The Neurobiology of Nicotine Dependence and Co-Morbid Psychiatric Disorders

George F. Koob, Ph.D. Athina Markou, Ph.D. Department of Neuropharmacology The Scripps Research Institute La Jolla, California

Criteria for Substance Dependence (DSM-IV)

From: Koob GF and Le Moal M, Science, 1997, 278:52-58.

Acute Nicotine Increases Brain Stimulation Reward

From: Huston-Lyons D and Kornetsky C, Pharmacol Bioch Behav, 1992, 41:755-759.

Nicotine Self-Administration

Human data adapted from: Henningfield JR, Miyasato K and Jasinski DR, Pharmacol Biochem Behav 1983, 19:887-890.

From: Watkins SS, Epping-Jordan MP, Koob GF and Markou A, Pharmacol Biochem Behav, 1999, 62:743-751.

Effects of DHbE on Nicotine Self-Administration in Rats

(0.03 mg/injection)

From: Watkins SS, Epping-Jordan MP, Koob GF and Markou A, Pharmacol Biochem Behav, 1999, 62:743-751

Key Neurochemical Systems Comprising Brain Drug Reward Circuitry

Effects of 6-OHDA or Vehicle Infusions into the Nucleus Accumbens on Nicotine Self-Administration in Rats

From: Corrigall WA, Franklin FBJ, Coen KM, and Clarke PBS, Psychopharmacology, 1992, 107:285-289.[

Mechanisms by which Nicotine Interacts with Dopamine and Glutamate Transmission

Nicotine activates nAChRs located on glutamate terminals in the ventral tegmental area (VTA) Nicotine-stimulated glutamate release acts at glutamate receptors located on VTA dopamine neurons Activation of glutamate receptors stimulates dopamine release into terminal regions, such as the nucleus accumbens
From: Kelley AE, Nature Med, 2002, 8:477-479.

Dependence: An Affective Definition

The notion of dependence on a drug, object, role, activity or any other stimulus-source requires the crucial feature of negative affect experienced in its absence. The degree of dependence can be equated with the amount of this negative affect, which may range from mild discomfort to

extreme distress, or it may be equated with the amount of

difficulty or effort required to do without the drug, object, etc.

From: Russell MAH, What is dependence? In Edwards G (ed), Drugs and Drug Dependence, Lexington Books, Lexington, MA, 1976, pp. 182-187.

Withdrawal from nicotine elicits an aversive behavioral syndrome in humans

Gastro-intestinal discomfort

Bradycardia
Increased appetite Anxiety Depressed Mood Craving

Dysphoria
Irritability Difficulty concentrating

ICSS Threshold Procedure

Adapted from: Markou A and Koob GF, Physiol Behav, 1992, 51:111-119.

Spontaneous Nicotine Withdrawal

Adapted from: Epping-Jordan MP, Watkins SS, Koob GF and Markou A, Nature, 1998, 393:76-79.

DHbE-precipitated Nicotine Withdrawal

From: Epping-Jordan MP, Watkins SS, Koob GF and Markou A, Nature, 1998, 393:76-79.

Brain Reward Function During Acute Withdrawal (0-72 hours)

Decreases in Extracellular Levels of Dopamine During Precipitated Nicotine Withdrawal

From: Hildebrand BE, Nomikos GG, Hertel P, Schilstrom B and Svensson TH, Brain Res, 1998, 779:214-225.

From: Panagis G, Hildebrand BE, Svensson TH and Nomikos GG, Synapse, 2000, 35:15-25.

Effects of Nicotine and a Nicotinic Antagonist Injected into the Dorsal Raphe Nucleus on the Social Interaction Test

From: Cheeta S, Tucci S and File SE, Pharmacol Biochem Behav, 2001, 70:491-496.

Nicotine Withdrawal

From: Harrison AA, Liem YTB and Markou A, Neuropsychopharmacology, 2001, 25:55-71.

The mGluII Receptor Antagonist LY341495 Reversed Spontaneous Nicotine Withdrawal

From: Kenny PJ, Gasparini F and Markou A, unpublished results.

Glutamatergic and GABAergic regulation of dopamine transmission in the VTA

Pre-synaptic Modulation
Glutamate Terminal

Post-synaptic Modulation

VTA Dopamine Neuron

Adapted from: Schoepp DD, J Pharmacol Exp Ther, 2001, 299:12-20.

CNS Actions of Corticotropin Releasing Factor (CRF)

Neurotransmitter Systems Hypothesized to be Involved in the Motivational Aspects of Nicotine Withdrawal

Acetylcholine pedunculopontine tegmental nucleus Dopamine nucleus accumbens, amygdala Opioid Peptides nucleus accumbens, amygdala, ventral tegmental area Serotonin median raphe

Lanca et al., 2000

Hildebrand et al., 1999 Pangis et al., 2000 Malin et al., 1993 Ise et al., 2000 Watkins et al., 2000 Harrison et al., 2001 Cheeta et al., 2001 Kenny et al., 2001

Glutamate ventral tegmental area

Corticotropin-Releasing Factor (???)

Depression and Withdrawal from a Variety of Drugs of Abuse are Associated with Altered Function in Several Neurotransmitter Systems

5-HT

NE or

Ach

DA

GABA

CRF

NPY

SS

Opioids

Depression
Drug withdrawal Psychostimulants Opiates Ethanol

Nicotine

Hypothetical Anatomical Circuit Underlying Melancholic Depression and Adversity

From: Schulkin J, McEwen BS and Gold PW, Neurosci Biobehav Rev, 1994, 18:385-396.

Hypothetical Anatomical Circuit Underlying the Dark Side of Drug Dependence

The Atypical Antidepressant Bupropion Reversed Nicotine Withdrawal

Cryan, Bruijnzeel, Skjei & Markou, Psychopharmacology, 168:347-358, 2003

Allostatic Change in Mood State associated with Transition to Drug Addiction

From: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.

Potential Substrates in the Extended Amygdala for the Motivational Effects of Drug Dependence

Modified from: Heimer L and Alheid G, Piecing together the puzzle of basal forebrain anatomy. In: Napier TC, Kalivas PW and Hanin I (Eds), The Basal Forebrain: Anatomy to Function (series title: Advances in Experimental Medicine and Biology, Vol. 295), Plenum Press, New York, 1991, pp. 1-42.

Summary and Conclusions

Nicotine is readily self-administered by animals and enhances brain
reward

Neurochemical substrates important for the acute reinforcing effects of

nicotine include dopamine, GABA, opioid peptides, serotonin, and glutamate systems in the basal forebrain.

The focus of research to date on the acute reinforcing effects of nicotine

has been on specific nicotinic receptor dynamics in the context of glutamate/GABA interactions with dopamine neurons in the ventral tegmental area.

Development of motivational dependence to nicotine is associated

with dysregulation of the brain reward system and decreased function in some of the same neurochemical systems involved in negative affect associated with co-morbid psychiatric disorders

Collaborators Athina Markou

John Cryan Mark Epping-Jordan Amanda Harrison Paul Kenny Neil Paterson Svetlana Semenova Luis Stinus Shelly Watkins
Support from the National Institute on Drug Abuse and National Institute on Mental

Health Research Grant from Novartis Support from the Tobacco Etiology Research Network of the Robert Wood Johnson Foundation Support from the Tobacco-Related Disease Research Program, State of California

Laura O Dell

Summary and Conclusions (What is unknown)

The reward dysregulation of early and late withdrawal from nicotine is hypothesized to result from allostatic, rather than homeostatic, changes in the brain reward circuitry. The dark side of dependence to nicotine may also involve the recruitment of changes in the brain stress systems including corticotropin releasing factor and/or norepinephrine. The subdivisions of the extended amygdala provide a heuristic framework for integrating the hypothesis that normal motivational function is usurped by chronic drugs of abuse to produce a deficit emotional state associated with addiction. Neuropharmacological changes in the circuits of the extended amygdala may persist during protracted withdrawal and provide a motivational basis for vulnerability to co-morbid psychiatric disorders.