995, 1999; Heinrichs et al.,
1997a). A preliminary (open-label) report that blockade of
CRF1 receptors elicits anxiolytic actions in depressive pa-
tients awaits extension to controlled studies in subjects with
“pure” anxious disorders (Zobel et al., 2000).
Relatively little information is available concerning con-
flict procedures. Despite the absence of changes in VCT per-
formance in mice overexpressing CRF, i.c.v. administration
of CRF is anxiogenic in the rat VCT (Table 19) (Britton et al.,
1985, 2000; Liebsch et al., 1995; Van Gaalen et al., 2002).
Further, the anxiogenic effects of social defeat in the VCT
were abolished in mice lacking CRF1 receptors (Liebsch
et al., 1995; Steckler and Holsboer, 1999). More recently,
the selective CRF1 antagonists, CP154,256 and DMP695,
were documented to elicit specific and dose-dependent ac-
tions in the VCT of a magnitude comparable to the BZP,
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 149

750 750
LICKS/ 3 MIN
LICKS/3 MIN

500 500

250 250

0 0
VEH VEH 5.0 40.0 80.0 MG/KG, I.P. VEH VEH 0.63 10.0 40.0 MG/KG, I.P.
CP 154,626 GR 205,171
NO SHOCK SHOCK NO SHOCK NO SHOCK

750
LICKS/3 MIN

500

250

0
VEH VEH 10.0 40.0 MG/KG, I.P.
SNAP-7941

NO SHOCK SHOCK

Fig. 9. Actions of the CRF1 receptor antagonist, CP154,526, of the NK1 receptor antagonist, GR205,171, and of the MCH1 receptor antagonist,
SNAP-7941, in the Vogel Conflict Test. Data are means ± S.E.M.s. Star indicates significance of differences to corresponding vehicle values. ( )
P < 0.05. Data are from Millan et al. (2001a), and Brocco and Millan (unpublished observations).

chlordiazepoxide (Table 19 and Fig. 9) (Griebel et al., 1998b;
Millan et al., 2001a). In contrast to this benzodiazepine,
CRF1 receptor antagonists were active at doses devoid of
sedative properties. Griebel et al. (2002b) reported simi-
lar anxiolytic actions of two further CRF1 receptor antag-
onists, SSR125543A and antalarmin, in the VCT. Thus,
chemically-diverse and selective antagonists at CRF1 recep-
tors reproducibly express anxiolytic actions in the VCT. In
view of the equivocal actions of CRF1 antagonists in certain
rodent paradigms (see Millan et al., 2001a; Griebel et al.,
2002b), and the stressful nature of the VCT, it would ap-
pear particularly well-suited to the future characterization of
CRF1 antagonists as potential anxiolytic agents.
Very recently, employing a microinjection approach, it
was shown that the lateral septum contributes to the anxi-
olytic properties of CRF1 receptor antagonists in the VCT
(Thomas et al., 2002).
9.1.2.3. CRF2 receptors. CRF2 receptors are localized in
the lateral septum, amygdala, ventromedial hypothalamus
and hippocampus (primates), while modest levels are found
in the DRN: therein they have been implicated in the re-
sponse to serotonergic neurones to stress, though this action
remains to be confirmed (Chalmers et al., 1995; Sanchez
et al., 1999; Van Pett et al., 2000; Lin et al., 2001; Higelin
et al., 2001; Smagin et al., 2001; Hammack et al., 2002,
2003; Linthorst et al., 2002).
The phenotype of CRF2 receptor-deficient mice has
proven variable with reports of both reduced and—
predominantly—heightened anxiety, together with a
hyper-responsiveness to stress. The predisposition to en-
hanced anxiety may, at least partially, reflect a compen-
satory up-regulation of the actions of CRF (or urocortin) at
anxiogenic CRF1 sites. However, these observations likely
unveil a more complex role of CRF2 receptors whereby they
mediate both anxiogenic and (possibly delayed) anxiolytic
actions (Heinrichs et al., 1997a; Bale et al., 2000, 2002;
Coste et al., 2000; Kishimoto et al., 2000b; Takahashi, 2001;
Takahishi et al., 2001a; Radulovic et al., 2002; Todorovic
et al., 2002; Valdez et al., 2002a,b). Possibly related to an
anxiolytic role for CRF2 sites, mice lacking urocortin reveal
an anxiogenic phenotype (Vetter et al., 2002), while i.c.v.
application of urocortin III suppresses anxious behaviours
in rats (Valdez et al., 2002b). Contrariwise, though antisense
150 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
probes provoking modest reductions (∼20%) in the central
density of CRF2 receptors levels did not markedly affect
anxiety in rats, a more pronounced (∼70%) loss of CRF2
receptors in the lateral septum—a site at which CRF itself
behaves anxiogenically—was associated with an anxiolytic
profile (Radulovic et al., 1999; Kishimoto et al., 2000b; Ho
et al., 2001; Takahashi, 2001). In line with these variable
findings, blockade of CRF2 sites by injection of the pep-
tidergic antagonist, antisauvagine-30, into the septum (and,
possibly, the amygdala) was accompanied by anxiolytic
actions in several studies, whereas others observed a lack
of effect (Radulovic et al., 1999; Ho et al., 2001; Taka-
hashi, 2001; Takahashi et al., 2001a; Pelleymounter et al.,
2002). Regrettably, in none of the above experiments was
the significance of CRF2 receptors evaluated employing
punishment-based conflict procedures.
9.1.2.4. Multiple roles of CRF. To summarize, a convinc-
ing body of evidence supports a critical role of CRF1 re-
ceptors in the response to stress, and it has been clearly
demonstrated that selective blockade of CRF1 receptors di-
minishes anxious states. However, there is a complex pat-
tern of—not necessarily discordant—data (Contarino et al.,
1999b; Bale et al., 2002; Dautzenberg and Hauger, 2002;
Holsboer, 1999; Valdez et al., 2002a) suggesting that: (1)
stimulation of CRF2 receptors amplifies anxiogenic actions
transduced by CRF1 sites and/or (2) possibly via actions in
other regions and over different time-scales (during recov-
ery from stress), activation of CRF2 receptors opposes the
anxiogenic properties elicited via CRF1 sites. The applica-
tion of the VCT and other conflict models would likely pro-
vide important insights into these multiple role(s) of CRF in
the response to stress and the modulation of anxious states.
Currently, it would be premature to attempt concrete predic-
tions regarding the influence of (systemic administration of)
CRF2 receptor antagonists upon anxiety disorders in man.
9.1.3. Vasopressin and oxytocin
9.1.3.1. Vasopressin, V1A and V1B receptors. The actions
of vasopressin are mediated by V1A , V1B and V2 receptors,
of which both the V1A subtype (which stimulates phos-
pholipase C via Gq) and the V1B subtype (which likewise
engages phospholipase C via Gq) are found in the CNS
(Lolait et al., 1992, 1995; Hallbeck et al., 1999). Hypophy-
seal populations of V1B receptors transduce the facilitatory
influence of vasopressin (mediated in synergy with CRF)
upon the outflow of ACTH—including both basal release
and its induction by anxiogenic stimuli. Conversely, hy-
pothalamic populations of V1A receptors indirectly con-
tribute to activation of the corticotropic axis (Antoni, 1993;
Burbach et al., 1995; Aguilera and Radadan-Diehl, 2000;
Birnbaumer, 2000; Morimoto et al., 2000; Keck et al.,
2002; Serradeil-Le Gal et al., 2002; Carrasco and Van de
Kar, 2003). Tracking the broad, supraspinal distribution of
vasopressin-containing pathways (which principally origi-
nate in parvocellular neurones of the hypothalamic paraven-
tricular nucleus, the amygdala and the PAG), V1A receptors
are enriched in the cortex as well as the septum, hip-
pocampus and amygdala (Burbach et al., 1993, 1995, 1998;
Hallbeck et al., 1999). V1B receptors have been identified
in the amygdala, cingulate cortex, frontal cortex, nucleus
accumbens and hippocampus, as well as in the DRN and the
LC (Lolait et al., 1992, 1995; Burbach et al., 1995; Vaccari
et al., 1998; Brinton et al., 2000; Hernando et al., 2001).
Functional evidence for a role of vasopressin in the mod-
ulation of anxious states is provided by observations of an
induction of central vasopressin synthesis and release in the
amygdala, septum and elsewhere upon exposure to stress
(Chen and Herbert, 1995; Albeck et al., 1997; Wotjak et al.,
1998; Aguilera and Radadan-Diehl, 2000; Ebner et al., 2002;
Makino et al., 2002a). Further, Brattleboro rats, which genet-
ically lack vasopressin, show low levels of anxiety (Williams
et al., 1985; Herman et al., 1986), while anxiolytic prop-
erties of mixed V1A /V1B receptors antagonists have been
documented (Liebsch et al., 1996). Antisense knockdown
of V1A sites in the septum suppressed anxious behaviour
in rats (Landgraf et al., 1995) and V1A receptors have been
implicated in the control of social behaviour in rodents and
other species (Hammock and Young, 2002). Further, though
the phenotype of mice lacking V1B sites was interpreted
as anxiogenic, the novel, selective V1B receptor antagonist,
SR149,415, elicited a selective and significant increase in
punished responses in the VCT in parallel with anxiolytic ac-
tions in other paradigms of untrained behaviours (Table 19)
(Lolait et al., 2000; Hernando et al., 2001; Griebel et al.,
2002a; Serradeil-Le Gal et al., 2002).
Thus, while there is a reasonable body of evidence in-
dicating that central, stress-responsive VP-containing path-
ways are dedicated to the control of mood, the precise roles
of V1A and V1B sites in the control of anxious states remain
poorly-understood.
9.1.3.2. Oxytocin and oxytocin receptors. By analogy to
vasopressin, oxytocin is synthetized by magnocellular neu-
rones situated in the supraoptic and paraventricular nuclei
of the hypothalamus which project to the median eminence
and the posterior lobe of the pituitary. On the other hand,
parvocellular neurones of the paraventricular nucleus deliver
OT-containing afferents to a broad range of CNS structures
including the cortex, hippocampus, LC, DRN, septum and
amygdala (Gimpl and Fahrenholz, 2001; Millan, 2002a).
Oxytocin-containing neurones manifest pronounced respon-
sivity to emotional stress, and the presence of eponymous
oxytocin receptors (which are coupled via Gq to phospholi-
pase C) throughout corticolimbic structures—including the
hypothalamus and amygdala—offers a substrate for a po-
tential role in the modulation of anxious behaviour (Bale
et al., 1995; Burbach et al., 1995; Nishioka et al., 1998;
Uvnäs-Moberg, 1998; Vaccari et al., 1998; Wotjak et al.,
1998; Gimpl and Fahrenholz, 2001; Millan, 2002a; Winslow
and Insel, 2002).
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Surprisingly, little functional information concerning OT
and anxious behaviour is currently available. Nevertheless,
anxiolytic properties of OT have been reported upon cen-
tral administration to rodents and the amygdala plays a key
role in its control of anxious states (Stoehr et al., 1992;
Uvnäs-Moberg et al., 1994; McCarthy et al., 1996; Windle
et al., 1997; Bale et al., 2001). Further, mice with genetically
disabled oxytocin receptors were found to display an anx-
iogenic profile, though conflicting findings have also been
reported (DeVries et al., 1997; Mantella and Amico, 2002;
Winslow and Insel, 2002).
The above observations indicate that, in addition to the
familiar role of oxytocin in the modulation of social, ag-
gressive and maternal behaviour, this neuropeptide may con-
tribute to the control of anxious states (Witt, 1995; DeVries
et al., 1997; Popik and Van Ree, 1998; Uvnäs-Moberg, 1998;
Argiola, 1999; Winslow and Insel, 2002).
Intriguingly, then, it appears that OT and VP may fulfil
opposite anxiolytic and anxiogenic roles, respectively.
9.1.4. Substance P and other tachykinins
9.1.4.1. Multiple classes of neurokinin receptor. The
mammalian tachykinins, substance P (SP, 11 amino acids
in length), neurokinin A and neurokinin B, are thought
to exert their actions principally via excitatory neurokinin
(NK)1 , NK2 and NK3 receptors, respectively, each of
which stimulates phospholipase C via recruitment of
Gq (Maggi, 1995; Quartara and Maggi, 1997; Mantyh,
2002).
9.1.4.2. SP and NK1 receptors. Moderate to high con-
centrations of SP and NK1 receptors have been detected
in limbic regions of the brain, including the FCX, amyg-
dala, hypothalamus, LC, PAG and hippocampus: in the lat-
ter structure, a sub-population of NK1 receptors is localized
on GABAergic neurones. In addition to broadly-distributed
clusters of local neurones, several SP-containing projections
have been identified, including pathways from the septum
and mammillary bodies to the hippocampus, from the amyg-
dala to the hypothalamus and from the parabrachial nucleus
to the amygdala itself (Pernow, 1983; Mantyh et al., 1984;
Kiyama et al., 1993; Otsuka and Yoshioka, 1993; Nakaya
et al., 1994; Saria, 1999; Ribeiro-da-Silva and Hökfelt, 2000;
Sloviter et al., 2001). Interestingly, SP is colocalized with
raphe-derived serotonergic pathways in man, though not nec-
essarily in other species (Sergeyev et al., 1999). These obser-
vations, the responsiveness of corticolimbic SP-containing
neurones to stress (Maggi, 1995; De Felipe et al., 1998;
Smith et al., 1999; Steinberg et al., 2002), their interaction
with monoaminergic pathways (vide infra), and the facilita-
tory influence of NK1 receptors upon corticolimbic release
of GABA and glutamate (Sloviter et al., 2001; Stacey et al.,
2002a,b) underpin interest in a role of SP in the modula-
tion of anxious states (Rupniak and Kramer, 1999; Mantyh,
2002).
151
There is still much confusion concerning the—probably
multiple—roles of NK1 receptors in the modulation of anx-
ious states. Thus, SP fragments have been reported to exert
anxiolytic-like effects in primates (Barros et al., 2002),
while SP exerts anxiolytic actions upon administration into
the ventral pallidum/nucleus basalis magnocellularis of ro-
dents (Hasenöhrl et al., 1998; Nikolaus et al., 2000, see also
Zernig et al., 1993). Mice strains possessing low levels of SP
manifested a high level of anxiety in the VCT—possibly due
to a reduction in the activity of hippocampal populations of
GABAergic neurones (Sloviter et al., 2001; Sudakov et al.,
2001). Further, the functional inactivation of NK1 receptors
(indirectly) reinforces the activity of corticolimbic nora-
drenergic, dopaminergic and—principally upon long-term
administration—serotonergic pathways (Froger et al., 2001;
Millan et al., 2001e; Santarelli et al., 2001; Adell et al., 2002;
Conley et al., 2002; Léger et al., 2002; Lejeune et al., 2002;
Liu et al., 2002; Maubach et al., 2002; Commons et al.,
2003). These actions highlight the attractiveness of NK1
receptors as innovative targets for the improvement of de-
pressive states but, arguably, are inconsistent with the acute
expression of anxiolytic properties. However, as mentioned
below, at doses which do not themselves affect noradrener-
gic pathways, NK1 antagonists can (probably directly) pre-
vent their activation by CRF and stress (Hahn and Bannon,
1999; Bert et al., 2002; Steinberg et al., 2002). More-
over, by analogy to other classes of antidepressant agent
(Section 4.4), it may be speculated that the sustained en-
gagement of corticolimbic monoaminergic projections by
chronic administration of NK1 receptor antagonists initiates
postsynaptic adaptive changes ultimately reflected in the
long-term alleviation of anxious states.
Moreover, an extensive body of evidence has accrued in-
dicating that activation of NK1 receptors triggers or aggra-
vates anxious states.
First, upon introduction into sites in the PAG, amygdala
and lateral septum, SP elicited defensive, anxiogenic and
aversive actions (Ravard et al., 1994; Aguiar and Brandao,
1996; Mongeau, 1998; Gavioli et al., 1999, 2002a; Rupniak
and Kramer, 1999; Smith et al., 1999; Baretta et al., 2001;
De Araújo et al., 2001; Rupniak et al., 2001).
Second, local application of SP into the LC (directly)
enhanced the activity of noradrenergic neurones, while (as
mentioned above) acute, systemic administration of NK1
receptor antagonists abrogated their activation by CRF and
stress (Hahn and Bannon, 1999; Chen et al., 2000a; Bert
et al., 2002; Steinberg et al., 2002). Further, in analogy to
BZPs, NK1 receptor antagonists blocked the induction of
frontocortical DA release by stress (Barton et al., 1999).
Third, in accordance with these findings, in a diversity of
models (Rupniak and Kramer, 1999; File, 2000; Rupniak
et al., 2000, 2001; Vassout et al., 2000; Ballard et al., 2001;
Baretta et al., 2001; Cheeta et al., 2001b; Santarelli et al.,
2001, 2002; Steinberg et al., 2002; Varty et al., 2002a,b),
specific anxiolytic actions of non-peptidergic NK1 receptor
antagonists have been reported in several species. Though
152 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
results concerning effects of NK1 receptor antagonists in
conflict procedures have, to date, been conspicuous by their
absence, anxiolytic actions have been documented in a
paradigm of conditioned fear (Ballard et al., 2001). Further,
we recently found that the potent and selective antago-
nist, GR205,171, elicits robust and stereospecific anxiolytic
properties in the VCT (Table 19 and Fig. 9). Inasmuch as
clinically-available 5-HT1A receptor agonists are poorly
effective in subjects pre-treated with BZPs (Section 18.3)
(De Martinis et al., 2000), it would be of importance to
confirm observations that NK1 antagonists suppress the anx-
iety which accompanies their abrupt withdrawal in rodents
(Ribeiro and De Lima, 2002).
Fourth, behavioural and neurochemical analyses of mice
lacking NK1 sites revealed a diminution of anxious be-
haviour and stress-related responses (Rupniak and Kramer,
1999; Rupniak et al., 2000, 2001; Vassout et al., 2000;
Ballard et al., 2001; Santarelli et al., 2001, 2002). More re-
cently, selective deletion of the “tacl” gene which encodes
SP (and NK A) yielded an anxiolytic profile in a broad range
of experimental procedures, including a conflict paradigm
(Bilkei-Gorzo et al., 2002).
Fifth, reduced anxiety was reported upon ablation of NK1
receptor-bearing neurones in the amygdala by local injection
of a SP-saporin, cytotoxic conjugate which enters cells via
NK1 receptor internalisation (Mantyh, 2002).
Finally, there is evidence that prolonged exposure to an-
tidepressant agents depletes central levels of SP, for exam-
ple, in the amygdala, observations which have been related
to their treatment of affective disorders (Jones et al., 1985;
Shirayama et al., 1996; Burnet et al., 2001). The possibil-
ity that a modulation of SP/NK1 receptor-mediated trans-
mission by antidepressants is involved in the long-term de-
velopment of their anxiolytic properties would, thus, be of
interest to evaluate.
Anxiolytic actions of a NK1 receptor antagonist (aprepi-
tant) were reported in a clinical study undertaken in sub-
jects suffering from major depression (Kramer et al., 1998;
Rupniak and Kramer, 1999; Krishnan, 2002). Though in-
formation from patients presenting with pure GAD or other
anxious states does not appear to have been divulgued, this
highly-publicized therapeutic trial has sparked a resurgence
of interest in the clinical utility of NK1 antagonists. In-
deed, these encouraging observations will hopefully crys-
tallize into definitive proof that NK1 receptor antagonists
genuinely represent a novel approach to the management of
anxious (and depressive) disorders.
9.1.4.3. NK2 and NK3 receptors. Though NK2 receptors
are sparse in the CNS and have proven difficult to visualize,
compelling evidence for their existence in the septum, hip-
pocampus and cerebral cortex of rodents and man was re-
cently reported (Steinberg et al., 1998; Bensaid et al., 2001;
Saffroy et al., 2001, 2003; Candenas et al., 2002). Despite
their positive effects in models based on exploratory and
defensive behaviours, NK2 receptor antagonists failed to
display anxiolytic properties in the VCT (Walsh et al., 1995;
Teixeira et al., 1996; Griebel et al., 2001a,c; Ribeiro and
De Lima, 2002). This inactivity is somewhat perplexing in
view of the interrelated observations that: (1) NK2 recep-
tor antagonists interfere with the activation of LC-derived
noradrenergic neurones by CRF (Steinberg et al., 2001)
and that (2) anxiolytic actions of CRF1 receptor antago-
nists in the VCT involve their suppressive influence upon
stress-induced release of NA (Section 9.1.2). An alterna-
tive, non-noradrenergic explanation for anxiolytic actions
of NK2 receptor antagonists in models of exploratory be-
haviour invokes their modulatory influence upon the activity
of DRN-derived serotonergic pathways (Walsh et al., 1995).
NK3 receptors are concentrated in several limbic regions,
including the PAG, amygdala and hypothalamus, and they
are also found in the cerebral cortex (Ding et al., 1996; Yip
and Chahl, 1997, 2001; Mileusnic et al., 1999). They exert a
facilitatory influence upon corticolimbic noradrenergic and
dopaminergic—but not serotonergic—neurones (Seabrook
et al., 1995; Jung et al., 1996; Marco et al., 1998; Panocka
et al., 2001; Bert et al., 2002; Léger et al., 2002. These find-
ings are consistent with a role in the modulation of anx-
ious states, and of mood in general. However, information
remains fragmentary (Ribeiro et al., 1999; Panocka et al.,
2001) and data from the VCT and other conflict procedures
are not, as yet, available.
There is, thus, a need for additional study of the roles of
multiple classes of NK receptor in the control of anxious
behaviour by use of the VCT and other procedures. This
would be of particular importance in view of the ongoing,
therapeutic evaluation of selective antagonists at NK1 , NK2
and NK3 receptors for the treatment of various categories of
psychiatric and neurologic disorder Raffa (1998).
9.1.5. Neuropeptide Y
9.1.5.1. Localization and coupling to multiple receptor sub-
types. Together with peptide YY and pancreatic polypep-
tide PP, likewise 36 amino acids in length, NPY exerts its
actions via multiple classes of receptor, of which Y1 , Y2 ,
Y4 and Y5 receptors occur in rat and human CNS and are
of pertinence to the modulation of anxious states—a further
Y6 receptor possibly exists in murine CNS (Heilig et al.,
1994; Wettstein et al., 1995; Dumont et al., 1996a,b; Michel
et al., 1998; Zimanyi et al., 1998; Bischoff and Michel, 1999;
Redrobe et al., 2002b; Thorsell and Heilig, 2002). Y1 , Y2 ,
Y4 and Y5 receptors all exert an inhibitory influence upon
adenylyl cyclase via recruitment of Gi . The high levels of
NPY (principally in interneurones) in corticolimbic tissues,
including the nucleus accumbens, PAG, septum and amyg-
dala, underscore interest in its role in the control of anxious
states. Further, in the amygdala, NPY is partially colocalized
with GABA (McDonald and Pearson, 1989; Aoki and Pickel,
1990; Caberlotto et al., 2000; Kask et al., 2002) or with NA
(Wettstein et al., 1995; Zimanyi and Poindexter, 2000). Y1
receptors (the most abundant subtype in the CNS) are highly
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
expressed in the hippocampus, PAG, frontal cortex, hypotha-
lamus and amygdala while Y2 receptors, which share their
occurrence in the hippocampus, amygdala and hypothala-
mus, are also found in the lateral septum, nucleus accum-
bens, raphe nuclei and the LC. In contrast to Y1 sites, Y2
receptors may operate as autoreceptors on NPY-containing
neurones (Dumont et al., 1996a,b, 2000; Naveilhan et al.,
1998; Parker and Herzog, 1999; Caberlotto et al., 2000;
Migita et al., 2001; Kask et al., 2002; Redrobe et al., 2002b).
9.1.5.2. Modulation. Modulation of the cerebral synthe-
sis of NPY by a variety of acute and chronic, fear-inducing
stimuli, including an acceleration of its production in the
amygdala in parallel with behavioural habituation to stress,
has prompted the hypothesis that NPY “buffers” the ef-
fects of long-term exposure to anxiogenic stimuli (Krysiak
et al., 2000; Kask et al., 2002; Thorsell and Heilig, 2002).
This assertion is supported by the relative insensitivity to
fear-inducing situations and stress of transgenic mice over-
expressing (hippocampal) NPY: moreover, they display an
anxiolytic profile in the VCT (Inui et al., 1998; Thorsell
et al., 1999, 2000). Contrariwise, mice lacking NPY are
prone to exaggerated anxiety upon exposure to fear-inducing
situations (Palmiter et al., 1998; Bannon et al., 2000). Inter-
estingly, levels of NPY in the cerebrospinal fluid of patients
with major depression were inversely proportional to the in-
tensity of concomitant anxious symptom: this suggests that
subjects with a low rate of NPY release had a greater procliv-
ity towards anxious behaviour (Widerlöv et al., 1989). Other
alterations in NPY levels in patients with affective and anx-
ious disorders were likewise interpreted as congruent with
a role in the control of emotivity (Kask et al., 2002). Com-
plementing these observations, NPY exerts an inhibitory in-
fluence upon ACTH secretion in man Antonijevic et al.,
2000.
9.1.5.3. Key roles of Y1 and Y2 sites in the control of anx-
ious states. In accordance with the above comments, cen-
tral administration of NPY (and fragments thereof) results
in robust anxiolytic actions in a diversity of paradigms in-
cluding both natural and conditioned behaviours and con-
flict tests. Microinjection studies indicate that these effects
are exerted in at least three structures: the amygdala (Heilig
et al., 1993; Heilig, 1995; Sajdyk et al., 1999b), the dorsolat-
eral septum (Kask et al., 2001a,b) and the PAG (Kask et al.,
1998b), though the possible implication of additional sites in
the hypothalamus, hippocampus and elsewhere should not
be discounted (Kask et al., 2002). Characterization of anti-
sense probes, and of NPY fragments possessing differential
potency at Y1 versus Y2 receptors, revealed that activation
of the former was responsible for these anxiolytic actions:
indeed, a decrease in activity at Y1 sites in the PAG is asso-
ciated with anxiogenic effects suggestive of a tonic role of
Y1 receptors in the control of anxious states (Heilig et al.,
1989, 1993, 1994; Wahlestedt et al., 1993; Broqua et al.,
1995; Heilig, 1995; Britton et al., 1997; Kask et al., 1998b,
153
1999, 2000, 2002). Consistent with these findings, Heilig
et al. (1989) demonstrated that NPY is highly active in el-
evating punished responses in the VCT (Table 19). Though
the (polyvalent) role of NPY in the control of nociception
(Millan, 1999; Kask et al., 2002) suggests caution in the in-
terpretation of these data, it appears that the anxiolytic ac-
tions of NPY are specifically expressed in the absence of
alterations in nociceptive thresholds and water appetite. In-
terestingly, in light of the robust anxiolytic actions of CRF1
receptor antagonists in the VCT (Section 9.1.2.2), it has been
proposed that NPY opposes the anxiogenic actions of CRF
in at least two cerebral regions, the septum and the amygdala
(Heilig et al., 1994; Kask et al., 1997, 2001a, 2002; Britton
et al., 2000). While engagement of GABAergic mechanisms
has been implicated in the sedative and sleep-promoting
properties of NPY, the relationship of GABAA /BZP recep-
tors to anxiolytic actions mediated by Y1 receptors remains
to be clarified (Antonijevic et al., 2000; Naveilhan et al.,
2001).
In the above-evoked studies of the central administration
of NPY and related sequences, it was concluded that Y2
receptors play an insignificant role as compared to their
Y1 counterparts in transducing the anxiolytic actions of
NPY (Table 19) (Heilig et al., 1989, 1992, 1993, 1994;
Wahlestedt et al., 1993; Broqua et al., 1995; Britton et al.,
1997; Kask et al., 2002). Indeed, activation of Y2 recep-
tors in the amygdala may actually be accompanied by
anxiogenic effects (Nakajima et al., 1998; Sajdyk et al.,
2002a,b; Thorsell and Heilig, 2002), and an anxiolytic
phenotype has been documented for mice lacking Y2 re-
ceptors (Redrobe et al., 2002a, 2003). However, Y2 sites
have been reported to mediate anxiolytic actions via loci in
(or near) the LC. This observation is consonant with the
predominant role of Y2 as compared to Y1 receptors in the
NPY-mediated inhibition of noradrenergic pathways, acti-
vation of which may aggravate anxious states (Section 4.1.1)
(Finta et al., 1992; Illes et al., 1993; Kask et al., 1998a, 2000,
2002).
9.1.5.4. Other NPY receptor subtypes. Most investigations
have focussed on the appetite-modulating role of Y5 recep-
tors, but their discovery in regions controlling emotionality,
such as the amygdala, hippocampus and septum, indicates
that they may also contribute to the control of anxious states
(Bischoff and Michel, 1999; Nichol et al., 1999; Parker and
Herzog, 1999; Zimanyi and Poindexter, 2000; Thorsell and
Heilig, 2002). Further, Y5 receptors have been identified
on limbic populations of GABAergic and CRF-containing
neurones (Bischoff and Michel, 1999; Grove et al., 2000).
A study with the Y5 receptor antagonist, CGP71683A, re-
vealed only a modest influence upon anxious states un-
der resting conditions, but an anxiogenic effect under con-
ditions of stress, coinciding with a recent report that Y5
receptors transduce anxiolytic actions in the (basolateral)
amygdala (Broqua et al., 1995; Kask et al., 2001c, 2002;
Sajdyk et al., 2002a). Thus, additional work with further
154 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
selective antagonists and agonists—and with models such
as the VCT—would be instructive in defining their potential
role.
Y4 receptors have been detected in the amygdala, the hip-
pocampus and the mammillary bodies, raising the possibil-
ity of a role in the modulation of emotionality and anxious
states (Zimanyi et al., 1998; Parker and Herzog, 1999). How-
ever, there is currently no direct support for this contention
inasmuch as mice lacking pancreatic polypeptide (which dis-
plays marked affinity for Y4 receptors) did not manifest sig-
nificant alterations in their behaviour in models of potential
anxiolytic activity (Asakawa et al., 1999).
There is, thus, a compelling body of evidence that NPY
fulfils a crucial role in the response to, and modulation of,
anxious states. Continued use of the VCT, together with
subtype-selective ligands, should provide further insights
into the significance of NPY in the etiology and, optimisti-
cally, management of anxiety disorders.
9.1.6. Glucagon-like peptide-1
While the major processing product of pre-pro-glucagon
in the pancreas is glucagon, the primary splicing products
in the CNS are glucagon-like peptide-1 (7-36 amide) and
glicentin peptide (Lopez et al., 1983; Flint et al., 1998).
Glucagon-like peptide-1 (which activates adenylyl cylase)
plays a key role in the control of appetite, likely reflect-
ing actions in the nucleus solitarius and the hypothalamus
(Lopez et al., 1983; Flint et al., 1998). However, brainstem
neurones producing glucagon-like peptide-1 (localized near
the nucleus of the solitary tract) also innervate the DRN,
LC and many limbic regions, including the PAG, hippocam-
pus, septum and amygdala: these structures are also en-
riched in receptors for this peptide (Turton et al., 1996; Jin
et al., 1988; Merchenthaler et al., 1999). Direct injection of
glucagon-like peptide-1 into the amygdala specifically sup-
pressed punished responding in the VCT, indicative of an
anxiogenic role in this structure (Table 19) (Möller et al.,
2002). Though virtually nothing else is known of its role of
the control of emotionality, underpinning these findings in
the VCT, it was recently shown that glucagon-like peptide-1
also exerts aversive properties by actions in the amygdala
(Kinzig et al., 2002).
9.1.7. Galanin
The 29 amino acid, galanin, is broadly distributed
throughout the corticolimbic system, including the hip-
pocampus, the nucleus accumbens, the amygdala, the con-
tiguous bed nucleus of the stria terminalis and the PAG
(Skofitsch and Jacobowitz, 1985; Bartfai et al., 1992, 1993;
Merchenthaler et al., 1993; Waters and Krause, 2000; Perez
et al., 2001). In these structures, galanin is both synthesized
locally and released from ascending noradrenergic path-
ways wherein it co-exists with NA: both of these pools of
galanin are recruited in response to stress (Holmes et al.,
1995, 2002a,b; Hokfelt et al., 1998; Crawley et al., 2002;
Khoshbouei et al., 2002a,b).
Under conditions of aversive stimulation, it has been pos-
tulated that the harnessing of local or LC-derived sources of
galanin negates the anxiogenic effects of NA in the amyg-
dala (Crawley et al., 2002; Khoshbouei et al., 2002a,b). In
this light, it is something of a conundrum that direct intro-
duction of galanin into the amygdala resulted in a specific
suppression of punished responses in the VCT (Table 19)
(Bing et al., 1993; Möller et al., 1999). Moreover, though the
i.c.v. administration of galanin reduced anxiety in the VCT,
the dose–response curve was bell-shaped and higher doses
increased anxiety. Mice overexpressing GAL showed lit-
tle change in anxious behaviour, though anxiogenic actions
of the ␣2 -antagonist, yohimbine, were abolished (Crawley
et al., 2002; Holmes et al., 2002a). Several reasons may un-
derlie these apparently discordant data.
First, galanin may exert contrasting anxiogenic and anxi-
olytic actions via different receptor subtypes, of which three
are currently recognized. Inhibitory “GAL1 ” and “GAL3 ”
receptors are negatively coupled via Gi to adenylyl cylase,
whereas excitatory “GAL2 ” receptors are positively coupled
to phospholipase C via Gq (Branchek et al., 2000; Waters and
Krause, 2000). In the amygdala, PAG and LC, GAL1 sites
predominate, but GAL2 and GAL3 sites are also present.
Further, GAL1 , GAL2 and GAL3 receptors are all local-
ized in the hypothalamus, PAG, hippocampus and cortex
(O’Donnell et al., 1999; Waters and Krause, 2000). Though
little is known of the functional roles of these GAL recep-
tor subtypes, mice genetically deficient in GAL1 receptors
exhibited an anxiogenic profile, suggesting that GAL1 sites
may counter anxious states (Holmes et al., 2002b). Second,
the influence of galanin upon anxious states may depend
upon its site of action. For example, via actions at both the
cell body and terminal level, a “negative feedback” autore-
ceptor action of galanin upon the activity of LC-derived no-
radrenergic neurones (Hökfelt et al., 1998; Perez et al., 2001;
Millan, 2002a; Yoshitake et al., 2003a) may act anxiolyt-
ically. On the other hand, anxiogenic and/or anxiolytic
actions may be exerted postsynaptically to noradrenergic
projections in limbic regions (vide supra). Third, in addition
to its co-storage with NA in noradrenergic neurones, GAL
is colocalized with 5-HT (Hökfelt et al., 1998; Perez et al.,
2001). Indeed, galanin exerts a modulatory influence upon
serotonergic transmission and displays a complex pattern of
(generally inhibitory) interactions with 5-HT1A autorecep-
tors in raphe nuclei, as well as with postsynaptic 5-HT1A
sites in the amygdala and hippocampus (Hökfelt et al., 1998;
Misane et al., 1998; Diaz-Cabiale et al., 2000; Kehr et al.,
2002a,a,b; Yoshitake et al., 2003b). Finally, galanin exerts
an excitatory influence upon the mesolimbic release of
dopamine (Ericsson and Ahlenius, 1999). Galanin may, thus,
act via several substrates in the modulation of anxious states.
Much work remains to be performed with the VCT and
other models to determine the precise influence of GAL upon
anxious states and, in particular, to delineate the respective
roles and potential clinical pertinence of GAL1 , GAL2 and
GAL3 receptor subtypes.
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
9.1.8. Neurotensin
Neurotensin (13 amino acids in length) and the related
sequence, neuromedin N (six amino acids in length), are
processed from a common precursor peptide. They exert
their actions via “NT1 ” and “NT2 ” receptors—the func-
tional status of a third neurotensin binding entity (identical
to the protein, sortilin) is questionable since it is not a
G-protein-coupled receptor (Vincent et al., 1999; McMahon
et al., 2002). NT1 and NT2 receptors are both positively
coupled via Gq to phospholipase C, and differentially inter-
act with several other intracellular cascades (Rostène and
Alexander, 1997; Vincent et al., 1999; McMahon et al.,
2002). While NT1 receptors are particularly abundant in the
lateral septum, NT2 receptors are concentrated in the cortex,
hippocampus and hypothalamus (Sarret et al., 1998; Walker
et al., 1998). Stress is accompanied by alterations in central
(hypothalamic) levels of neurotensin. Under these condi-
tions, via recruitment of the anxiogenic peptide, CRF, neu-
rotensin exerts a facilitatory influence upon ACTH secretion
(Rowe et al., 1995; Helmreich et al., 1999; Seta et al., 2001).
The above comments, together with the facilitatory influ-
ence of NT upon serotonergic pathways (Shipley et al., 1987;
Li et al., 2001a), support a role of neurotensin in the control
of emotivity. Though the selective NT1 antagonist, SR48692,
was ineffective in several rodent paradigms, including the
VCT (Griebel et al., 2001a), analysis of its actions in a mouse
defensive behaviour procedure suggested that engagement
of NT1 receptors may contribute to the adaptive response
to unavoidable stress (Griebel et al., 2001a). Further, any
role of the more widespread NT2 receptors in the modula-
tion of anxious states remains to be explored. While selec-
tive antagonists for NT2 sites are not apparently available,
centrally-active, neurotensin analogues (agonists) have re-
cently been described and their actions in the VCT and re-
lated protocols would be of interest to evaluate (Boules et al.,
2001; McMahon et al., 2002).
9.1.9. Multiple opioid peptides and melanocortins
9.1.9.1. Endorphins, µ-, δ- and κ-receptors. Multiple opi-
oid peptides exert their actions via ␮-, ␦- and ␬-opioid re-
ceptors, for which ␤-endorphin/endomorphins, enkephalins
and dynorphin-related peptides, respectively, comprise their
endogenous ligands. ␮-, ␦- and ␬-opioid receptors all share
an inhibitory influence upon neuronal activity attributable
to their suppression and enhancement of Ca2+ - and K+ -
currents, respectively, and to their stimulation of adenylyl
cyclase (Kachaturian et al., 1985; Herz et al., 1993; Mansour
et al., 1995; Satoh and Minami, 1995; Millan, 2002a). Like
stress-responsive pools of opioid peptides, multiple opi-
oid receptors are highly (though differentially) expressed
throughout corticolimbic structures (Kachaturian et al.,
1985; Millan, 1986, 1990, 2002a; Herz et al., 1993; Mansour
et al., 1995; Martin-Schild et al., 1999; Kozicz et al., 2002).
They fulfil contrasting roles in the control of mood,
and display reciprocal interactions with monoaminergic
155
and GABAergic networks, including an inhibitory influence
upon GABAergic neurones in the hippocampus, amygdala
and PAG (Mansour et al., 1988; Cohen et al., 1992; Herz
et al., 1993; Sugita and North, 1993; Kang et al., 2000;
Kieffer and Gavériaux-Ruff, 2002; Kozicz, 2002; Liberzon
et al., 2002; Millan, 2002a; Tao and Auerbach, 2002a,b).
Indicative of contrasting roles of multiple opioid receptor
subtypes, whereas mice lacking ␬-opioid receptors do not
reveal an altered phenotype, populations deprived of either
enkephalins or ␦-opioid receptors reveal enhanced anxiety.
These findings suggest an anxiolytic role for enkephalins
at ␦-receptors. Correspondingly, pharmacological evidence
was forwarded that ␦-opioid receptors participate in express-
ing the anxiolytic properties of cannabinoids (Köning et al.,
1996; Filliol et al., 2000; Ragnauth et al., 2001; Berrandero
and Maldonado, 2002).
It has been reported that high doses of the opioid receptor
antagonist, naloxone, interfere with the anxiolytic actions of
BZPs in the VCT and several other procedures (Millan and
Duka, 1981; Ågmo et al., 1995; Tsuda et al., 1996). Inas-
much as naloxone preferentially blocks ␮- and ␦-opioid as
compared to ␬-opioid receptors, the need for a high dose in-
dicated that blockade of ␬-opioid rather than ␮- or ␦-opioid
receptors was involved, an assertion supported by anxiolytic
actions of ␬-opioid receptor agonists in the mouse VCT
(Table 19) (Tsuda et al., 1996) and a plus-maze procedure
in rats (Privette and Terrian, 1995). This contention is, how-
ever, inconsistent with studies of mice deficient ␬-opioid
receptors which do not show an anxious phenotype (vide
supra). Further, supporting evidence for an anxiolytic role of
␬-opioid receptors is unavailable and their activation is gen-
erally anxiogenic and aversive to rodents and higher species
(Millan, 1990; Bals-Kubik et al., 1993; Nobre et al., 2000;
Sante et al., 2000; Marin et al., 2003). Thus, a contribu-
tion of ␦-opioid receptors to the anxiolytic effects of BZPs
would offer an alternative interpretation. Though such a role
of ␦- or ␬-opioid receptors in mediating the anxiolytic ac-
tions of BZPs appears intuitively improbable—and clearly
requires corroboration—it would be of interest to examine
further inasmuch as naloxone was reported to attenuate the
anxiolytic actions of BZPs in human subjects (Millan and
Duka, 1981; Duka et al., 1982).
Surprisingly, mice genetically deprived of ␮-receptors
showed an anxiolytic phenotype suggesting that, in
distinction to ␦-receptors, ␮-opioid receptor activation
may enhance anxiety (Filliol et al., 2000; Kieffer and
Gavériaux-Ruff, 2002). One possible explanation may be
relief of the tonic, inhibitory influence of ␮-opioid recep-
tors upon limbic populations of GABAergic interneurones
(Cohen et al., 1992; Sugita and North, 1993; Millan, 2002a).
Further, in contrast to studies mentioned above (Millan and
Duka, 1981; Ågmo et al., 1995; Tsuda et al., 1996), em-
ploying non-conflict paradigms, other investigations have
found that modest doses (sufficient to block ␮-receptors) of
the opioid antagonists, naloxone and naltrexone, potentiate
anxiolytic properties of BZPs (Belzung and Agmo, 1997;
156 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Belzung and Dubreuil, 1998; Frussa-Filho et al., 1999;
Silva and Frussa-Filho, 2002). These observations are con-
ceivably related to anecdotal reports of nervousness and
dysphoria upon a first administration of morphine to naive,
human subjects. However, naloxone and naltrexone en-
hance or fail to affect anxious states in man (Grevert and
Goldstein, 1978; Millan and Duka, 1981), pharmacological
blockade of ␮-opioid receptors alone is not associated with
anxiolytic properties in rodents or primates, and mice lack-
ing ␤-endorphin showed no changes in anxious behaviour
(Millan and Duka, 1981; Nobre et al., 2000; Sante et al.,
2000; Kieffer and Gavériaux-Ruff, 2002). Further, ␮-opioid
analgesics (such as morphine) are reliably active in a con-
ditioned emotional response procedure in rats, as well as
certain other models of anxiolytic activity, while their calm-
ing and mood-improving properties are quintessential to the
unique quality of long-term pain-relief which they afford
(Millan and Duka, 1981; Millan, 1990, 1999, 2002a; Herz
et al., 1993; Filliol et al., 2000; Berrandero and Maldonado,
2002; De Boer and Koolhaas, 2003; Sanchez, 2003). Thus,
the possibly bimodal (anxiolytic and anxiogenic) role of
␮-opioid receptors in the control of anxious states remains
puzzling and deserves further investigation.
The profound analgesic properties of opioid agonists,
most strikingly at ␮-opioid receptors (Millan, 1999, 2002a),
might be expected to compromise evaluation of their actions
in models incorporating noxious stimuli. In fact, ␮-opioid
agonists show negligible activity in the VCT and only weak
and variable actions in the Geller–Seifter conflict model of
anxiolytic activity, underpinning the argument that antinoci-
ceptive actions are not, in principle, sufficient for disinhi-
bition of punished responses (Table 19) (Vogel et al., 1971;
Millan and Duka, 1981; Pollard and Howard, 1989; Heilig
et al., 1992; Millan and Brocco, 2003). Indeed, though the
danger of “false positives” should systematically be exam-
ined for all drugs possessing pronounced analgesic effects,
irrespective of pharmacological class, there appears to be a
general dissociation between antinociceptive properties and
anxiolytic actions in punishment-based conflict procedures
such as the VCT and other behavioural models (Millan and
Brocco, 2003).
9.1.9.2. OrphaninFQ and ORL1 receptors. Recently, con-
siderable attention has been devoted to the role of a novel
member of the opioid family, orphaninFQ (OFQ, also re-
ferred to as nociceptin), in the modulation of anxious states
(Bertorelli et al., 2000; Mogil and Pasternak, 2001). Its
(naloxone-insensitive) receptor, “ORL1 ”, shares the cou-
pling profile of its ␮-, ␦- and ␬-opioid receptor counterparts
to diverse intracellular signals and similarly exerts an in-
hibitory influence upon neuronal activity (Section 9.1.9.1)
(Hawes et al., 2000a). Like ORL1 receptors, orphaninFQ is
widely distributed in virtually all centres involved in the eti-
ology and modulation of anxious states: the hippocampus,
the amygdala, the hypothalamus, the nucleus accumbens, the
PAG, the cortex and the lateral septum (Neal et al., 1999a,b;
Slowe et al., 2001; Millan, 2002a). In the amygdala, or-
phaninFQ suppresses the release of both glutamate and
GABA (Meis and Pape, 2001). Further, in addition to corti-
colimbic structures, expression of ORL1 receptors in the LC
and raphe nuclei provides a substrate for the pronounced
inhibitory influence of OFQ upon the activity of noradrener-
gic and serotonergic pathways, respectively (Connor et al.,
1999; Calo et al., 2000; Sbrenna et al., 2000; Schlicker and
Morari, 2000; Millan, 2002a; Rominger et al., 2002; Marti
et al., 2003).
Upon central administration—to circumvent problems of
limited CNS penetration—both orphaninFQ and a synthetic
ORL1 receptor agonist, Ro64-6198, elicited a coherent pat-
tern of anxiolytic actions in various experimental models,
including conflict procedures, at doses which did not perturb
(though see Higgins et al., 2001) motor or cognitive func-
tion (Jenck et al., 1997; Mogil and Pasternak, 2001; Carey
and Varty, 2002). (Further, orphaninFQ elicits hyperalge-
sia rather than antinociception via actions in supraspinal
structures (Millan, 2002a)). Very recently, in line with these
findings, i.c.v. administration of orphaninFQ was reported
to display anxiolytic properties in the VCT (Table 19) (Lu
et al., 2002). Amongst other cerebral regions, ORL1 recep-
tors in the amygdala and the PAG are involved in transduc-
ing the anxiolytic actions of orphaninFQ (Jenck et al., 1997,
2000; Griebel et al., 1999b; Kyuhou and Gemba, 1999;
Mogil and Pasternak, 2001; Millan, 2002a; Sajdyk et al.,
2002c). Underscoring the tonic role of OFQ in the control
of anxious states, ORL1 receptor antagonists exhibit anx-
iogenic properties. Further, though ORL1 knock-out mice
show few changes, animals lacking the OFQ gene reveal
an increased vulnerability to stress, impaired adaptation to
anxiogenic situations and elevated circulating levels of glu-
cocorticoids (Köster et al., 1999; Reinscheid et al., 2000;
Reinscheid and Civelli, 2002; Sajdyk et al., 2002c).
Confounding assessment of the pathophysiological role(s)
of orphaninFQ, the pre-pro-orphaninFQ precursor from
which it is spliced gives rise to several, further bioactive
sequences, notably nocistatin (Calo et al., 2000; Mogil and
Pasternak, 2001; Millan, 2002a). The latter sequence can
interfere (via actions at a separate site) with the effects of
orphaninFQ and was recently reported to exert anxiogenic
properties in mice (De Lima et al., 2002; Gavioli et al.,
2002b). Further, it was recently suggested that orphaninFQ
and nocistatin interact with GABAergic systems in the con-
trol of anxious states (De Lima et al., 2002). Whether, by
analogy to ORL1 receptor agonists, nocistatin antagonists
possess anxiolytic properties remains to be established. The
interrelationship between OFQ and nocistatin in the modu-
lation of anxious behaviour would clearly be conducive to
further study employing the VCT.
9.1.9.3. Melanocortins and related peptides. Both in the
pituitary and in perikarya localized in the arcuate hypotha-
lamus and nucleus tractus solitarious, posttranslational
cleavage of the pro-opiomelanocortin precursor to generate
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
␤-endorphin (Section 9.1.9.1) yields several other bioactive
neuropeptides. These include the melanocortins: ACTH,
␣-melanocyte-stimulating hormone (MSH)—the N-terminal
13 amino acids fragment of ACTH-␤-MSH, and ␥-MSH
(Bagnol et al., 1999; Adan and Gispen, 2000; MacNeil et al.,
2002; Millan, 2002b). Melanocortins exert their actions via
five classes of receptor, all of which—in contrast to opi-
oid receptors—couple positively via Gs to adenylyl cyclase
(Wikberg, 1999; Adan and Gispen, 2000). ␣-MSH has high
affinity for each subtype of melanocortin receptor except
MC2 , while ACTH is the only melanocortin to show high
affinity for all subtypes including MC2 receptors which are
concentrated in the adrenal gland (Adan and Gispen, 2000).
Like MC2 sites, MC1 receptors are poorly represented in
the CNS, though a small population has been located in the
PAG (Adan and Gispen, 2000; Millan, 2002b). Modest lev-
els of MC5 receptors have been detected supraspinally but
the principle sites of relevance to the modulation of anxious
states are MC3 and MC4 receptors. The former, which may
act as autoreceptors on melanocortin-containing neurones,
are highly expressed in various hypothalamic nuclei and
they are also found in the septem, nucleus accumbens, hip-
pocampus, amygdala, raphe and ventrotegmental area. On
the other hand, MC4 sites are enriched in several hypotha-
lamic nuclei, the amygdala, the lateral septum, the bed
nucleus of the stria terminalis and the PAG, while they are
also detectable in the LC, DRN and, despite scarce inner-
vation by melanocortin-containing fibers, the hippocampus
and cortex (Mountjoy et al., 1994; Lindblom et al., 1998;
Roselli-Rehfuss et al., 1993; Bagnol et al., 1999; MacNeil
et al., 2002; Kishi et al., 2003). In distinction to opioids,
melanocortins may exert an excitatory influence upon
adrenergic neurones in the LC (René et al., 1998) and they
have been shown to activate CRF-containing neurones in
the parvocellular division of the paraventricular nucleus of
the hypothalamus (MacNeil et al., 2002).
By analogy to ␤-endorphin (Section 9.1.9.1), hypophy-
seal and supraspinal pools of melanocortins are responsive
to stress (Millan, 1986, 2002a; Adan and Gispen, 2000).
Further, via actions in the PAG and other cerebral struc-
tures, both ACTH and ␣-MSH elicit grooming behaviour
in rodents—a characteristic stress-related response (Section
4.2.1)—while antibodies directed against ACTH suppress
the grooming response to novelty Dunn et al. (1979), Adan
et al. (1999), Adan and Gispen (2000). More direct evidence
for an anxiogenic role of ACTH and ␣-MSH is provided by
their suppression of social interaction in rodents, their in-
duction of anxiety upon infusion into the ventromedial nu-
cleus and, most pertinently, their robust and dose-dependent
reduction of responses in the VCT upon i.c.v. administra-
tion (Table 19) (File and Clarke, 1980; Corda et al., 1990;
Gonzalez et al., 1996). Though a role of MC3 receptors
should not be discounted, it is likely that MC4 sites are im-
plicated in these actions. Thus, in “preliminary studies”, a
synthetic MC4 agonist was similarly found to display anxio-
genic effects in the VCT while a selective, non-peptidergic
157
MC4 receptor antagonist reversed the anxiogenic effects of
pre-exposure to stress in the light–dark box procedure in
mice and a plus-maze in rats (Chaki et al., 2003a).
Interestingly, an endogenous antagonist (inverse ago-
nist) of MC4 and MC3 receptors has been discovered
(agouti-related peptide) which, like melanocortins, is syn-
thetised in the arcuate nucleus and shares the localization
of MC4 and MC3 receptors in the bed nucleus of the stria
terminalis and the lateral septum. Its physiological and
potential therapeutic significance to the control of anxious
states awaits clarification (Haskell-Luevano et al., 1999;
Haskell-Luevano and Monck, 2001).
Neurones containing melanocortins also produce a 132
amino acid peptide termed cocaine- and amphetamine-
regulated transcript (CART) which is also synthesized in
several limbic structures, including the nucleus accum-
bens, the amygdala and the hippocampus (Koylu et al.,
1998; Kuhar and DallVechia, 1999). The synthesis of
CART is elevated by stress, and CART markedly activates
CRF-containing neurones in the hypothalamus and accel-
erates the secretion of ACTH (Vrang et al., 1999; Stanley
et al., 2001; Chaki et al., 2003b). Moreover, its bioactive
fragment, CART55-102 , elicited anxiety upon i.c.v. admin-
istration to mice and enhanced the electrical activity of
the LC in rats, a structure in which it is co-localized with
adrenergic neurones (Chaki et al., 2003b).
These mutual anxiogenic properties of CART and
melanocortins are all the more interesting inasmuch as they
likewise share the ability to inhibit appetite and to elicit hy-
peralgesia (Adan and Gispen, 2000; MacNeil et al., 2002;
Millan, 2002b).
Clearly, then, exploration of the interrelationships of
melanocortins, CART, agouti-related peptide and ␤-endor-
phin in the modulation of anxious states is likely to provide
fertile territory for research over the coming years.
9.1.10. Melanin Concentrating Hormone
Melanin Concentrating Hormone (MCH) is a cyclic
neuropeptide of 19 amino acids which is intimately in-
volved in the control of energy balance: it is synthetized
in the lateral hypothalamus—and zona incerta (Nahon,
1994; Shimada et al., 1998). MCH-containing projections
from these regions extensively innervate corticolimbic
regions of the brain, including the FCX, hippocampus,
septum, PAG and VTA (Bittencourt et al., 1992; Casatti
et al., 2002; Dallvechia-Adams et al., 2002). These cen-
tral MCH-containing pathways, which are inhibitory to the
hypothalamo-corticotropic axis, are subject to modulation
both by CRF and by stress, concordant with a role in the
control of emotionality (Nahon, 1994; Bluet-Pajot et al.,
1995; Griffond and Baker, 2002).
MCH exerts its actions via MCH1 receptors (originally
designated the orphan receptor, SLC-1/GPR24) and MCH2
(SLT/S643b) receptors, both of which couple via Gq to phos-
pholipase C and intracellular pools of Ca2+ . Further, MCH1
receptors are inhibitory to adenylyl cyclase, depress the
158 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
operation of VDCCs and activate K+ -channels via Gi/o ,
though their major mode(s) of transduction remain(s) to
be specified (Hawes et al., 2000b; Audinot et al., 2001a,b;
Rodriguez et al., 2001; Griffond and Baker, 2002; Gao and
Van Der Pol, 2002). The distribution of central MCH1 recep-
tors parallels that of MCH itself, with notably high concen-
trations in the cortex (entorhinal, frontal, cingulate and tem-
poral), the hippocampus, lateral septum, nucleus accumbens,
amygdala, hypothalamus and the mammillary nuclei (Her-
vieu et al., 2000; Saito et al., 2001; Borowski et al., 2002).
The occurrence of MCH1 sites in the LC and DRN implies
a role for MCH in the modulation of ascending noradren-
ergic and serotonergic transmission, a possibility requiring
direct neurochemical and electrophysiological verification.
Mice genetically devoid of MCH or MCH1 receptors
display, predictably, alterations in appetite and energy
metabolism, but potential changes in their emotionality, re-
sponse to stress and anxious behaviour do not appear to have
been examined (Shimada et al., 1998; Chen et al., 2002a;
Marsh et al., 2002). Further, there are conflicting reports con-
cerning the influence of central administration of MCH upon
anxious behaviour in rats. These disparities conceivably re-
flect the expression of anxiolytic as compared to anxiogenic
actions in different CNS regions, such as the amygdala, the
hippocampus and the hypothalamus, though the respective
roles of these structures remain to be clarified (Gonzalez
et al., 1996b; Monzon and De Barioglio, 1999; Monzon
et al., 2001). Selective, non-peptidergic antagonists at MCH1
sites have recently been disclosed and shown to possess
anxiolytic properties upon parenteral administration in a so-
cial interaction procedure (Borowski et al., 2002; Takekawa
et al., 2002). In view of their modest efficacy in the VCT
(Table 19 and Fig. 9) (Brocco and Millan, unpublished ob-
servations), MCH1 sites appear a promising novel target for
the management of anxious and other psychiatric disorders.
MCH2 receptors share the localization of their MCH1
counterparts in the cortex (entorhinal and temporal), amyg-
dala and hippocampus of primates, including man. How-
ever, functional MCH2 receptors appear to be absent from
rats and mice—which possess inactive, truncated forms—
invalidating rodents in the exploration of their functional
significance (Griffond and Baker, 2002; Tan et al., 2002b).
Thus, any potential role of MCH2 sites in the modulation of
anxious states will be difficult to discern.
9.1.11. Angiotensin/AT receptors
Angiotensin II (an octomer) is derived from angiotensin
I by an action of angiotensin converting enzyme, while an-
giotensin I itself is cleaved from angiotensinogen by renin
(Morimoto and Sigmund, 2002; Turner and Hooper, 2002).
The familiar role of angiotensin II in the control of cardio-
vascular function, water homeostasis and sodium reabsorp-
tion reflects actions at AT1␣ , AT1␤ and AT2 receptors—each
of which is differentially implicated in its functional effects
(Allen et al., 1998; Morimoto and Sigmund, 2002; Turner
and Hooper, 2002). Though the primary loci of action
of angiotensin II are peripheral, the entire multi-enzyme
renin–angiotensin system is found in the brain. Indeed,
though the percentage of angiotensinogen synthesized by
neurones as compared to astrocytes may be modest, it
has been detected in the amygdala, hippocampus, septum,
hypothalamus and cortex (Bunnemann et al., 1993; Gard,
2002; Morimoto and Sigmund, 2002). Moreover, AT1 recep-
tors, which stimulate phospholipase C and inhibit adenylyl
cyclase via recruitment of Gq and Gi , respectively, are
localized in the FCX, hippocampus, hypothalamus, PAG,
amygdala and LC (Wright and Harding, 1995; Lenkei et al.,
1997; Allen et al., 1998; De Gasparo et al., 2000). AT2 sites
(for which coupling mechanisms are poorly defined, though
they are inhibitory to neuronal activity) have been detected
in the entorhinal cortex, amygdala, PAG, raphe nuclei and
LC (Wright and Harding, 1995; Lenkei et al., 1997; De
Gasparo et al., 2000).
Employing models of exploratory behaviour, data have
been acquired indicating that the selective AT1 receptor an-
tagonist, losartan, possesses anxiolytic properties (Barnes
et al., 1991; Okuyama et al., 1999b; Gard, 2002). Such
findings are congruent with reports of anxiolytic actions
of angiotensin converting enzyme inhibitors, and with anx-
iomimetic effects of angiotensin II itself in several models,
including the VCT, though caution must be exercised in in-
terpreting the latter action in view of the role of angiotensin
in the control of water appetite (Costall et al., 1990; Georgiev
et al., 1990; Kaiser et al., 1992; Tsuda et al., 1992; Costall
and Naylor, 1997; Okuyama et al., 1999a; Gard, 2002). An-
giotensin II also reduced defensive burying behaviour in
mice (Tsuda et al., 1992). At variance with these observa-
tions, upon acute administration, in a time-dependent fash-
ion, angiotensin II elicited a delayed “rebound” reduction
in anxiety, and not all studies with AT1 antagonists have
observed anxiolytic effects (Gard, 2002). The role of an-
giotensin II in the control of anxious states may, thus, be
complex, reflecting multiple and contrasting roles of AT1
and AT2 receptors (Shepherd et al., 1996; Okuyama et al.,
1999b; Gard, 2002). Indeed, mice lacking AT2 receptors
showed heightened anxiety-like behaviour, possibly medi-
ated (indirectly) via actions of NA at ␣1 -adrenoceptors in
the amygdala (Section 4.1.5) (Ichiki et al., 1995; Walther
et al., 1999; Okuyama et al., 1999b).
Finally, AT4 receptors—for which angiotensin IV (derived
from angiotensin II) may be the major endogenous ligand—
are located in the amygdala, PAG and hippocampus, sug-
gesting that they may also be involved in the modulation of
anxious states (Wright et al., 1995; Allen et al., 1998; Chai
et al., 2000; Gard, 2002; Turner and Hooper, 2002).
9.2. Peptides/receptors as yet to be evaluated in the VCT
9.2.1. Vasoactive intestinal peptide and pituitary adenlyl
cyclase activating peptide
Vasoactive intestinal peptide and pituitary adenyl cy-
clase activating peptide (PACAP)—which belong to a
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
family of peptides including glucagon (Section 9.1.6)—are
structurally-related peptides of 28 and 38 amino acids in
length, respectively. Both share high affinity for so-called
“VPAC1 ” and “VPAC2 ” receptors. These sites, which are
positively coupled to adenylyl cyclase via Gs, are localized
in the hippocampus, amygdala and cortex, congruent with
an, as yet unexplored, role in the modulation of anxiety
(Vertongen et al., 1997; Dumont et al., 2000; Vaudry et al.,
2000; Laburthe and Couvineau, 2002). However, PACAP
also potently activates excitatory “PAC1 ” receptors which
stimulate phospholipase C via Gq. Like PACAP, PAC1
receptors are concentrated in the hippocampus, septum,
amygdala, hypothalamus, hippocampus and cortex, while
they have also been found in the LC and DRN, from which
noradrenergic and serotonergic pathways, respectively, arise
(Hashimoto et al., 1996; Piggins et al., 1996; Laburthe and
Couvineau, 2002).
These anatomical studies provide a framework for a
potential influence of PACAP upon anxious states, pos-
sibly involving a facilitatory influence upon the activity
of monoaminergic projections. In line with this notion,
knock-out mice in which PAC1 receptors were deleted (and,
possibly, mice lacking PACAP itself) display a reduction
in anxious behaviour: this phenotype apparently reflects a
loss of tonic activity at PAC1 sites in the LC, amygdala and
septum (Sauvage et al., 2000; Hashimoto et al., 2001; Otto
et al., 2001). Regrettably, however, pharmacological studies
have not, as yet, been undertaken concerning the role of
these peptides in the control of anxious states.
9.2.2. Somatostatin
Somatostatin 14 and the N-terminal extended somatastin
28, together with various cortistatins, interact with at least
five classes of receptor (Dournaud et al., 1998, 2000;
Hervieu and Emson, 1998; Csaba and Dournaud, 2001).
Like somatostatin, sst2 receptors (which inhibit adenylyl
cyclase via Gi ) are predominantly localized in corticolim-
bic structures, including the PAG, amygdala, cortex and
hippocampus. Further, they are also located in the LC,
coinciding with the modulatory influence of somatostatin
via sst2 —and other—receptor subtypes upon noradrener-
gic neurones (Epelbaum et al., 1994; Chessell et al., 1996;
Dournaud et al., 1996, 1998, 2000; Selmer et al., 2000;
Csaba and Dournaud, 2001; Pittaluga et al., 2001). Inter-
estingly, numerous somatostatin-containing neurones in the
amygdala, though devoid of CCK and vasoactive intestinal
polypeptide, contain GABA and NPY, transmitters inti-
mately involved in the modulation of anxious states and
behavioural performance in the VCT (Sections 2.2.2 and
9.1.5, respectively) (McDonald and Mascagni, 2002). Mice
with a null mutation for sst2 receptors displayed a pro-
nounced enhancement in emotional reactivity, in anxious
behaviour and in their response to stress (Viollet et al.,
2000). These observations encourage the use of the VCT
in the examination of a potential suppressive influence of
somatostatin via sst2 sites upon anxious behaviour. In this
159
respect, recently-discovered non-peptidergic antagonists
at sst2 receptors should prove instructive tools (Crider,
2002). Despite anatomical studies indicating their broad
localization in diverse corticolimbic regions, the functional
significance of other sst receptor types in the modulation
of anxious states remains obscure (Csaba and Dournaud,
2001).
9.2.3. Natriuretic peptides
Atrial natriuretic peptide (28 residues in length), together
with brain natriuretic peptide (26 amino acids) and C-type
natriuretic peptide (34 amino acids), play important roles
in the central and peripheral regulation of endocrine and
autonomic function (Gutkowska and Nemer, 1989; Imura
et al., 1992).
The high levels of atrial natriuretic peptide and “ANP-A”
receptors in the entorhinal cortex, FCX, hippocampus,
amygdala, septum, hypothalamus, as well as the DRN, sug-
gest a role in the control of emotionality (Langub et al.,
1995). This supposition is supported by increases in its se-
cretion in patients undergoing panic attacks (Kellner et al.,
1997). Furthermore, in human subjects, atrial natriuretic
peptide concurrently inhibited the anxiogenic response to
CCK4 and suppressed its induction of ACTH secretion
(Kellner et al., 2002). In line with these findings, both the
i.c.v. and intra-amygdala administration of atrial natriuretic
peptide and brain natriuretic peptide elicited anxiolytic
effects in rats, while isartin, a putative, endogenous in-
hibitor of ANP-A receptors exerted anxiogenic properties
(Bidzseranova et al., 1992; Glover et al., 1995; Bhatta-
charyya et al., 1996; Biro et al., 1996; Ströhle et al., 1997).
Supporting a role in the control of behaviour under condi-
tions of anxiety, both atrial and brain natriuretic peptides
facilitate fear-motivated learning in rats (Bidzseranova
et al., 1992; Biro et al., 1996; Ströhle et al., 1997). Though
GABA does not appear to participate in the modulation of
anxiety by atrial natriuretic peptide, monoaminergic mech-
anisms may be involved (Vatta et al., 1994; Bhattacharyya
et al., 1996; Biro et al., 1996; Griebel, 1999a). In contrast
to these data, atrial natriuretic peptide failed to modify pun-
ished responses in a Geller–Conflict model (Heilig et al.,
1992). Additional studies of the potential actions of atrial
natriuretic peptide would, thus, be informative to resolve its
role in the modulation of anxious states.
C-type natriuretic peptide, which is concentrated in limbic
regions such as the hippocampus (Langub et al., 1995), is
a preferential ligand at “ANP-B” sites (Koller et al., 1991).
Though the functional role of C-type natriuretic peptide is
less well-defined than that of atrial natriuretic peptide, there
is evidence that it promotes the CRF-induced secretion of
ACTH in man and that it concomitantly elicits anxiety-like
symptoms, actions opposite to those of ANP (Kellner et al.,
1997, 2002; Montkowski et al., 1998). Interestingly, then,
its central administration to rodents proved to be anxio-
genic, an action which possibly reflects recruitment of CRF
(Jahn et al., 1997, 2001; Montkowski et al., 1998). Inasmuch
160 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
as CRF controls behaviour in the VCT, this procedure would
evidently be appropriate for further characterization of the
influence of C-type natriuretic peptide upon anxious be-
haviour.
9.2.4. Bombesin-related peptides
The bombesin-like family of peptides incorporates the
mammalian neuromedin B and gastrin-releasing peptide.
They are 32 and 27 amino acids in length, respectively, but it
is probably their 10 amino acid N-terminal sequences which
constitute their bioactive fragments (Battey and Wada, 1991;
Kroog et al., 1995; Ohki-Hamazaki, 2000). Mammalian neu-
romedin B and gastrin-releasing peptide are preferential ag-
onists of “BB1 ” and “BB2 ” receptors, respectively, though
they also display modest affinity for a third “BB3 ” site for
which an endogenous ligand remains to be isolated (Benya
et al., 1995; Kroog et al., 1995; Ohki-Hamazaki, 2000).
BB1 , BB2 and BB3 receptors all engage phospholipase C via
Gq/11 , though they may also recruit (independently of phos-
pholipase C) other intracellular signals, such as adenylyl
cyclase and mitogen-activated protein kinase (Benya et al.,
1995; Kroog et al., 1995; Ohki-Hamazaki, 2000).
Neuromedin B and BB1 receptors have been visualized in
the lateral septum, frontal cortex, PAG, hippocampus, amyg-
dala, LC and raphe nuclei (Wada et al., 1990, 1991; Ohki-
Hamazaki, 2000). The latter observation has attracted par-
ticular attention inasmuch as neuromedin B and bombesin
exert an excitatory influence upon raphe-localized seroton-
ergic neurones via the activation of BB1 receptors (Pinnock
and Woodruff, 1991; Pinnock et al., 1994), Further, in mice
lacking BB1 receptors, the facilitatory influence of stress
upon serotonergic neurones is abrogated (Yamano et al.,
2002). Though these mice did not exhibit any modification
of behaviour in the plus-maze, they showed alterations in
emotionality in other procedures, heightened susceptibility
to stress, and a down-regulation of 5-HT1A receptors both
pre- and postsynaptically to serotonergic pathways (Yamada
et al., 2002a,b,c; Yamano et al., 2002). Further, stress induces
the release of bombesin-related peptides in the amygdala and
hypothalamus (Kent et al., 1998; Merali et al., 1998), while
neuromedin B interacts with the anxiogenic peptide, CRF,
in the modulation of appetite and satiety (Ohki-Hamazaki,
2000). Thus, inasmuch as the first non-peptidergic antag-
onists at BB1 receptors have been described (Ryan et al.,
1999), it would be instructive to evaluate their actions in the
VCT and other procedures of potential anxiolytic properties.
Though the distribution of gastrin-releasing peptide and
BB2 receptors in the CNS is distinct to that of neuromedin B
and BB1 receptors, like the latter, they are expressed in the
hippocampus, the hypothalamus, the amygdala, the PAG and
the LC (Wada et al., 1990, 1991; Battey and Wada, 1991).
Stress promotes the release of gastrin-releasing peptide in
the amygdala. Therein, following release from glutamatergic
terminals, it excites GABAergic interneurones and plays a
role in the modulation of fear-induced memory (Shumyatsky
et al., 2002). Though mice lacking gastrin-releasing peptide
show no alterations in anxious behaviour, populations with a
null mutation for BB2 receptors display an increase in social
behaviour: this was suggested to reflect an enhancement in
activity at GABAA receptors though it remains unclear as to
how this is brought about (Wada et al., 1997; Merali et al.,
1998; Yamada et al., 2000b, 2001, 2002b). Though only
peptidergic antagonists for BB2 sites are currently available
(Jensen and Coy, 1991), the foregoing observations incite
further exploration of their role in the modulation of anxious
states (Yamada et al., 2002a).
BB3 receptors are most prevalent in the hypothalamus,
but they are also found in the amygdala (Ohki-Hamazaki
et al., 1997; Yamada et al., 2000a). In addition to metabolic
changes, mice in which BB3 receptors have been genetically
ablated show alterations in non-aggressive social behaviour,
and they present an anxiolytic profile in both the plus-maze
and light-box procedures (Yamada et al., 2000a). Thus, once
discovered, it would be of interest to examine potential anx-
iolytic properties of selective antagonists at these sites.
Collectively, then, the above data suggest that all three
subtypes of BB receptor are (perhaps differentially) involved
in the control of emotionality and anxious states.
10. Melatonin
10.1. Coupling and localization
Melatonin, which is synthesized in the pineal gland,
plays an important chronobiotic role in the control of diur-
nal activity, of seasonal rhythms and of sleep, all of which
are perturbed in anxious states (Borjigin et al., 1999). Its
secretion is enhanced by activation of stress-sensitive, sym-
pathetic noradrenergic input (Seggie et al., 1985; Joshi et al.,
1986; Golombek et al., 1996). Melatonin acts via “MLT1 ”
(Mel1A ) and “MLT2 ” (Mel1B ) receptors. Both are coupled
via Gi/o to inhibition of adenylyl cyclase. MLT1 receptors
also regulate the activity of phopholipase A via Gq, while ac-
tivation of MLT2 receptors diminishes intracellular levels of
cyclic guanidine monophosphate (Reppert et al., 1996; Von
Gall et al., 2002; Witt-Enderby et al., 2003). The cerebral
pattern of distribution of melatonin receptors is strikingly
species-specific. Though MLT1 sites have been visualized
in the cortex, the amygdala, septum and other limbic struc-
tures of various species, such observations have not to date,
been made in mice, rats (or man). Nevertheless, MLT2 sites
have been identified in the hippocampus and FCX of rodents
and primates, consistent with a role in the control of anx-
ious states (Reppert et al., 1995; Mazzucchelli et al., 1996;
Vanecek, 1998; Wan et al., 1999; Witt-Enderby et al., 2003).
10.2. Control of anxious states
Though melatonin was not effective in a rat VCT over
a broad dose range (Table 18) (Brocco et al., unpublished
observations), it exerted anxiolytic actions (preventable
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
by a specific MLT1/2 receptor antagonist) in other mod-
els, primarily those based on exploratory behaviour
(Guardiola-Lemaı̂tre et al., 1992; Golombek et al., 1993,
1996; Kopp et al., 1999a, 2000; Nava and Carta, 2001). The
blockade by flumazenil (an antagonist at the BZP binding
site on GABAA ) receptors (Section 2.2.2), of the anxiolytic
actions of melatonin gels with other behavioural evidence
suggesting that an interaction with GABAergic mechanisms
contributes to its influence upon behaviour, (Pierrefiche
et al., 1993; Golombek et al., 1996; Kopp et al., 1999a,b,
2000; Wan et al., 1999; Wang et al., 2003). However, this
has been disputed and the precise mechanisms underlying
anxiogenic effects of melatonin remain puzzling inasmuch
as MLT2 receptors exert an inhibitory control upon GABAA
receptor-mediated transmission in the hippocampus (Wan
et al., 1999). Further, it should be pointed out that melatonin
is not involved in the anxiolytic effects of BZPs which actu-
ally exert a suppressive influence upon melatonin secretion
(Winters et al., 1991; Djeridane and Touitou, 2001).
Though clinical studies of melatonin as a pre-medication
prior to surgery are consistent with reduced anxiety, its
sedative and hypnotic properties are clearly relevant to its
influence upon mood under such conditions (Naguib and
Samarkandi, 2000). Indeed, while prescription of melatonin
improves the compliance of patients discontinuing BZP
treatment for sleep disorders, there is no evidence that this
action reflects an influence upon anxious states and there
are currently no compelling arguments to support the ther-
apeutic utility of melatonin in the management of anxious
disorders (Garfinkel et al., 1999; Cardinali et al., 2002).
Thus, negative findings with melatonin in the VCT are not
surprising and any potential utility of melatonin alone in the
control of anxious states may primarily reflect its chronobi-
otic role in normalizing perturbed circadian (and seasonal)
rhythms rather than anxiolytic properties per se. Indeed, in
certain paradigms, anxiolytic effects of melatonin have only
been seen upon night-time administration (Golombek et al.,
1993). On the other hand, it is conceivable that the associa-
tion of agonist properties at melatonin receptors with other
components of activity (either in a single molecule or as an
adjunctive agent) may be beneficial in the treatment of clin-
ical anxiety disorders.
11. Glucocorticoids
11.1. Genomic and non-genomic actions in the CNS
Following their rapid secretion by the adrenal cortex into
the systemic circulation in response to stress, glucocorticoids
mobilize energy reserves by attenuating cellular glucose up-
take and inducing hepatic gluconeogenesis. More recently,
numerous studies have yielded convincing evidence that,
under conditions of stress and fear, glucocorticoids exert a
pronounced influence upon cerebral function and plastic-
ity via both long-term and more short-term actions (Cahill
161
and McGaugh, 1998; Chen and Qiu, 2001; Gass et al.,
2001; Haller, 2001; Korte, 2001; Makino et al., 2002b).
The familiar genomic actions of glucocorticoids reflect
their docking to a cytosolic receptor which is then translo-
cated into the nucleus: therein, in conjunction with other
transcription proteins, glucocorticoids bind to DNA and
modify gene expression (Joëls and Vreugdenhil, 1998; Chen
and Qiu, 2001; Kellendonk et al., 2002). The transcription
factors, type I mineralocorticoid receptors (MR) and type II
glucocorticoid (GR) receptors, which mediate these actions
of glucocorticoids, are well-represented in the CNS, wherein
they appear to fulfil contrasting functional roles. The latter
are broadly distributed in the amygdala, hippocampus and
other corticolimbic structures (including sites involved in
the feedback control of the hypothalamo-corticotropic axis),
and they are also localized in the LC and DRN. In contrast,
the distribution of MR receptors is more confined in that
they are highly expressed in the hippocampus, amygdala
and septum (De Kloet et al., 1991; Morimoto et al., 1996;
De Kloet et al., 1998; Joëls and Vreugdenhil, 1998; Gass
et al., 2001; Kellendonk et al., 2002). MR receptors dis-
play high affinity for glucocorticoids and may be virtually
saturated under “resting” conditions, whereas low-affinity
GR receptors are phasically occupied upon imposition of
stressful stimuli (op. cit.).
It has been proposed that chronic exposure to stress
results, via mechanisms implicating glucocorticoids, in
deleterious morphological and functional changes in the
hippocampus, amygdala and cortex, including an impair-
ment of synaptic transmission (notably, of “long-term
potentiation”), a (probably reversible) dendritic atrophy,
suspension of oligocyte proliferation and a reduction in
neurogenesis, effects contributing to the emotional and
cognitive deficits of persistent anxious and depressive
states. Changes in the hippocampus involve a variety of
transmitters and reflect effects mediated both locally and
“upstream” in other structures such as the amygdala with
which it is interlinked (Akirav and Richter-Levin, 1999;
Gould and Tanapat, 1999; Sherwood-Brown et al., 1999;
Kim et al., 2001; Alfarez et al., 2002; Kim and Diamond,
2002; Makino et al., 2002a,b; Venero et al., 2002).
On an opposite time-scale, several organs, including the
CNS, can respond rapidly (within seconds or minutes) to
glucocorticoids indicative of non-genomic actions elicited
independently of gene transcription (Borski, 2000; Sapolsky,
2000a,b; Sapolsky et al., 2000; Chen and Qiu, 2001; Makara
and Haller, 2001; Kellendonk et al., 2002). These effects
may require engagement of a membrane-bound receptor
structurally similar to GR sites. An inhibitory influence of
glucocorticoids upon neuronal excitability likely reflects
a diminution in the activity of adenylyl cyclase and their
opening of K+ -channels, though, based on studies effected
in the hippocampus and cortex, modulation of Ca2+ -influx
(via VDCCs) and of intracellular Ca2+ -concentrations can
underlie excitatory actions of glucocorticoids. Thus, the
effects of glucocorticoids are complex, and both genomic
162 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
and non-genomic mechanisms trigger tissue-dependent
alterations in cellular excitability (Sze and Iqbal, 1994;
Ffrench-Mullen, 1995; Qiu et al., 1998; Borski, 2000; Karst
et al., 2000; Chen and Qiu, 2001).
11.2. Interactions with neurotransmitters
Though the relative contribution of rapid versus long-term
and genomic versus non-genomic processes to the central
actions of glucocorticoids remains to be clarified, there is
a vast literature (Haller et al., 1998; Meijer and De Kloet,
1998; Raber, 1998; Sapolsky, 2000a,b; Sapolsky et al., 2000;
Korte, 2001; Makara and Haller, 2001; Kellendonk et al.,
2002) dedicated to the interaction of central pools of gluco-
corticoids with corticolimbic noradrenergic (including ␣1
and ␣2 -ARs) (Stone et al., 1986, 2002; Stone and Quarter-
main, 1999; Makino et al., 2002b), dopaminergic (Piazza
et al., 1996; Rougé-Pont et al., 1998; Sillaber et al., 1998),
serotonergic (including 5-HT1A , 5-HT2A and 5-HT2C recep-
tors and 5-HT transporters) (Chaouloff, 1995; Maines et al.,
1999; Cyr et al., 2001; Czyrak et al., 2002), glutamater-
gic (including NMDA receptors) (Lowy et al., 1993;
Moghaddam et al., 1994) and GABAergic transmission
(Haller et al., 1998; Falkenstein et al., 2000; Haller, 2001).
This complex pattern of actions provides a diversity of
substrates for the modulation of anxious states.
11.3. Control of anxious states
Studies of glucocorticoid depletors (Plihal et al., 1996;
Murphy, 1997), of ligands selective for MR and/or GR re-
ceptors (Korte et al., 1995; Plihal et al., 1996; Murphy, 1997;
Korte, 2001), of transgenic mice expressing an antisense se-
quence directed against GR sites (Montkowski et al., 1995;
Steckler and Holsboer, 1999; Müller et al., 2002), and of
the behaviour of mice in which the gene encoding central
GR receptors has been impaired, deleted or over-expressed
(Rochford et al., 1997; Tronche et al., 1999; Gass et al., 2001;
Oitzl et al., 2001; Clément et al., 2002; Müller et al., 2002),
indicate that short- or long-term interference with central ac-
tions of glucocorticoids generally alleviates anxious states
and improves mood, whereas a reinforcement in their ac-
tions results in their aggravation. These actions are largely
mediated independently of adrenal corticosterone secretion.
However, not all observations conform to this schema, al-
terations in cognitive function complicate interpretation of
data, most studies have employed models of spontaneous,
exploratory behaviour rather than conflict paradigms, and
contrasting functional roles of MR and GR receptors should
be borne in mind (Korte et al., 1995; Montkowski et al.,
1995; Roozendaal et al., 1996; Rochford et al., 1997; Ströhle
et al., 1998; Tronche et al., 1999; Calvo and Volosin, 2000;
Gass et al., 2001; Korte, 2001; Clément et al., 2002; Gold
and Chrousos, 2002; Kellendonk et al., 2002; Makino et al.,
2002a,b). For example, it has been argued—on the basis of
pharmacological studies—that the facilitatory influence of
glucocorticoids (mediated via GR receptors) upon nucleus
accumbens release of DA, in engaging reward mechanisms,
counteracts aversive states and reduces vulnerability to stress
(Section 4.2.1) (Marinelli and Piazza, 2002).
It is also important to consider the temporal framework
inasmuch as the roles and mechanisms of action of gluco-
corticoids depend upon: (1) the timing of their administra-
tion (release) relative to the stressor (before, during or af-
ter) and (2) the duration of their secretion in response to
stress. For example, it has been conjectured that a failure of
the counter-regulatory glucocorticoid feedback mechanism
to contain excessive and protracted CRF and vasopressin re-
lease under conditions of chronic stress contributes to the
development of pathological anxious states (Meijer and De
Kloet, 1998; Kovacs et al., 2000; Makino et al., 2002a,b).
This argument, as discussed in Sections 9.1.2 and 9.1.3, is
coherent with the major roles of CRF (and vasopressin) in
the induction of anxiety.
On the other hand, upon transient exposure to stress, the
enhanced occupation of central GR receptors by glucocor-
ticoids may reinforce the activity of raphe-derived seroton-
ergic projections in relieving their inhibition by 5-HT1A au-
toreceptors (Meijer and De Kloet, 1998; Man et al., 2002).
Indeed, many investigations have examined the intricate in-
terrelationship between glucocorticoids and both corticolim-
bic and raphe-localized populations of 5-HT1A receptor—
and other classes of 5-HT receptor. The majority of data
suggest an inhibitory influence of glucocorticoids upon the
functional status of 5-HT1A receptors both pre- and post-
synaptic to serotonergic pathways (Chaouloff, 1995; Lopez
et al., 1998; Stutzmann et al., 1998; Karten et al., 1999;
Sibug et al., 2000; Wissink et al., 2000; Gur et al., 2001;
Czyrak et al., 2002; Farisse et al., 2000; Man et al., 2002;
Mueller and Beck, 2000; Müller et al., 2002). Though the
precise nature of these actions remain both confusing and
controversial, presumably reflecting such a reduction in ac-
tivity at 5-HT1A sites, glucocorticoids interfere with anxi-
olytic properties of the 5-HT1A receptor partial agonist, bus-
pirone (Haller et al., 1998, 2001).
Glucocorticoids probably also intervene in the interfer-
ence by stress with the anxiolytic actions of BZPs (Haller
and Halasz, 2000). Though anxiolytic properties of CRF1
receptor antagonists are, in contrast, more pronounced un-
der conditions of stress (Section 9.1.2), this observation
may be explained by an induction of CRF synthesis and
release rather than actions of glucorticocoids (Steckler and
Holsboer, 1999). Interestingly, an augmentation of CRF gene
expression in the amygdala and adjacent bed nucleus of
the stria terminalis by chronic administration of glucocor-
ticoids may participate in their long-term exacerbation of
anxious states (Schulkin et al., 1998; Shepard et al., 2000;
Gass et al., 2001; Makino et al., 1999, 2002a). Similarly,
in mice overexpressing GR receptors, the amplification of
CRF gene expression in the amygdala may contribute to
their anxious phenotype (Wei et al., 2001; Müller et al.,
2002).
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
In view of the responsiveness of the VCT to 5-HT1A re-
ceptor ligands, BZPs and CRF1 antagonists (Sections 2.2.2,
4.3.2 and 9.1.2), its stressful nature, and the involvement
of glucocorticoids in the emotional and cognitive response
to conditioned fear (Korte, 2001), it would be well-adapted
to further exploration of the modulatory influence of gluco-
cortocoids upon anxious states and the actions of anxiolytic
agents.
11.4. The complex role of glucocorticoids
Despite the pivotal importance of glucocorticoids in in-
tegrating the peripheral and central, acute-and long-term
response to stress—including its emotional dimension—
remarkably little is known concerning their precise influence
upon anxious states. Similarly, comparatively little informa-
tion is available concerning the relevance of glucorticocoids
to the management of anxious disorders by BZPs (Section
2.2.2), antidepressants (Section 4.4.2) and other classes of
psychotropic agent. In this context, it should be recalled
that anxiety itself is accompanied by an enhancement in the
activity of the hypothalamo-corticotropic axis, underlining
the reciprocal interrelationship between glucocorticoid se-
cretion and anxious states (Chaouloff, 1995; Herman, 1999;
Sibug et al., 2000; Makino et al., 2002a,b). In light of the
crucial pathophysiological role of glucocorticoids in the
central and peripheral response to stress, there is a need for
additional study of their role in the modulation of anxious
states.
12. Estrogen
12.1. Genomic and non-genomic actions in the CNS
Over recent years, it has become apparent that the gonadal
steroid hormone, 17-␤-estradiol (or estrogen), exerts a com-
plex, pleiotropic influence upon the development and func-
tion of many tissue types other than those of the reproductive
axis (Falkenstein et al., 2000; Driggers and Segars, 2002;
Littleton-Kearney et al., 2002; Carrasco and Van de Kar,
2003). The CNS is no exception in this regard inasmuch as
estrogen exerts pronounced effects upon neurones and, un-
der certain conditions, astrocytes and microglia (Belcher and
Zsarnovszky, 2001; Koenig, 2001; Van Amelsvoort et al.,
2001; Wise et al., 2001a,b; Liang et al., 2002). The genomic
actions of estrogen are expressed via intracellular “ER-␣‘’
and “ER-␤‘’ receptors: following a conformational change,
receptor-estrogen dimers bind to a palindromic DNA se-
quence which, together with several co-factors, leads to al-
terations in the gene transcription of “estrogen-responsive”
elements (McDonnell, 1999; Driggers and Segars, 2002;
Littleton-Kearney et al., 2002; Vasudevan et al., 2002).
These genomic actions, which are exerted over a time-scale
of hours or more, are responsible for the neurotrophic
and neuroprotective actions of estrogen (Van Amelsvoort
163
et al., 2001; Wise et al., 2001a,b; Vasudevan et al.,
2002).
However, estrogen also elicits rapid (over seconds)
changes in neuronal activity reflecting non-genomic actions.
Though still poorly understood, they involve: alterations
in the activity of G-protein receptor-coupled transduc-
tion cascades, diverse protein kinases, adenylyl cyclase
and nitric oxide; modulation of current flux through ion
channels, and interactions with neurotrophins (Falkenstein
et al., 2000; Belcher and Zsarnovszky, 2001; Driggers and
Segars, 2002; Littleton-Kearney et al., 2002; Segars and
Driggers, 2002). These actions—which can evoke further
downstream changes in cellular gene expression—may,
at least partially, be mediated by membrane-localized re-
ceptors closely-related to intracellular ER-␣ and ER-␤
sites, though other mechanisms probably also intervene
(Kelly and Wagner, 1999; Razandi et al., 1999; Nadal
et al., 2000; Belcher and Zsarnovszky, 2001; Wise et al.,
2001a,b). As an additional complication, it should be men-
tioned that ER receptors are susceptible to activation by
phosphorylation, providing a potential mechanism for their
estrogen-independent recruitment by a variety of intracel-
lular signals (Cenni and Picard, 1999; Litttleton-Kearney
et al., 2002; Segars and Driggers, 2002).
12.2. Control of anxious states
The following observations lend credence to the view that
the central effects of estrogen are involved in the induction
and modulation of anxious states.
First, both rapid and longer-term actions of estrogen are
expressed in the hippocampus, septum, amygdala, PAG,
frontal cortex and other corticolimbic regions known to be
rich in (differentially-distributed) ER-␣ and ER-␤ receptors.
For example, both are found in the hypothalamus, amyg-
dala and LC, while ER-␣ sites predominate in the PAG
and ER-␤ sites are prevalent in the cortex, hippocampus
and DRN (Kuiper et al., 1997; Shughrue et al., 1997; Van
Amelsvoort et al., 2001).
Second, central actions of estrogens can profoundly
modify mood, including depressive episodes (Halbreich,
1997; Van Amelsvoort et al., 2001; Brinton, 2002; Littleton-
Kearney et al., 2002). Suggestive of an influence upon anx-
ious states, acute administration of estrogen displayed an
anxiolytic profile in a plus-maze procedure in rats (Rubinow
et al., 1998; Figueiredo et al., 2002) and facilitated the
anxiolytic properties of oxytocin in mice (McCarthy et al.,
1996). Further, mice genetically lacking ER-␣ receptors
show alterations in emotionality (Ogawa et al., 1997).
Third, mechanistic studies have demonstrated that es-
trogens impact upon several transmitter pathways known
to fulfil a crucial role in the control of anxious states.
Thus, (1) experimental and clinical investigations indi-
cate a pronounced influence of estrogen upon serotonergic
transmission including, upon prolonged administration, al-
terations in 5-HT1A receptor binding in the limbic system
164 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
of rats and an elevation in the density of cortical 5-HT2A
receptors: the latter finding has, notably, been repro-
duced in postmenopausal women (Sumner and Fink, 1995;
Osterlund and Hurd, 1998; Rubinow et al., 1998; Moses
et al., 2000; Roca et al., 2002); (2) estrogen potentiates
non-NMDA receptor-mediated glutamatergic transmission
in the hippocampus via the recruitment of protein kinase
A (Gu and Moss, 1996). Moreover, following long-term
treatment, estrogen increases spine density and intensifies
NMDA receptor-mediated signalling in hippocampal pyra-
midal neurones (Pozzo-Miller et al., 1999). On the other
hand, estrogen elicits a (delayed) acceleration of gluta-
mate clearance via an up-regulation of astrocytic glutamate
transporters in the human cortex (Liang et al., 2002). (3)
Estrogen attenuates the potency of agonists at GABAB re-
ceptors (Kelly and Wagner, 1999). Contrariwise, there is
evidence that estrogen reinforces transmission at GABAA
receptors, possibly by modifying their subunit composition:
this action translates into a diminution in their sensitivity to
the anxiogenic properties of GABAA receptor antagonists,
though any alteration in the anxiolytic actions of allosteric
modulators awaits description (Herbison and Fénelon, 1995;
Jung et al., 2002). (4) Short-term exposure to estrogen both
suppresses the synthesis of ␣2A -ARs and interferes with
their inhibitory influence upon NA release in rodent cor-
tex (Karkanias and Etgen, 1993; Karkanias et al., 1997).
Further, estrogen exerts a more persistent, sex-dependent
facilitatory (female) and inhibitory (male) influence upon
LC-derived noradrenergic projections (Thanky et al., 2002).
Fifth, estrogen exerts a pronounced but complex pattern of
influence upon the hypothalamo-pituitary–corticotropic axis
as a function of the condition of study (resting state or stress),
gender, species and parameter under evaluation (Carrasco
and Van de Kar, 2003). Notably, in postmenopausal women,
estrogen replacement therapy moderates the corticotropic
response to emotional stress (Lindheim et al., 1992).
In light of the above, it is not unreasonable to propose
that the dual genomic and non-genomic, central actions of
estrogen are expressed in, as yet little-evaluated, alterations
in anxious states. However, in view of the diversity of these
interactions and the paucity of behavioural data, it would
be perilous to attempt concrete predictions concerning the
overall influence of ER ligands upon anxious states in man.
12.3. Clinical pertinence: gender and anxiety
Impetus to studies of the functional significance of estro-
gens in the control of anxious states is provided by human
exposure (voluntary and involuntary) to many environmental
estrogen mimics and antagonists. They are generally clas-
sified as: (1) xenoestrogens (including pollutants and pes-
ticides) and (2) phytoestrogens (Belcher and Zsarnovszky,
2001; Naftolin and Guadalupe Stanbury, 2002). The lat-
ter, which are derived from plants, bacteria and funghi, are
present in the diet and have been advocated as alternatives
to estrogen replacement therapy in postmenopausal women,
a population in which the role of estrogen in the control of
mood and cognition is under intensive scrutiny. Indeed, syn-
thetic “selective estrogen receptor modulators”, engineered
to optimise procognitive and neuroprotective properties and
to minimize adverse side-effects, are under serious consider-
ation as a treatment option for postmenopausal women pos-
sessing low levels of ovarian steroids (Koenig, 2001; Van
Amelsvoort et al., 2001; Wise et al., 2001a,b; Brinton, 2002;
Littleton-Kearney et al., 2002).
As regards males, it should be pointed out that testos-
terone exerts a marked influence upon mood both: (1) fol-
lowing its aromatisation to estradiol in the brain, via actions
at ER receptors and (2) following its metabolism to neu-
rosteroids, via actions at GABAA receptors (Section 2.2.3).
Intriguingly, testosterone has been reported to increase pun-
ished responses in the VCT (Table 18). Though it was ten-
tatively suggested that this action should be attributed to its
pro-impulsive properties rather than to a reduction in anxi-
ety, testosterone displays anxiolytic actions in other models
(Bitran et al., 1993; Su et al., 1993; Bing et al., 1998; Mc-
Intyre et al., 2002b; Yang et al., 2002). It will interesting to
determine the extent to which actions at ERs as compared
to GABAA receptors are implicated in its influence upon
anxious states.
Though long disregarded, inter-sex disparities in the re-
sponse to fear and stress and the actions of anxiolytic agents
are attracting increasing attention (Rubinow et al., 1998;
Bale et al., 2002; Canli et al., 2002; Jung et al., 2002; McIn-
tyre et al., 2002a,b; Monleon et al., 2002; Stroud et al., 2002;
Thanky et al., 2002; see Palanza, 2001). Notably, there is
substantial evidence for sexual dimorphism in the behaviour
of males as compared to females (which are seldom em-
ployed in pharmacological studies) in tests of anxious be-
haviour (Gray, 1971; Archer, 1975; Johnston and File, 1991;
Gogos et al., 1998; Palanza, 2001). Sex differences have
been documented for conflict tests in general and for the
VCT in particular. However, the contribution of enhanced
emotionality to the lower level of punished responses emit-
ted by female as compared to male rats in the VCT remains
uncertain since this difference may, at least partially, reflect
their greater sensitivity to noxious and other modes of aver-
sive stimuli, in addition to enhanced anxiety per se (Johnston
and File, 1991; Peričić and Pivac, 1995; Palanza, 2001).
Indeed, the interpretation of test-dependent differences be-
tween genders is fraught with difficulty inasmuch as certain
variables which systematically differ between males and fe-
males, such as appetite, endocrine status and motor func-
tion, impact upon performance in models of anxious be-
haviour. Thus, though the significance of inter-sex differ-
ences in the response to and control of anxious states is
widely acknowledged, there still remain some uncertainty
concerning their precise nature and significance—an issue
of not inconsiderable interest to the researcher and lay public
alike!
In analogy to the central actions of glucorticoids, then,
estrogen has been strongly implicated in the control of mood,
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
and numerous biochemical studies have demonstrated its
interaction with corticolimbic neurotransmitters involved in
the modulation of anxious states. Nevertheless, there is a
need for considerable further study of its influence upon
behaviour under conditions of stress and fear in order to
more accurately define its relevance to the pathogenesis and
management of anxiety disorders.
13. Ion channels
13.1. Calcium channels
13.1.1. Operation and localization
Calcium influx into central neurones is mediated, in re-
sponse to depolarisation, by VDCCs: that is, voltage-gated,
heteromeric (4 and 5 subunits) Ca2+ -channels composed
of ␣1 -subunits, membrane-anchored (largely extracellular)
␣2␦ -subunits, intracellular ␤-subunits and transmembrane
␥-subunits. The ␣1 -subunit, which constitutes the cur-
rent sensor and conduction pore, bears most regulatory
sites. Ten forms of ␣1 -subunit are differentially incorpo-
rated into, and determine the characteristics of, several
types of Ca2+ -channel, L, N, P, Q, R and T (Miljanich
and Ramachandran, 1995; Hofmman et al., 1999; Ertel
et al., 2000). Three (rodents) or four (in man) subtypes of
␣2␦ -subunit, four subtypes of ␤-subunit and several subtypes
of ␥-subunit also exist. Though their exact roles remain
unclear, co-expression of the ␣2␦ moiety with other VDCC
subunits promotes current flow and yields additional bind-
ing sites (Klugbauer et al., 1999; Ertel et al., 2000; Hobom
et al., 2000; Marais et al., 2001). ␣2␦ -subunits are
well-represented in corticolimbic structures. While all sub-
types are present in the cortex, ␣2 /␦1 - and ␣2 /␦3 -subtypes
are highly expressed in the hippocampus, and ␣2 /␦2 -subunits
are concentrated in the septum (Hill et al., 1993; Klugbauer
et al., 1999; Hobom et al., 2000; Marais et al., 2001; Fink
et al., 2002).
13.1.2. Control of anxious states
Though the composition of specific populations of VDCC
involved in the control of anxious states cannot, as yet,
be stated, their potential importance is underpinned by the
following observations: (1) in line with the above-described
localization of VDCC subunits, L-type VDCCs are virtu-
ally ubiquitous in the CNS and radiolabelled antagonists
intensely label binding sites in the hippocampus, amygdala
and cortex (Gould et al., 1985; Hobom et al., 2000); (2)
VDCC antagonists modulate monoaminergic, glutamatergic
and GABAergic transmission (Harvey et al., 1996; Dooley
et al., 2000a,b; Katagiri et al., 2001; Chen et al., 2002b;
Fink et al., 2002; Kitayama et al., 2002); (3) high-threshold
L-type VDCCs fulfil a role complementary to that of
NMDA receptors in the mediation of fear-conditioning
in the amygdala, a process with parallels to the VCT,
though their precise implication in mechanisms of acquisi-
165
tion and/or extinction is still debated (Bauer et al., 2002;
Cain et al., 2002); (4) L-type VDCCs trigger a sustained
neuronal influx of Ca2+ upon depolarisation which, via a
diversity of soluble messengers and transcription factors,
initiates long-term processes of synaptic plasticity in the
hippocampus and amygdala: such alterations in calcium
signalling are implicated both in the control of emotion
and in the pathology of mood disorders (Helmeste and
Tang, 1998; Yamawaki et al., 1998; Dolmetsch et al., 2001)
and 5), Most pertinently within the present context, L-type
VDDC antagonists, such as nicardipine, display specific
anxiolytic actions in the VCT (Table 18) (Matsumoto et al.,
1994).
13.1.3. Actions of GABApentin and pregabalin
Notwithstanding the importance of GABAA receptors
(Section 2.2.4), direct actions at VDCCs may partici-
pate in the anxiolytic properties of non-volatile anes-
thetics such as propofol (Kitayama et al., 2002). Interest
in VDCCs as targets for potential anxiolytic agents is
also encouraged by recent observations with pregabalin
(S-isobutylGABA) and GABApentin (neurontin), both of
which are structurally-related to GABA. As mentioned in
Section 2.3.1, it was recently suggested that GABApentin
behaves as a positive modulator of GABAB receptors, ac-
tivation of which suppresses VDCC-induced transmitter
release (Wu and Saggau, 1997; Taylor et al., 1998; Ng et al.,
2001). Thus, an action of GABApentin at GABAB sites
might contribute to its anxiolytic profile. However, this con-
tention has been strongly challenged (Stringer and Lorenzo,
1999; Lanneau et al., 2001; Bowery et al., 2002). Indeed, a
compelling body of evidence has accumulated showing that
pregabalin and GABApentin potently interact with ␣2 /␦1
and ␣2 /␦2 (but not ␣2 /␦3 ) subunits of VDCCs (Gee et al.,
1996; Stefani et al., 1998a; Bryans and Wustrow, 1999;
Gong et al., 2001; Marais et al., 2001), and actions at these
sites appear to mediate their anxiolytic actions in conflict
and other paradigms (Singh et al., 1996; Field et al., 2001).
Specifically, one component of the anxiolytic actions of
GABApentin and pregabalin may reflect interference with
P/Q type Ca2+ -channels controlling transmitter outflow.
Thus, they suppress NA release both directly and indirectly
via a reduction of glutamate release: the latter action leads
to a moderation of the excitatory tone of AMPA receptors
at noradrenergic terminals. Further, a decrease in the release
of glutamate onto corticolimbic NMDA receptors may also
be involved in the anxiolytic properties of GABApentin
(Dooley et al., 2000a,b, 2002; Fink et al., 2002; Van Hooft
et al., 2002).
Inasmuch as pregabalin and GABApentin express marked
anxiolytic properties in man (Beydoun et al., 1995; Pande
et al., 1999a, 2000; Kasper et al., 2002; Rickels et al., 2002;
Smith et al., 2002b), their actions in the rat VCT would be
of interest to evaluate. Indeed, very recently, a preliminary
report of anxiolytic properties of pregabalin in a mice VCT
appeared (Lotarski et al., 2002).
166 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
13.2. Sodium channels
Of the many types of voltage-gated Na+ -channels now
recognized, several tetrodotoxin-sensitive, heteromeric (one
␣-, one ␤1 - and one ␤2 -subunit) classes are concentrated in
the cerebral cortex and hippocampus (Catterall, 2000; Clare
et al., 2000; Denac et al., 2000; Novakovic et al., 2001;
Lindia and Abbadie, 2003). In the latter structure, via en-
gagement of VDCCs, Na+ -influx accelerates the release of
NA (Gerevich et al., 2001). To date, studies of the functional
significance of central Na+ -channels have focussed on pain
and anesthesia—reflecting actions at thalamo-cortical affer-
ents and peripheral nerves (Schwarz and Puil, 1998; Millan,
1999; Waxman et al., 1999; Clare et al., 2000; Laughlin
et al., 2002)—and on neuroprotection and epilepsy (Taylor
and Narasimhan, 1997; Ragsdale and Avoli, 1998; Clare
et al., 2000; Anger et al., 2001). More recently, attention
has been directed towards the influence of lamotrigine—an
anticonvulsant which acts as an antagonist of voltage-gated
Na+ -channels (as well as VDCCs)—upon the limbic re-
lease of glutamate and GABA in relation to its influence
upon mood and affective disorders (Xie et al., 1995b; Cun-
ningham and Jones, 2000; Dursun and Deakin, 2001; Braga
et al., 2002; Spadoni et al., 2002). A further multi-target drug
which interferes with glutamate release—and also shows
modest antagonist properties at NMDA receptors—is rilu-
zole, currently approved for the treatment of amyotrophic
lateral sclerosis. It has been reported to abrogate anxiogenic
properties of inverse agonists at BZP receptors in rodents,
and to suppress activation of the hypothalamo-corticotrophic
axis by stress in human subjects (Stutzmann et al., 1989;
Kniest et al., 2001). It would be instructive to evaluate a
possible influence of lamotrigine, riluzole and related drugs
acting via central voltage-gated Na+ -channels upon anxious
behaviour in the VCT.
13.3. Potassium-channels
The electrical activity of neurones is regulated by a strik-
ing diversity of K+ -channels sub-classified into several fam-
ilies as a function of their regulation by calcium, adenosine
triphosphate, membrane current, GPCRs and other signals
(Aronsen, 1992; Kobayashi et al., 1995; Dascal, 1997; Doyle
et al., 1998; Kaczorowski and Garcia, 1999; Reimann and
Ashcroft, 1999). The role of the majority of these multi-
meric K+ -channels in the induction and control of anxious
states remains essentially unexplored, largely reflecting the
limited availability of agents for their selective manipula-
tion. This paucity of experimental tools applies in particular
to voltage-gated and GPCR-gated K+ -channels for which,
nevertheless, the following observations justify mention.
Various classes of voltage-dependent, heteromeric
K+ -channels are composed of four (␣ and ␤) subunits of
which the latter are responsible for their functional regu-
lation and rapid inactivation (Aronsen, 1992; Kaczorowski
and Garcia, 1999). Recently, a preliminary communication
demonstrated that mice genetically deprived of the ␤-subunit
of Kv1.1 channels display an anxiolytic phenotype raising
the possibility that—an, as yet undefined population of—
these sites may favour anxious states (Brennan et al., 2002).
Of the seven families of inwardly-rectifying K+ -channels
currently accepted, the Kir3 class of G-protein activated
K+ -channels (GIRKs) is activated by ␤␥-subunits released
from pertussis toxin-sensitive Gi/o -proteins coupled to
several classes of GPCR, including GABAB receptors,
opioid and OFQ receptors, 5-HT1A , D2 and D3 receptors,
M2 -receptors, ␤2 - and ␣2 -ARs and A1 receptors: they may
also be directly engaged by ethanol (North, 1989; Dascal,
1997; Lewohl et al., 1999; Reimann and Ashcroft, 1999;
Mark and Herlitze, 2000; Lavine et al., 2002). More re-
cently, attention has also been directed to the inhibition
of GIRKs by GPCRs coupled to (pertussis-insensitive)
Gq-proteins: they appear to act in concert with phospholi-
pase C by facilitating the diffusion away from the channel
of the positive modulator, phosphatidylinositol phosphate
(Lei et al., 2001). Of the four subunits to date cloned, neu-
ronal GIRK tetramers are composed of GIRK1, GIRK2 and,
possibly, GIRK3 subunits—generally two of each, each of
which bear binding sites for ␤␥. The broad distribution
of GIRKs in the FCX, amygdala, bed nucleus of the stria
terminalis, hippocampus, LC and ventrotegmental area, for
example, underpins interest in their role in the modulation
of emotional states (Kobayashi et al., 1995; Karschin et al.,
1996; Reimann and Ashcroft, 1999; Lavine et al., 2002;
Sadja et al., 2002). Indeed, mice deficient in GIRKs reveal
a low level of anxiety (Blednov et al., 2001, 2002).
Though little else is known concerning a potential role
of K+ -channels in the control of anxious states, it has been
speculated that the blockade of GIRK2s by fluoxetine, to-
gether with its inhibition of voltage-gated (Kv1.1 and Kv3.1)
channels, contributes to its influence upon anxious and other
psychiatric disorders (Choi et al., 2001; Kobayashi et al.,
2003).
14. Nitric oxide
The short-lived, highly-reactive free radical, NO, is
generated from the cleavage of l-arginine by various
forms of NO synthase (I, II and III) in both neuronal and
non-neuronal elements throughout the CNS: it modulates
neurotransmission by anterograde and retrograde actions
(Zhang and Snyder, 1995; Millan, 1999; Tao and Poo,
2001; Wiesinger, 2001; Alger, 2002). Constitutively-active,
cytosolic, Ca2+ -dependent neuronal NO synthase (or NO
synthase I), is present in several corticolimbic structures,
including the amygdala and hippocampus (Egberongbe
et al., 1994; Braissant et al., 1999). It shows a broad pat-
tern of interaction with monoaminergic pathways and also
modulates GABAergic transmission (Szabo, 1996; Segieth
et al., 2001; Adell et al., 2002; Millan, 2002a). Thus, NO
appears to interfere with the activity of GABAA receptors,
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
and acute application of neuronal NO synthase inhibitors
potentiates the actions of allosteric modulators at GABAA
sites (Robello et al., 1996). Further, their long-term admin-
istration elicits a widespread increase in the cerebral density
of GABAA recognition and BZP binding sites, together
with a complex pattern of alterations in the gene expression
of various GABAA receptor subunits (Kim and Oh, 2002).
On the other hand, inhibitors of NO synthase enhance the
activity of GABA-transaminase, thereby accelerating the
catabolic transformation of GABA (Jayakumar et al., 1999).
Though many G-protein-coupled receptors can modulate
neuronal synthesis of NO (Christopoulos and El-Fakahany,
1999), most interest has focussed on the activation of NO
by NMDA receptors via an increase in intracellular levels of
Ca2+ , and NO may itself modulate glutamatergic transmis-
sion (Millan, 1999; Wiesinger, 2001). Further by analogy to
glutamatergic transmission and NMDA receptors, acute and
chronic exposure to fear and other stressors enhances the
activity of neuronal NO synthase in the PAG, amygdala and
other cerebral tissues (De Oliveira et al., 2000; Echeverry
et al., 2002; Masood et al., 2003.
One might expect from the above comments that inhibi-
tion of neuronal NO synthase would mimic functional ac-
tions of positive GABAA receptor modulators (Section 2.2)
and of NMDA receptor antagonists (Section 3.2.3.1). This
has proven the case in models of, for example, antinocicep-
tive properties (Harkin et al., 1999; Millan, 1999). Further,
inhibitors of NO synthase have been reported to display
anxiolytic properties, while l-arginine blunts the anxiolytic
properties of BZPs (Faria et al., 1997; Volke et al., 1997,
1998; Dunn et al., 1998). Notably, the anxiolytic actions
of NO synthase inhibitors in the VCT were blocked by
l-arginine demonstrating the specificity of these observa-
tions (Table 18) (Dunn et al., 1995).
However, serious reservations concerning the generality
of anxiolytic properties of neuronal NO synthase inhibitors
are raised by other studies indicative of anxiolytic and anx-
iogenic actions of NO and NO synthase inhibitors, respec-
tively (Vale et al., 1998; Monzon et al., 2001; Li et al., 2003;
Masood et al., 2003)). In addition, the latter agents inter-
fered with anxiolytic actions of BZPs in mice (Quock and
Nguyen, 1992).
Long-term treatment with BZPs induced NO synthase II
in immunocompetent, cerebral populations of microglia and
astroglia. Whether this action is related to their anxiolytic
properties to be ascertained (Suzuki et al., 2002a,b). Like-
wise, inasmuch as chronic (but not acute) exposure to SSRIs
similarly augmented the gene expression of NO synthase II,
it would be interesting to establish the relationship of this ac-
tion to their long-term alleviation of anxious states (Suzuki
et al., 2002a,b)).
While the above-described behavioural actions reflect
roles of either neuronal NO synthase or NO synthase II, ge-
netic deletion of endothelial NO (synthase III) led, via an un-
clear mechanism, to an anxiogenic phenotype (Frisch et al.,
2000), indicative of an anxiolytic role for this source of NO.
167
Evidently, various pools of NO are differentially impli-
cated in the response to and control of anxious states, and
this mediator is unlikely to fulfil a uniform role. A prerequi-
site for an improved understanding of its significance would
be the more precise delineation of the functional roles of all
three isoforms of NO-synthase, and a more thorough func-
tional evaluation of the interaction of NO with glutamater-
gic, GABAergic and monoaminergic pathways in discrete
corticolimbic structures.
15. Neurotrophins
15.1. Actions of neurotrophins at “Trk” receptors:
cerebral localization of BDNF
Neurotrophins act via members of the tropomyosin-related
kinase (Trk) family of tyrosine kinases. Nerve growth fac-
tor (NGF) activates TrkA receptors; brain-derived growth
factor (BNDF), neurotrophin4/5 and, to a lesser degree,
neurotrophin3 , are ligands of TrkB sites, while neurotrophin3
engages TrkC sites (Millan, 1999; Kaplan and Miller, 2000;
Patapoutian and Reichardt, 2001).
The localization of TrkB receptors and BDNF in the DRN,
LC, hypothalamus, amygdala, cortex, PAG, septum and,
most strikingly, the hippocampus suggests a role in the con-
trol of mood via both long-term (“neurotrophic”) and more
rapid (transmitter-like) actions (Altar et al., 1996; Yan et al.,
1997; Black, 1999; Drake et al., 1999; Akbarian et al., 2002;
Reiriz et al., 2002; Tolwany et al., 2002). As concerns the lat-
ter, BDNF can recruit non-selective cation channels via stim-
ulation of phospholipase C. However, its excitatory (depo-
larising) influence upon neuronal activity primarily reflects
the rapid activation of a specific class of voltage-dependent
Na+ -channels (Li et al., 1999; Blum et al., 2002). By anal-
ogy to NO (Section 14) and cannabinoids (Section 8), BDNF
can act both via conventional anterograde and also via ret-
rograde modes of signalling (Millan, 1999; Tao and Poo,
2001; Alger, 2002).
15.2. Role of BDNF in the control of anxious states
The gene expression of BDNF is positively regulated by
protein kinase A, following recruitment of adenylyl cyclase.
It is also engendered by an increase in intracellular concen-
trations of Ca2+ provoked either by activation of phospho-
lipase C and/or the engagement of VDCCs. Thus, the gen-
eration of BDNF may, at least in theory, be enhanced by
numerous mechanisms discussed in this review, of which
glutamatergic mechanisms appear to be of particular impor-
tance (Hartmann et al., 2001; Mackowiak et al., 2002).
Acute and chronic exposure to stress or corticosteroids
elicits dendritic retraction and remodelling, provokes neu-
ronal atrophy and (perhaps causally) suppresses BDNF ex-
pression in the hippocampus, amygdala and other cerebral
areas (Smith et al., 1995b; Altar, 1999; Duman et al., 1999;
168 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
Nibuya et al., 1999; Vaidya et al., 1999; Sousa et al., 2000;
Fuchs and Flügge, 2002; Vyas et al., 2002). These patholog-
ical changes can be countered by long-term administration
of SSRIs and other classes of antidepressant agent which
amplify the gene expression of BDNF in the hippocampus
and amygdala: the accompanying alterations in synaptic ar-
chitecture and intracellular signalling may be involved in
their delayed onset of therapeutic efficacy (Siuciak et al.,
1997; Altar, 1999; Duman et al., 1999; Zetterström et al.,
1999; Mössner et al., 2000; Conti et al., 2002; Nestler et al.,
2002; Tolwany et al., 2002; Saarelainen et al., 2003). Indeed,
though such events have widely been interpreted within the
perspective of depressive states and their treatment, it is pos-
sible that they are also related to their long-term manage-
ment of anxiety disorders.
The following observations further support the argument
that acute and chronic actions of BDNF in limbic structures
may be of relevance to anxious as well as depressive states
(Drake et al., 1999; Duman et al., 1999; Duman et al., 2001;
Shirayama et al., 2002). First, in the hippocampus, BDNF
is partially colocalized with GABAergic neurones. In this
structure, in addition to its developmental role in regulat-
ing the maturation of GABAergic neurones and the forma-
tion of GABAergic synapses, BDNF rapidly down-regulates
postsynaptic GABAA receptors in the adult hippocampus,
thereby attenuating GABAergic transmission (Brünig et al.,
2001; Henneberger et al., 2002). Second, the facilitatory
influence of BDNF upon the activity of DRN-derived sero-
tonergic and—though less-well-characterized—LC-derived
noradrenergic neurons (Siuciak et al., 1995, 1996, 1998;
Celada et al., 1996; Madhav et al., 2001) has been (causally)
related to its positive actions in models of potential an-
tidepressant activity. However, potential alterations in be-
haviour in models of anxious states may also be envisaged
and, by analogy to SSRIs, acute induction of corticolimbic
release of 5-HT and NA by BDNF may well be accompa-
nied by a transient accentuation of anxiety. Third, the ac-
celeration by BDNF of hippocampal glutamate release may
similarly contribute to its influence upon mood—though the
participation of glutamatergic mechanisms to the changes in
synaptic strength evoked by BDNF remains under discus-
sion (Gooney and Lynch, 2001; Messaoudi et al., 2002).
Fourth, heterozygotic BDNF (±) mice show alterations
in aggressive behaviour, in performance in tests of antide-
pressant activity, in hippocampal excitability and in sero-
tonergic transmission (Croll et al., 1999; Lyons et al., 1999;
MacQueen et al., 2001), though potential alterations in anx-
ious behaviour have not, as yet, been reported.
The use of genetically-transformed mice either deficient
in (or overexpressing) BDNF, together with studies of
BDNF itself and small molecules recognizing TrkB recep-
tors (Obara and Nakahata, 2002; Pollack and Harper, 2002),
should permit the future designation of the role of BDNF in
the control of anxious states. It would also be informative to
determine the influence of long-term treatment with BZPs
and other classes of anxiolytic agent upon the functional
status of BDNF-expressing neurones in the hippocampus
and other corticolimbic regions.
15.3. BDNF/TrkB receptors as a therapeutic target
Despite the general significance of BDNF in the con-
trol of mood, and its (potential) role in the anxiolytic and
antidepressant effects of long-term administration of psy-
chotropic agents, there remain several caveats concerning
its validity as a “target” for improved management of anx-
ious (and depressive) states. First, even if highly-selective,
brain-penetrant, bioactive mimics (or blockers) of BDNF
can be identified, they will likely elicit marked actions at
non-cerebral TrkB sites localized in the spinal cord and the
peripheral nervous system wherein BDNF fulfils important
roles both developmentally and in the modulation of sensory
and neuroendocrine function in adults (Lewin and Barde,
1996; Millan, 1999; Pollack and Harper, 2002). Second, it is
still controversial whether BDNF is merely a marker of drug
actions, or whether it genuinely initiates processes underly-
ing the delayed onset of therapeutic activity in the treatment
of affective disorders (Duman et al., 2001; Popoli et al.,
2002; Nestler et al., 2002). Third, assuming that neuroge-
nesis and other structural changes involving BDNF/TrkB
receptors do participate in the long-term actions of SSRIs
and other agents, and that they are causative of clinical
improvement (Duman et al., 1999; Nestler et al., 2002), it
would be desirable to devise clinical protocols permitting
the demonstration that such events occur in the course of
therapeutic trials. Fourth, it is difficult to predict with any
certainty the long-term consequences of sustained and direct
manipulation (facilitation or disruption) of neurotrophin sig-
nalling: for example, whether the presumptive modifications
of synaptic architecture and transmission—desirable and/or
undesirable—would be reversible.
For these and other reasons, it may be more prudent to
therapeutically intervene upstream of BDNF/TrkB recep-
tors employing drugs which permit the precise targeting
of discrete, therapeutically-pertinent, corticolimbic pools of
BDNF and TrkB receptors implicated in the etiology and,
potentially, management of mood disorders. Clearly, such
agents are already available, as represented by SSRIs and
other classes of antidepressant agents (Duman et al., 2001;
Popoli et al., 2002; Nestler et al., 2002), though it is likely
that innovative and more efficacious approaches for modu-
lation of the activity of BDNF will be developed.
Within this perspective, then, considerable further re-
search is needed to decipher the role of BDNF in the patho-
genesis and treatment of anxiety and other mood disorders
prior to its potential exploitation as a therapeutic target.
15.4. Other neurotrophins
In this regard, the possible significance of NGF/TrkA re-
ceptors and NT3/TrkC receptors would also justify evalua-
tion since, though data are far less extensive, they are also
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
implicated in the cerebral and endocrine response to psy-
chosocial stress, and in the modulation of monoaminergic
transmission both in animals and in man (Alleva and Aloe,
1989; Smith et al., 1995a,b; McLay et al., 1997; Schaaf et al.,
1997; Winkler et al., 2000; Akbarian et al., 2001; Alleva and
Santucci, 2001; Aloe et al., 2002; Haddad, 2002).
16. Cytokines
A diverse group of proteins termed cytokines, of which
tissue necrosis factor␣ and Interleukin1␤ are representative
members, play key roles in communication between immune
cells (McLay et al., 1997; Müller and Ackenheil, 1998; Had-
dad, 2002). More recently, cytokines—derived both from
peripheral and from intrinsic, cerebral sources—have been
implicated in the modulation of neuronal activity in regions
such as the amygdala, the hippocampus, the hypothalamus
and the cortex (Besedovsky and Del Rey, 1996; Elenkov
et al., 2000). In addition to their interaction with GABAer-
gic neurones, cytokines potentiate the activity of monoamin-
ergic and CRF-containing pathways in these corticolimbic
structures (Hopkins and Rothwell, 1995; Merali et al., 1997;
Kamikawa et al., 1998; Cho et al., 1999; Day et al., 1999b;
Millan, 1999; Bonaccorso et al., 2000; Nickola et al., 2000;
Kronfol and Remick, 2000; Schaefer et al., 2002). These ob-
servations, together with the pronounced response of central
and peripheral pools of cytokines to stress and their facil-
itatory influence upon the hypothalamo-corticotrophic axis
(Kung, 1999; Kronfol and Remick, 2000; Schaefer et al.,
2002; Leonard and Song, 2002), have prompted interest in
the role of cytokines in the pathogenesis of affective and
anxious states (Bluthé et al., 1992; Connor and Leonard,
1998; Müller and Ackenheil, 1998; Bonaccorso et al., 2000;
Kronfol and Remick, 2000; Schaefer et al., 2002). Indeed,
alterations in circulating levels of interleukin1␤ have been
demonstrated in patients with anxiety disorders (Brambilla
et al., 1994; Zorrilla et al., 1994; Leonard and Song, 2002)
and both experimental and clinical investigations have high-
lighted the marked influence of antidepressant agents upon
the production of cytokines (Kenis and Maes, 2002).
As concerns anxious states, overexpression of cytokines
in autoimmune mice is associated with behaviours indicative
of enhanced anxiety, and mice overexpressing interleukin6
or tissue necrosis factor␣ likewise reveal an anxiogenic
phenotype: underpinning these findings, anxiogenic actions
of cytokine administration have been reported in rodents
(Bluet-Pajot et al., 1992; Bluthé et al., 1992; Sakic et al.,
1994; Schrott and Crnic, 1996; Connor and Leonard, 1998;
Flore et al., 1998; Bonaccorso et al., 2000). On the other
hand, certain cytokines may be inhibitory to processes in-
ducing anxious states, inasmuch as deletion of the gene
encoding Interferon␥ led to heightened anxiety (Flore et al.,
1998; Kustova et al., 1998).
In light of the above comments, the heterogeneous role
of specific cytokines in the control of anxious states jus-
169
tifies evaluation employing the VCT and other experimen-
tal strategies. However, cytokine signalling in the CNS and
other organs is crucial to the control of immune function
both under “resting” conditions and in the response to stress
and illness. Thus, notwithstanding accumulating evidence
for a modulatory influence of cytokines upon neuronal com-
munication and emotion, great care would need to be taken
in their hypothetical exploitation as therapeutic targets for
the treatment of anxiety—or other mood—disorders.
17. Sigma1 and sigma2 sites
17.1. Sigma1 sites
“Sigma receptors” were originally welcomed into the fold
of opioid receptors but were subsequently banished on the
basis of their insensitivity to the “universal” opioid receptor
antagonist, naloxone (Section 9.1.9) (Quirion et al., 1992;
Herz et al., 1993). Subsequently, they were confounded with
the “phencyclidine receptor” which transpired to be a bind-
ing site located in the ion channel coupled to NMDA recep-
tors (Section 3.2.1) (Dingledine et al., 1999; Quirion et al.,
1992). Indeed, the odyssey of “sigma receptor” classification
only concluded with the discovery of genuinely-discriminant
ligands (Quirion et al., 1992) and, ultimately, the cloning
of sigma1 sites. This 223 amino acid protein, which pos-
sesses a single transmembrane domain, bears conspicuously
little resemblance to other mammalian proteins yet discon-
certing similarities to a yeast enzyme (C8–C7 isomerase) of
ergosterol synthesis, the fungal counterpart of cholesterol—
though sigma1 sites do not exhibit equivalent enzymatic ac-
tivity (Hanner et al., 1996; Moebius et al., 1997; Prasad et al.,
1998; Seth et al., 1998). Further, sigma1 sites bear a bind-
ing domain for steroids (Section 2.2.3) which shows high
affinity for progesterone (an antagonist) and pregnanelone
(an agonist), though other neurosteroids such as allopreg-
nanalone are less potent ligands (Maurice et al., 2001).
The functional status of sigma1 sites and the notion of
“agonists” and “antagonists” is still ambivalent inasmuch
they have no apparent endogenous ligand—with the possi-
ble exception of steroids (Alonso et al., 2000; Maurice et al.,
2001). Further, they possess an endoplasmic reticulum re-
tention signal and are enriched on mitochondria and other
intracellular membranes (Hanner et al., 1996; Dussossoy
et al., 1999; Maurice et al., 1999). Mechanisms of intracel-
lular transduction also remain poorly-defined. The balance
of evidence suggests, in line with their structure, that they do
not directly couple to G-proteins though they may, upon ac-
tivation and recruitment to plasma membranes, interact with
phospholipase C and VDCCs (Morin-Surun et al., 1999;
Tokuyama et al., 1999; Hayashi et al., 2000a,b; Hong and
Werling, 2000; Romero et al., 2000). Further, they modulate
intracellular concentrations of calcium by a novel mecha-
nism. Thus, activation of sigma1 sites complexed to the cy-
toskeletal adaptor protein, ankyrin, on the endoplasmic retic-
170 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
ulum leads to their dissociation from inositol triphosphate
receptors: this results in an enhancement in the binding of in-
ositol phosphates to the latter and an efflux of calcium from
the endoplasmic reticulum (Hayashi et al., 2000a; Hayashi
and Su, 2001; Maurice et al., 2001). Very recently, evidence
that the modulation of calcium signalling (intra and extra-
cellular) by sigma1 ligands contributes to their behavioural
(antidepressant) actions was acquired (Urani et al., 2002).
Sigma1 sites may also inhibit potassium currents (Wilke
et al., 1999) which would further enhance cellular excitabil-
ity. In rodents, primates and man, sigma1 sites are present
in high concentrations in neurones in the hippocampus, ol-
factory bulb and hypothalamus and a moderate density has
been described in the cortex, lateral septum, amygdala and
PAG (Largent et al., 1986; Mash and Zabetian, 1992; Alonso
et al., 2000; Kitaichi et al., 2000; Maurice et al., 2001).
Central sigma1 receptors modulate corticosterone secre-
tion, though the precise nature of their influence remains
unclear (Matheson et al., 1991). They also display func-
tional interactions with NMDA receptors (Whitemore and
Woodward, 1997; Kitaichi et al., 2000). Notably, sigma1
agonists potentiate the facilitatory influence of NMDA re-
ceptors upon hippocampal NA release (Monnet et al., 1996
though see Gonzalez-Alvear and Werling, 1995) and may,
administered alone, enhance extracellular levels of NA in
the cortex (Cooke et al., 1998) though this remains to be
confirmed. Further, sigma1 site agonists reproducibly accel-
erate the activity of ventrotegmental dopaminergic perikarya
innervating the limbic system and cortex (Ceci et al., 1988;
Zhang et al., 1993; Matsumo et al., 1995; Volonté et al.,
1995). The influence of sigma1 ligands upon serotonergic
transmission is less pronounced, though certain agonists
elicit a long-term enhancement in the activity of serotonergic
neurones (Bermack and Debonnel, 2001; Takahashi et al.,
2001b).
The above data have been interpreted as consistent with
potential antidepressant actions of sigma1 ligands. Corre-
spondingly, the ability of the “agonist”, (+)SKF10,047, to
suppress conditioned freezing in rats—an action blocked
by the selective antagonist, NE 100—was attributed to
antidepressant rather than anxiolytic properties (Kamei
et al., 1996) and may be related to the facilitatory influence
of sigma1 sites upon mesolimbic dopaminergic pathways
(Kamei et al., 1994, 1997). This action was accompanied
by alterations in the binding density of central sigma1 sites
indicating their responsiveness to stress (Nabeshima et al.,
1988). Anxiogenic effects were, in fact, reported for sigma1
agonists in a preliminary communication concerning the rat
VCT (Lai et al., 1989) but Akunne et al., 1997 reported
that the selective sigma1 agonist, PD144418, was inactive
in this model. In a mice edition of this procedure, Umezu,
1999 likewise failed to detect significant anxiolytic proper-
ties of a mixed sigma1/2 agonist, racemic cyclazocine (vide
infra). Finally, McMillan et al., 1991 reported that sigma1
agonists were ineffective in a Geller–Seifter conflict proce-
dure in rats, underscoring findings from the VCT and other
behavioural models (Umezu, 1999). To date, there appear
to be little or no data regarding the potential influence of
genuinely-selective sigma1 antagonists upon anxious states,
an issue which would be of interest to examine by use of
the VCT and other procedures.
The tricyclic compound, opipramol, which shows high
affinity for sigma1 sites, demonstrated anxiolytic efficacy in
a controlled trial of GAD in man (Rao et al., 1990; Ferris
et al., 1990; Möller et al., 2001). However, while opipramol
has no affinity for monoamine transporters, its antagonist
actions at 5-HT2 or histamine1 receptors are likely of greater
significance to its anxiolytic properties than its actions at
sigma1 sites in view of the above-evoked pattern of negative
data from experimental models.
17.2. Sigma2 sites
Certain ligands which bind to sigma1 sites, such as DTG,
(+)PPP and haloperidol, also recognize sigma2 sites which
can be distinguished by their relatively low affinity for the
(+)- as compared to (−)-isomers of SKF10,047, penta-
zocine and cyclazocine, whereas sigma1 sites show the op-
posite pattern of preference: (+) > (−) (Quirion et al., 1992;
Hellewell et al., 1994). Unfortunately, sigma2 sites have not
as yet been sequenced and their identity remains nebulous.
Further, despite the (to date, unconfirmed) suggestion that
they also modulate release of intracellular calcium stores
(Vilner and Bowen, 2000), their mode of coupling remains
obscure. More encouragingly, in line with earlier studies
of non-selective radioligands, the novel, radiolabelled and
selective sigma2 ligand, siramesine (Lu28-719), bound to
sites in the cortex, hippocampus, locus coeruleus and amyg-
dala of rat brain, though quantitative differences amongst
discrete cerebral structures were modest (Bouchard and
Quirion, 1997; Heading, 2001; Soby et al., 2002). Sirame-
sine showed exceptionally potent anxiolytic activity (rem-
iniscent of miniscule doses of 5-HT3 antagonists (Section
4.3.5)) in a rat light–dark box (0.00018 ng/kg) and was
also potently active in a model of active social interaction
(0.1 ng/kg) though only substantially (million-fold) higher
doses were active in the VCT (10 and 22 mg/kg) (Sanchez
et al., 1997). Inasmuch as siramesine was well tolerated in
a Phase I trial (Heading, 2001), clinical data pertaining to
the anxiolytic potential of sigma2 ligands may be imminent.
17.3. Perspectives for sigma ligands as anxiolytic
agents
In view of the unclear nature of transduction mechanisms
for sigma2 sites, their resistance to cloning and the limited
quantity of experimental data, their physiological and ther-
apeutic significance to the control of anxious states remains
moot. For sigma1 sites, despite their distribution in cor-
ticolimbic structures, interaction with monoaminergic and
glutamatergic pathways and better-defined mechanisms of
coupling, the lack of selectivity of certain ligands—and,
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 171

probably as a consequence, surprising differences between
the actions of individual ligands in functional models—
complicates assessment of their pathophysiological perti-
nence. Though acute studies of agonists indicate no influ-
ence upon anxious states, by analogy to other classes of an-
tidepressant agent, examination of their actions (and those
of antagonists) upon chronic administration would certainly
be justified.
18. General discussion: open questions, conceptual
issues and future research directions
18.1. Multiple substrates of action
In concluding this survey of neuronal mechanisms in-
volved in the modulation of anxious states, certain themes
likely to inform future research merit brief recapitulation.
To reiterate comments made throughout this article,
the actions of numerous modulators implicated in the re-
sponse to stress and in the control of anxious states have
not, as yet, been evaluated by use of the VCT—or other
punishment-based conflict procedures. Even for the major-
ity of those modulators which have been shown to exert
anxiolytic and/or anxiogenic properties in these (and other)
models, comparatively little information is available con-
cerning the precise neuronal substrates underlying their
actions (Figs. 10 and 11). In the resolution of such ques-
tions, it will be of importance to adopt a variety of com-
plementary techniques including: local drug and antisense
administration; selective inactivation (lesions) of discrete
neuronal pathways, and monitoring of neurochemical and
electrophysiological events in specific brain regions. More-
over, “genetic” techniques permitting the manipulation of
function in circumscribed cerebral structures—for example,
deletion of post as compared to presynaptic populations of
receptors—offer novel and powerful strategies to address
this issue.
In the above light, as exemplified by studies of seroton-
ergic, cholinergic, NPY and CRF-containing neurones, it
should be recalled that certain transmitters—and even indi-
vidual classes of receptor—can mediate contrasting actions
as a function of, for example, their localization in different
cerebral structures (Figs. 10 and 11); their occurrence at pre-
as compared to postsynaptic sites; the duration of their ac-
tivation, and the type of anxiety under investigation. On the
other hand, certain mediators may exert a unitary influence
upon anxious states in acting synergistically at multiple loci.
The most obvious illustration is provided by GABAA recep-
tors, of which numerous supraspinal populations transduce
the powerful anxiolytic properties of BZP (Fig. 10). Indeed,
this broad-based spectrum of actions may account for the
distinctively robust and rapid anxiolytic profile of BZPs—
in analogy to the unexcelled pain-relieving properties of
␮-opioid analgesics which simultaneously act at multiple
levels of the neuroaxis (Millan, 2002a). Irrespective of neu-
ronal mechanisms underlying the control of anxious states,
however, it must be emphasized that the overall influence of

Fig. 10. Schematic representation of the sites of actions of various neurotransmitters and their receptors in the modulation of anxious states. The effects
indicated are a (non-exhaustive) synthesis of observations across all procedures. For the actions of certain transmitters and receptors, contradictory
data have been documented—even for the same procedure—and the action indicated represents an overall assessment for each structure. Anxiolytic
actions are indicated by a “+” sign and anxiogenic actions are indicated by a “−” sign: “±” indicates that a broad and balanced mixture of anxiolytic
and anxiogenic actions has been reported. A “0” indicates no effect though, to avoid over-encumbering the figure, only certain negative observations
are indicated. Abbreviations—GABA: ␥-amino-butyric acid; NMDA: N-methyl-d-aspartate; GLYB : glycineB ; MTB: metabotropic glutamatergic; 5-HT:
serotonin; ACh/n: acetylcholine/nicotinic and ACh/m: acetylcholine/muscarinic. For further details, see text.
172 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

Fig. 11. Schematic representation of the sites of actions of various neuropeptides and their receptors in the modulation of anxious states. The effects
indicated are a (non-exhaustive) synthesis of observations across all procedures. For the actions of certain neuropeptides and their receptors, contradictory
data have been documented—even for the same procedure—and the action indicated represents an overall assessment for each structure. Anxiolytic
actions are indicated by a “+” sign and anxiogenic actions are indicated by a “−” sign: “±” indicates that a broad and balanced mixture of anxiolytic
and anxiogenic actions has been reported. A “0” indicates no effect though, to avoid over-encumbering the figure, only certain negative observations are
indicated. Note that, in comparison to the hippocampus, the amygdala is a “hot-bed” of neuropeptide activity whereas, for “conventional” neurotransmitters
depicted in Fig. 10, both structures have been implicated to a comparable degree. Abbreviations are as follows; CCK: cholecystokinin; SP/NK1 : substance
P/neurokinin1 ; CRF: corticotropin releasing factor; VP: vasopressin; OT: ocytocin; NPY: neuropeptide Y; PAC1 : receptor for Pituitatry Adenyl Cyclase
Activating Peptide; GAL: galanin; OFQ: orphaninFQ; GLP1 : glucagon-like peptide-1 and ANP: atrial natruetic peptide. For further details, see text.

drugs upon their systemic (generally oral) administration is
of decisive importance in assessing their potential for thera-
peutic utilization. Hence, the continued importance—in ad-
dition to mechanistic analyses—of examining the actions of
all drug classes upon parenteral application.
In elucidating the functional significance of specific me-
diators, information concerning their localization is critical.
Not only their regional distribution in cerebral structures,
but also their precise patterns of neuronal connectivity
in relation to other modulators involved in the control of
anxious states. As accentuated in the present review, knowl-
edge of the relationships between specific neurotransmitters
and: (1) GABAergic interneurones; (2) serotonergic, no-
radrenergic and—as increasingly accepted—dopaminergic
projections and (3) key input and output channels of corti-
colimbic structures modulating anxious states, can provide
crucial insights into their potential influence upon the re-
sponse to stress and fear. Pursuing this line of reasoning,
delineation of the short- and long-term influence of specific
receptor types upon neuronal activity via their coupling to
diverse intracellular signals (soluble second messengers and
ion channels) can clarify their potential functional roles.
For example, agents which reinforce GABAergic trans-
mission in the amygdala may reasonably be anticipated to
diminish anxiety, whereas the excitation of CRF-containing
neurones would likely exert an opposite anxiogenic effect.
On the other hand, despite the significance of corticolim-
bic monoaminergic mechanisms in the control of anxious
states, as emphasized in Section 2.2.2.3, the assumption
that the suppression/enhancement of 5-HT, NA or DA re-
lease is synonymous with anxiolytic/anxiogenic properties,
respectively, is clearly fallacious. Accordingly, anxiolytic
and anxiogenic properties can be exerted independently of
changes in the release of these monoamines, and various
classes of anxiolytic agent exert contrasting patterns of in-
fluence upon extracellular levels of 5-HT, NA and DA—as
exemplified in Table 20, the data of which were generated
in parallel under identical conditions.
18.2. Cellular mechanisms of action
In the preceding paragraphs, the importance of defining
the actions of specific modulators at the neuronal level was
evoked. In this regard, though it is imperative to study cel-
lular coupling in “simple” transfection systems, it will be
increasingly necessary to integrate the following concepts in
interpreting—and predicting—the influence of drugs upon
anxious states.
First, neurotransmitters and other modulators manifest
extensive co-storage and co-release, and operate in a coor-
dinated rather than an independent fashion (Hökfelt et al.,
2000; Merighi, 2002; Millan, 2002a). Observations made
in heterologously-expressed, pure populations of cloned
receptors should not automatically be extrapolated to cere-
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244 173

Table 20
Influence of acute administration of diverse classes of anxiolytic agent upon extracellular levels of monoamines in the frontal cortex of freely-moving
rats as compared to their actions in the Vogel Conflict Test
Class Drug Dose Route Change (%) (vs. control) = 0% Change (%) (vs. basal) = 0%
(mg/kg)
VCT 5-HT NA DA

BZP Ago Diazepam 10.0 i.p. +186∗ −29 ± 4∗ −21 ± 4∗ −34 ± 3∗

Triazolo-BZP Ago Triazolam 2.5 i.p. +348∗ −48 ± 8∗ +5 ± 8 −16 ± 3
5-HT1A Ago Flesinoxan 10.0 s.c. +266∗ −50 ± 6∗ +104 ± 19∗ +60 ± 8∗
5-HT2A Ant MDL100,907 0.16 s.c. +239∗ −1 ± 8 +18 ± 8 0 ± 5
5-HT2C Ant SB242,084 10.0 i.p. +102∗ +6 ± 8 +90 ± 30∗ +73 ± 10∗
SSRI Citalopram 10.0 s.c. −3 +280 ± 32∗ +75 ± 7∗ +30 ± 15
SNRI Venlafaxine 10.0 s.c. +19 +251 ± 19∗ +360 ± 33∗ +190 ± 29∗
NARI Reboxetine 10.0 i.p. +43 0 ± 7 +330 ± 31∗ +220 ± 36∗
5-HT2C /␣2 AR Ant Mirtazapine 10.0 s.c. +156∗ +10 ± 5 +330 ± 47∗ +160 ± 27∗
␣2 -AR Ago Dexmedetomidine 0.005 s.c. +168∗ −45 ± 6∗ −79 ± 10∗ −35 ± 7∗
CRF1 Ant CP154,526 40.0 i.p. +135∗ 0 ± 8 +10 ± 5 +2 ± 5
NK1 Ant GR205,171 40.0 i.p. +131∗ 0 ± 0 +77 ± 9∗ +63 ± 12∗
Abbreviations—BZP: benzodiazepine; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin and noradrenaline reuptake inhibitor; NARI: nora-
drenaline reuptake inhibitor; AR: adrenergic receptor; CRF: corticotropin releasing factor and NK: neurokinin. All data were generated in the author’s
laboratory under identical conditions (Gobert and Millan, 1999a; Gobert et al., 2000; Dekeyne et al., 2000a,b; Millan et al., 2000b,c,d,e, 2001a,b,c,d;
Lejeune and Milan, 2002; Gobert and Millan, unpublished observations). The doses of drugs examined correspond to those at which they exert significant
anxiolytic actions in the VCT, with the exception of the reuptake inhibitors which are inactive in this paradigm. For these antidepressant agents, doses
are equivalent to those at which they exert anxiogenic actions in the social interaction procedure and antidepressant actions in other procedures (Dekeyne
et al., 2000a; Millan et al., 2001c,d). Note the diverse pattern of influence of drugs upon the levels of various monoamines. Star indicates significant
differences vs. control or basal values: ∗ P < 0.05.

bral neurones inasmuch as receptors may be coupled in a
region- and neuron-specific manner to intracellular trans-
duction mechanisms ((Jin et al., 2001; Porter et al., 2002;
Blank et al., 2003a,b)). Moreover, at specific neurones (and
even synapses), multiple transmitters/receptors converge
upon common and interacting transduction mechanisms—a
phenomenon sometimes referred to as “cross-talk”. Colo-
calized receptors may not only interact at the level of
intracellular messengers, but even physically associate to
form heterodimers with functional properties differing from
those of the respective homomers. For example, functional
heterodimers of ␣2C -AR/M2 , 5-HT1A /5-HT1B , D2 /D3 ,
␮-opioid/ORL1 , mGluR/A1 and adenosine A1 /mGluR1 re-
ceptors have all been shown to assemble, at least in cultured
all lines. Though their suspected existence in neurones
remains to be unequivocally proven, one example of a func-
tional CNS-localized heterodimer is provided by GABAB
receptors, which are composed of structurally-distinct
GABAB1 and GABAB2 proteins (Section 2.3.1) (Maggio
et al., 1993; Bouvier, 2001; Devi, 2001; Marshall, 2001;
Scarselli et al., 2001; George et al., 2002; Pan et al., 2002).
Second, via “agonist-directed trafficking”, individual
drugs may differentially favour the activation of one of sev-
eral alternative intracellular cascades coupled to the same
receptor. For example, certain ligands differentially recruit
the G-protein subtype Gi as compared to Gq via actions
at 5-HT1A or 5-HT2C receptors (Watson et al., 2000; Berg
et al., 2001; Cussac et al., 2002b,c; Stout et al., 2002;
Newman-Tancredi et al., 2002a; Blank et al., 2003a). Traf-
ficking has also been reported at, for example, ␣2A -ARs,
CB1 receptors and A1 receptors, which likewise play a role
in the modulation of anxious states (Bonhaus et al., 1998;
Cordeaux et al., 2000; Kukkonen et al., 2001). Assuming
contrasting functional correlates of alternative cellular path-
ways of signal transduction, selective engagement of one
may permit improved dissociation of beneficial properties
from untoward side-effects (Kenakin, 1995, 2002; Cussac
et al., 2002b). This notion of “divergent” coupling mecha-
nisms cascading from a single receptor is, in a sense, a mir-
ror image of the “convergence” of multiple receptors onto
a common tranduction signal, as outlined in the preceding
paragraph.
Third, receptors may be “constitutively-active”: that
is, they may show spontaneous, ligand-independent cou-
pling to G-proteins. Though the physiological pertinence
of this phenomenon at neuronal populations of receptor
(which are generally occupied by endogenous agonists) is
still disputed, so-called “inverse agonists” exert actions at
constitutively-active receptors opposite to those of agonists,
and the effects of both are blocked by “neutral” antago-
nists (Millan et al., 1999b; Morisset et al., 2000; Chavigne
et al., 2001). Heterologously-expressed 5-HT1A , 5-HT1B ,
5-HT2A and 5-HT2C receptors, ␣2A -ARs, histamine H3 re-
ceptors, CB1 receptor and M2 receptors provide examples
of constitutively-active receptors potentially relevant to anx-
ious states (Barker et al., 1994; Morisset et al., 2000; Murrin
et al., 2000; De Ligt et al., 2000; Menzaghi et al., 2002;
Newman-Tancredi et al., 2002a; Seifert and Wenzel-Seifert,
2002). Assuming the existence of constitutive activity at
receptor types contributing to the generation of anxious
states, inverse agonists could, in theory, prove to be more
efficacious anxiolytic agents than neutral antagonists.
174 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244

As for other fields of neurobiological research, these and Table 21

related concepts, despite their still uncertain pathophysio- Influence of acute administration of diverse classes of anxiolytic agent in
the Vogel Conflict Test as compared to other procedures
logical and therapeutic significance, will certainly enrich re-
search into the causes and cures of anxiety disorders. Class Drug VCT SINT PM USV

BZP Ago Diazepam + + + +

18.3. Long-term actions of anxiolytic agents Triazolo-BZP Ago Triazolam + + + +
5-HT1A Ago Flesinoxan + + IA +
Relatively little information is available concerning the 5-HT2A Ant MDL100,907 + IA IA IA
5-HT2C Ant SB242,084 + + IA IA
long-term actions of drugs in the VCT and other pro- SSRI Citalopram IA − − IA
cedures. Obviously, the potential development of toler- SNRI Venlafaxine IA − − IA
ance/desensitization to the anxiolytic actions of an agonist NARI Reboxetine IA − − IA
upon its recurrent administration is an issue of fundamental 5-HT2C /␣2 -AR Ant Mirtazapine + + IA +
importance. Moreover, upon suspension of chronic drug ␣2 -AR Ago Dexmedetomidine + IA IA +
CRF1 Ant CP154,526 + + IA IA
administration, the possible induction of a withdrawal syn- NK1 Ant GR205,171 + IA IA IA
drome (including rebound anxiety) necessitates evaluation.
A related issue requiring experimental investigation is the Abbreviations—SINT: social interaction test; PM: elevated plus-maze test;
USV: ultrasonic vocalization test; BZP: benzodiazepine; SSRI: selective
potential consequences of long-term pre-treatment with one serotonin reuptake inhibitor; SNRI: serotonin and noradrenaline reuptake
drug upon the subsequent effects of a second agent. This inhibitor; NARI: noradrenaline reuptake inhibitor; AR: adrenergic recep-
mirrors the clinical scenario whereby the discontinuation tor; CRF: corticotropin releasing factor; NK: neurokinin; MCH: melanin
of one drug (generally due to poor efficacy or unaccept- concentrating hormone; +, anxiolytic; −, anxiogenic; IA: inactive. All
able tolerance) is followed by the introduction of a second data were generated in the author’s laboratory under identical conditions
(Dekeyne et al., 2000a,b; Millan et al., 1997, 1998, 2000e, 2001a,b;
drug (often) of a different mechanistic class. For example, Brocco and Millan, unpublished observations). The tests are briefly out-
therapeutic trials revealed that buspirone aggravates the lined in Table 1. Note the diverse pattern of anxiolytic profiles.
withdrawal syndrome to BZPs, and that it is virtually in-
effective in patients recently treated with these agents (De
Martinis et al., 2000). For the appropriate design of clinical eral models of untrained behaviours are also well-adapted
trials, and for the switching of drugs in clinical practice, for the detection of anxiogenic properties: notably the
such information is essential. plus-maze and the social interaction procedures (Table 1
and Section 1.3). The ability of such experimental protocols
18.4. Detection of anxiogenic and anxiolytic properties to detect heightened anxiety is also a precondition for their
exploratory use in the characterization of models of “trait”
In studies where the actions of drugs are not, a priori, anxiety, such as novel populations of genetically-engineered
known, it is important that the parameters of the VCT and mice. Indeed, such an approach allows for the demonstra-
other paradigms be adjusted to render them responsive to tion that potential therapeutic agents can “normalize” aber-
both anxiolytic and anxiogenic agents (e.g. Sepinwall and rant reactivity to stressful/fear-inducing stimuli or exces-
Cook, 1980; Liljequist and Engel, 1984a,b; Meneses and sive “spontaneous” anxiety, rather than merely decreasing
Hong, 1993; Olivier et al., 2000). Otherwise, valuable in- anxiety below a “normal” baseline.
formation may be lost. For example, if under appropriate
conditions, anxiogenic actions of SSRIs were expressed in 18.5. Comparing actions in the VCT to other models
the VCT, it would provide an instructive model for study
of their delayed onset of anxiolytic efficacy (Section 4.4). As mentioned towards the beginning of this article
However, the VCT has not, regrettably, been extensively (Section 1.4) and summarized in Table 1, the VCT is a
employed for the detection of anxiogenic properties whereas paradigm of transient, “state” anxiety which incorporates
a related paradigm of “safety signal withdrawal” has proven a punishment component and which usually requires the
especially instructive in this regard. This model measures performance of a conditioned behaviour. Despite its broad
the influence of drugs upon food-rewarded responses upon utility and compelling predictive, face and construct valid-
the unexpected suppression of a “safety signal” (cue light) ity, like all other models currently available, it cannot be
indicating that the subsequent session will not be punished. considered alone as sufficient for the full characterization of
Thus, identical conditions can be used to characterize both any of the mechanisms discussed herein. Further, by analogy
anxiolytic and anxiogenic drugs and this intriguing proce- to other conflict models of response suppression, despite
dure has revealed robust anxiogenic actions of, for example, its empirical utility for drug characterization, it should not
adenosine antagonists, GABAA antagonists and inverse ag- be regarded as a “model” of clinical anxiety per se. Use of
onists at BZP receptors (Sections 2.2.2.1 and 7) (Thiébot the VCT must, then, be embedded in an experimental strat-
et al., 1991; Charrier et al., 1994). Upon appropriate adjust- egy incorporating complementary models reflecting other
ment of experimental conditions (essentially to moderate aspects of anxious states. Within this perspective, Table 21
the intensity of anxiety experienced during the test), sev- illustrates the strikingly diverse profiles of functional ac-
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
tivity displayed by various classes of agent in the VCT as
compared to other models of potential anxiolytic activity
performed in parallel under identical conditions.
18.6. Complementary pharmacological and genetic
strategies
Genetic (knock-out and transgenic) strategies have been
enthusiastically embraced by many groups, and they proven
extremely powerful tools in the identification and charac-
terization of mechanisms for the control of anxious states.
However, the extraordinary proliferation (see Section 1.1)
of “anxiogenic” (and, less frequently, “anxiolytic”) pheno-
types upon disruption of diverse genes raises the interrelated
questions of (1) whether the changes seen are genuinely in-
dicative of a key role in the control of anxious states, rather
than a modulatory role of perhaps subsidiary importance—
at least from a clinical point of view (Section 18.10); (2)
whether changes in anxious behaviour observed upon modi-
fication of gene function are truly indicative of physiological
and pathological significance when operational—we mea-
sure behaviour in their absence not presence; (3) whether
alterations in behaviour in experimental models of stress,
fear and anxiety, etc. are primary events specifically reflect-
ing emotionality rather than an epiphenomenon of other ac-
tions relevant to performance under these conditions, such
as cognitive-attentional function, motor behaviour, or im-
pulsivity (Section 18.9).
These questions should not, of course, be construed as
uniquely applicable to such genetic strategies—they are
no less pertinent to studies of, for example, discrete brain
lesions or chronic administration of antagonists. Neverthe-
less, after a decade or so of exploitation, we are currently
witnessing a “demystification” of genetic strategies with
the realization that these approaches, like all others, have
their advantages and disadvantages and present certain
inherent interpretational difficulties—genetic background,
strain differences and developmental compensation, etc.
(Section 1.1). Indeed, while there is clearly no such thing as
a definitive pharmacological study, even the most parochial
champion of genetic strategies would now accept that no
single study of knock-out or transgenic mice, irrespective
of its strengths, is sufficient to unequivocally define the role
of any mechanism for the control of anxious states.
Nevertheless, more sophisticated approaches encompass-
ing (for example) conditioned (“inducible”), region-specific
gene deletion and point mutations, together with more thor-
ough controls of the specificity and generality of changes ob-
served, continue to strengthen the use of genetic approaches
to the evaluation of mechanisms underlying the etiology
and management of anxious states. Further, the characteriza-
tion in genetically-modified mice of pharmacological agents
“selective” for the gene under study offers an elegant and
mutual control for these complementary pharmacological
and genetic strategies. For example, in mice lacking NK1
receptors, highly selective NK1 antagonists would not be ex-
175
pected to exert anxiolytic properties. An instructive anomaly
is provided by work with CB1 receptor-deficient mice in
which the actions of selective antagonists persisted, sug-
gesting the existence of additional, central “CB1 ” receptors
controlling anxious states (Section 8).
These comments serve to illustrate the synergistic and
indispensable nature of genetic and pharmacological ap-
proaches to the characterization of anxious states and their
management.
18.7. Neuronal networks and anxious states
As argued in Section 1.5.3, it would be naı̈ve to conceive
of the amygdala or of any other corticolimbic region as act-
ing in isolation in the induction, modulation and experience
of anxious states in view of the intermeshing of function
across diverse structures and modulators. Nonetheless, as in
other spheres of biological research, the field of anxiety is
dominated by a reductionist drive to disaggregate systems
into their individual components. This is explained by the
relative intractability of “systems” as units of study—despite
the utility of computer models of network organization, func-
tional imaging of brain function in man, genetic elimination
of specific transmitters and other useful approaches. Thus, an
inevitable and initial step in understanding the operation of
systems committed to the control of anxious states remains
the “top down” approach which focuses successively on cir-
cumscribed cerebral structures, their sub-territories, specific
classes of neurone, discrete transmitters, individual classes
of receptor, their subunits or isoforms, coupling to defined
intracellular signals, etc. (Of these elements, receptors re-
main, arguably, the lynch-pin of research in view of their
accessibility as targets for therapeutic agents). However, the
conceptual re-assembly of these components into functional
networks poses major analytical difficulties. Moving from
the bottom up, in a non-linear fashion, each higher stratum
will yield “emergent” properties not immediately apparent
from study of its constituents and their interactions—and
more than the sum total of their properties. This uncertainty
is compounded by the enormous degree of redundancy of
mechanisms for the control of anxious states (Section 18.9).
For example, from this holistic perspective, comprehensive
knowledge (even if possible) of the individual roles of all
5-HT or NPY receptor subtypes cannot reveal the overall
significance of these transmitters in the response to and con-
trol of anxious states. Likewise, a complete description of
the actions and interactions of each neurochemically and
anatomically-defined class of neuron in the amygdala will
not suffice to understand the global role of the amygdala per
se in the modulation of anxious states. The major challenges
remain then, of: (1) understanding the global function and
operating properties of networks incorporating diverse brain
regions and modulators and (2) making realistic predictions
about the clinical consequence of manipulating individual
units of broad-based systems for the control of anxious be-
haviours.
176 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
18.8. Anxious states and cognitive function
In Section 2.2.2.6, within the framework of developing
novel ligands for subunits of GABAA receptors, it was
pointed out that there is a reciprocal and—unfortunately—
negative interrelationship between anxious states and sleep:
accordingly, by analogy to other neuropsychiatric indica-
tions, it is crucial that drugs exert a positive (or, at least, no
deleterious) influence upon sleep.
As evoked throughout this article, there is also an intimate,
complex and reciprocal pattern of interactions between
anxious states and cognitive function which are integrated
and modulated in common structures, such as the amyg-
dala, hippocampus and cortex (Section 1.5) (Clément
and Chapoutier, 1998; LeDoux, 2000; Sarter et al., 2001;
Carter et al., 2003; McGaugh et al., 2002; McKell-Carter
et al., 2003; Ohl et al., 2003). Indeed, it might seriously be
questioned whether any mechanism which profoundly influ-
ences one of these functions will not, at least indirectly, im-
pact upon the other. In this light, it is interesting that certain
classes of anxiolytic agent exert a detrimental influence upon
cognitive function: most strikingly, conventional BZPs elicit
a marked anterograde amnesia epitomized by impaired in-
formation acquisition and recall (Lister, 1985; Clément and
Chapoutier, 1998; Mitler, 2000). NMDA receptor antago-
nists provide a further example of anxiolytic agents which
compromise cognitive function (Danysz and Parsons, 1998;
Tang et al., 2001). However, there are certain exceptions in-
dicating that the phenonema can be dissociated: CRF2 and
NK1 receptor antagonists, as well as 5-HT1A receptor partial
agonists, for example, exert anxiolytic properties without
compromising mnesic function (Maggi, 1995; Meneses,
1999; Steckler and Holsboer, 1999; Blank et al., 2003b),
while prototypical amnesic agents such as muscarinic an-
tagonists clearly do not present a consistent and robust
anxiolytic profile (Section 6.3).
More generally, as pointed out in Section 2.2.2.6, it
must not be naively assumed that an “enhancement” of
cognitive-attentional function will necessarily be favourable
for an anxiolytic agent. From an empirical, patient-based
perspective, many may actually wish (at least temporarily) to
“forget”. In addition, a disruption of processes of extinction
is a cardinal feature of certain classes of anxiety disorder
(Section 1.5.1). From a conceptual point of view, moreover,
it has been suggested that excessive attention and vigilance
may be maladaptive in amplifying the anxiogenic effects of
fear-inducing stimuli, a process which may also secondarily
compromise the performance of cognitive tasks (Clément
and Chapoutier, 1998; LeDoux, 2000; Sarter et al., 2001).
The roles of specific mechanisms discussed herein in the
control of mnesic processes in relation to their modulation
of anxious states is clearly a critical issue requiring, in most
cases, considerable further study. In this light, as for sleep
patterns, it is imperative that for all drugs intended for the
clinical control of anxious states, their influence upon cog-
nitive function be carefully evaluated.
18.9. Redundancy in the control of anxious states
Recent research has implicated an extravagant repertoire
of modulators in the response to stress and fear, and in the
modulation of anxious states. This panoply of mechanisms
will inexorably be further increased by ongoing studies of
novel genes derived from the human genome. Indeed, in
line with other psychiatric diseases, GAD, social phobias
and other anxiety disorders are: (1) polygenic (determined
by multiple genes), (2) reflect a complex interplay of hered-
itary, developmental and environmental factors and (3)
involve the aberrant functioning of a diversity of cerebral
mechanisms (Heim and Nemeroff, 1999; Scherrer et al.,
2000; Gratacos et al., 2001; Hettema et al., 2001; Stein
et al., 2001a,b; Clément et al., 2002; Freimer et al., 2002;
Glatt and Freimer, 2002). Correspondingly, there exists an
impressively large palette of potential targets for the im-
proved treatment of anxiety disorders. This raises several
points.
First, like all crucial, existential functions integrated cen-
trally (Section 1.5.1), such as pain, appetite and motor be-
haviour, anxious states are subject to a plethora of concurrent
positive and negative influences. Indeed, it is arguable that
the most effective means to guarantee the operation and sta-
bility of critical, adaptive functions is by a hierarchy of mul-
tiple, opposing controls. (This axiom is probably universal
as a “design principle” extending from cells—transduction
mechanisms and cycles of cell growth—though organs,
whole organisms and societies to ecosystems, etc.). How-
ever, several fundamental questions still remain: (1) which
mechanisms control the equilibrium between intrinsic anxio-
genic and anxiolytic mechanisms, and how is the “set-point”
determined for a specific level of reactivity to stress and
fear; (2) why do these tightly-regulated homeostatic mecha-
nisms sometimes fail, leading to the development of anxiety
disorders; (3) what is the precise contribution of hereditary,
developmental (aversive events during childhood or ado-
lescence) and environmental (transitory and/or repetitive
exposure to banal and/or extreme stressors) factors to their
pathogenesis and (4) from a phylogenetic perspective, how
and when did such an astonishing profusion of controls
evolve?
Second, with respect to the latter point (4) many media-
tors responsive to fear and stress influence other functions,
such as cognition, motor behaviour, nociception and en-
docrine secretion, in addition in emotion. In certain cases,
modulation of mood may constitute a subsidiary rather than
a primary function. In this light, it is possible that the evolu-
tion of multiple mechanisms for the control of anxious states
illustrates the principle whereby a modulator which plays
one functional and adaptive role, say in mnesic processes
related to conditioning, is then “co-opted” for a further role,
such as control of mood, under similar conditions. Though
virtually unexplored, this phenomenon of “exaptation”, at
the level of intracellular signals, receptors, neurotransmit-
ters, neurones and cerebral circuits, is arguably fundamen-
 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
tal to the evolution of multiple and redundant controls of
anxiety and other critical CNS functions.
Third, one positive aspect of the ongoing (genome-driven)
effort to identify novel mechanisms for the modulation
of anxious state is that we can now realistically aspire to
possess all the pieces of the metaphorical jigsaw puzzle
underlying anxious disorders and their treatment. However,
rather than a static, invariant and two-dimensional image,
the brain is a dynamic, flexible and multidimensional entity
(temporally as well as spatially) and all of these pieces (mod-
ulators) reciprocally interact and possess variable “forms”
(functional properties). This point underpins the argument
made above (Section 18.7) that studies of individual con-
stituents of networks of controlling anxious states—though
crucial—are unlikely to provide a full understanding of
mechanisms underlying their pathogenesis and treatment.
Further, apart from the “rational” element drug of discovery
(genome →gene →protein →“lead”), the creative “reality”
of target validation (elucidation of function(s)—likely
multiple, and both beneficial and deleterious), transposi-
tion of “leads” into real drugs and their thorough clinical
validation still remains the essence of innovative and suc-
cessful drug development for anxiety and other disorders.
In this respect, the imaginative exploitation of the VCT
and other experimental models, and both pharmacological
and genetic strategies, will continue to play a vital role in
ongoing efforts to ameliorate the management of anxiety
disorders.
Fourth, certain mechanisms discussed herein may make
only subliminal, minor contributions to the overall induc-
tion or suppression of clinical anxious states. It is essential,
thus, to identify those mechanisms which fulfil crucial and
clinically-relevant roles in the generation of anxious states
and, correspondingly, represent genuine targets for their ther-
apeutic relief.
Fifth, a related corollary of the striking redundancy of
endogenous mechanisms either favouring or opposing anx-
ious states is that drugs interacting with a single component
may be insufficient to achieve robust and broad therapeutic
efficacy. BZPs and SSRIs, the most widely-used drugs for
clinical treatment of anxiety disorders, may appear to con-
tradict this assertion in view of their selectivity for GABAA
receptors and 5-HT transporters respectively. However, re-
flecting the operation of GABAergic inhibition throughout
the CNS, BZPs effectively act at diverse corticolimbic loci
(Sections 2.2.2.2 and 18.1). Further, in view of the contrast-
ing subunit composition of various populations of GABAA
receptor, one might even conceive BZPs as “multi-target”
agents. As for SSRIs—and other classes of antidepressant
agent—they indirectly recruit a diversity of receptorial and
adaptive mechanisms (Section 4.4), including 14 classes of
postsynaptic 5-HT receptor. Thus, in analogy to the use of
multireceptorial agents such as clozapine in the treatment
of a further multifactorial disease, schizophrenia (Brunello
et al., 1995; Meltzer, 1995, 1999; Millan, 2000; Chakos
et al., 2001), agents possessing dual or multiple mechanisms
177
of action may emerge to be particularly effective therapeu-
tic agents in the control of anxiety disorders. For example,
drugs which reinforce endogenous mechanisms countering
anxious states while concurrently inhibiting those responsi-
ble for their induction.
18.10. Clinical validation of hypotheses
In view of the intricate and dynamic pattern of recipro-
cal interactions amongst mechanisms controlling anxious
states, the clinical consequences of their manipulation
are difficult to predict. Thus, despite the utility of the
VCT and other experimental models, considerable caution
should be exercised in extrapolating hypotheses to man.
This difficulty is compounded by the heterogeneous and
co-morbid nature of anxiety disorders in patients, and by
the more complex nature of cognitive and emotional fac-
tors in man as compared to other species. Very few of the
mechanisms discussed herein have been therapeutically as-
sessed and considerable feedback from the clinic will be
necessary to confirm, refine or refute hypotheses, and to
focus research strategies aimed at the improved manage-
ment of anxious states. Indeed, bearing in mind the sheer
abundance of mechanisms which control anxious states,
as implied above, the challenge will be to identify by
well-designed experimental and therapeutic studies those
targets of which the manipulation (either alone or together
with others) will lead to efficacious and well-tolerated
agents for the rapid and sustained management of anxiety
disorders.
Inasmuch as many mechanisms evoked herein await clin-
ical feedback—while experimental data are often scarce—
it would appear premature to emphatically assert which
would be currently the most likely to offer optimal man-
agement of clinical anxiety in terms of: enhanced efficacy,
rapid onset and sustained duration of action in the absence
of dependence, preservation of cognitive function and sleep
patterns, and acceptable tolerance. In any event, it is un-
likely that any single mechanism will offer a panacea for
the improved treatment of all anxiolytic states. This tenet
applies in particular to drugs with highly-selective mecha-
nisms of action—the current tendency in exploiting innova-
tive, genome-derived targets.
Unambiguous clinical proof of anxiolytic properties for
specific classes of agent may prove more difficult to ac-
quire than might be imagined since differences between
active drugs and placebo in the treatment of anxious (and
depressive) states are frequently unclear. Such ambivalent
outcomes do not necessarily undermine the validity of the
drug and the hypothesis under evaluation but, as discussed
elsewhere (Amsterdam and Brunswick, 2002; Greist et al.,
2002; Katz et al., 2002; Khan et al., 2002; Klein et al.,
2002; Mayberg et al., 2002), raise awkward questions about
the conditions under which therapeutic trials are currently
being undertaken in psychiatry, and about our ability to
definitively validate or refute concepts in man.
178 M.J. Millan / Progress in Neurobiology 70 (2003) 83–244
19. Concluding comments
In parallel with other experimental approaches, the VCT
has proven highly instructive in exploring the multitude of
mechanisms implicated in the control of anxious states. As
emphasized herein, as part of a broader programme of re-
search, there remains considerable scope for its continued
utilization in the identification and characterization of novel
classes of anxiolytic agent. Enormous progress has been
achieved in recent years as concerns our knowledge of en-
dogenous mechanisms for the modulation (enhancement and
suppression) of anxious states. The major challenge remains
of translating these gains in our understanding of the plural-
ity of neuronal substrates underlying anxiety disorders into
tangible benefits for patients.
Acknowledgements
The author would like to thank M. Soubeyran, M. Brocco,
A. Gobert, A. Dekeyne, B. Di Cara, J.-M. Rivet and S.
Dapremont for invaluable assistance in the preparation of
this manuscript. G. Dawson, B. Olivier and T. Sharp are
thanked for helpful comments on the manuscript.
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