Psychological Medicine, 1980, 10, 55-72

Printed in Great Britain

The pathophysiology of extrapyramidal

side-effects of neuroleptic drugs
C. D. MARSDEN1 AND P. JENNER
From the University Department of Neurology, Institute of Psychiatry, and
King's College Hospital Medical School, London

SYNOPSIS The mechanisms responsible for the production of major extrapyramidal side-effects
(parkinsonism, akathisia, acute dystonic reactions, chronic tardive dyskinesias) are reviewed in
the light of the complex effects of these drugs on cerebral dopamine systems.

INTRODUCTION it was found that neuroleptic drugs could

The introduction of neuroleptic drugs into
clinical practice by Delay et al. (1952) revo-
lutionized psychiatry. For the first time clinicians
had available a group of compounds which
could reduce delirium and acute psychotic
excitement without producing sedation. This
remarkable clinical property was matched by
a unique pharmacological profile in animals
(Bobon et al. 1970). Neuroleptic drugs could
quieten animals; indeed, they could promote
states of motor immobility (catalepsy) without
producing sleep.
Neuroleptic drugs immediately found many
clinical applications. They became the mainstay
of management of patients with acute toxic
confusional states (Meyer, 1956), and patients
in the throes of acute schizophrenia (NIMH,
1964). Subsequently, it was discovered that they
also controlled chronic schizophrenic thought
disorder, and prevented recurrent acute schizo-
phrenic episodes (Grinspoon et al. 1968; Leff &
Wing, 1971; Hirsch et al. 1973; Hogarty et al.
1974). Their clinical impact was dramatic. For
the first time the number of patients in chronic
mental hospitals began to drop, as more and
more individuals became manageable as out-
patients (Davis & Casper, 1977). Literally
thousands of patients returned to the community.
However, as is nature's way, a price was paid
for this success.
Almost immediately after their introduction,
1
Addressfor correspondence: Professor C D . Marsden,
University department of Neurology, Institute of Psychiatry,
De Crespigny Park, Denmark Hill, London SE5 8AF.
55
OO33-2917/8O/2828-5O9O $01.00 © 1980 Cambridge University Press
produce a range of extrapyramidal side-effects.
Broadly these fell into four categories. The
commonest was drug-induced parkinsonism,
which mirrored idiopathic Parkinson's disease
in practically all its clinical aspects (Steck, 1954).
Akathisia, a peculiar state of mental and motor
restlessness characterized by intense desire to
move in order to gain respite from overwhelming
feelings of distress, also was noted frequently
(Steck, 1954). Drug-induced parkinsonism and
akathisia commonly occurred only after some
weeks or months of treatment with neuroleptic
drugs, but a small proportion of patients develop-
ed explosive and bizarre acute dystonic reactions
in the first days or weeks of treatment (Delay &
Deniker, 1957). Finally, another more sinister
abnormal involuntary movement disorder,
chronic tardive dyskinesia, became recognized
after months or years of treatment (Sigwald et
al. 1959; Uhrbrand & Faurbye, 1960), a con-
dition which sometimes persisted even though
the offending drug was withdrawn.
The clinical features of these various drug-
induced extrapyramidal movement disorders
have been reviewed in detail elsewhere (Marsden
et al. 1975) and only those facts pertinent to
their cause will be mentioned here. The purpose
of this paper is to discuss the mechanisms
whereby these drugs cause their various extra-
pyramidal side-effects, drawing on information
obtained from observations in man and experi-
ments in animals. As a starting point, it may
be said that each of the four major categories
of drug-induced extrapyramidal movement dis-
orders - parkinsonism, akathisia, acute dystonic
 56 C. D. Marsden and P. Jenner

reactions, and chronic tardive dyskinesia - has administration. The mechanisms whereby such
a different pathogenesis. drugs cause a compensatory increase in dopa-
minergic activity in an attempt to overcome
post-synaptic receptor blockade are many (Fig. 1
DRUG-INDUCED PARKINSONISM
Idiopathic Parkinson's disease and post-encepha- Table 1. Neuroleptics block dopamine receptors
litic parkinsonism both share a common patho- Antagonize behavioural actions of DOPA, apo-
physiology: namely, a loss of pigmented brain- morphine and amphetamine"
stem neurons, particularly those of the substantia Without depleting brain monoamines6 (cf. reserpine)
Antagonize inhibition by iontophoretic dopamine0
nigra in the midbrain, associated with a profound Antagonize dopamine stimulation of adenylate
depletion of cerebral catecholamines, particularly cyclase'1
of dopamine in the caudate nucleus and putamen Antagonize sH-dopamine receptor binding"
Antagonize peripheral dopamine receptors' (e.g.
(the corpus striatum), as a result of degeneration kidney)
of the nigro-striatal dopaminergic pathway. The
main clinical features of Parkinson's disease are "Van Rossum, 1966. » Carlsson & Lindqvist, 1963;
Nyback & Sedvall, 1970. c Bunney et al. 1973; Aghajanian
due to this profound dopamine depletion in the & Bunney, 1977. d Kebabian et al. 1972; Clement-Cormier
brain (Ehringer & Hornykiewicz, 1960) and et al. 1974. " Seeman et al. 1975; Burt et al. 1976. ' Yeh et
al. 1969.
can be reversed (at least partially and initially)
by restoring brain dopamine action either by Striatum
oral feeding of the precursor amino acid L - D O P A
(Birkmayer & Hornykiewicz, 1961; Barbeau,
1962; Cotzias et al. 1967), or by directly acting
dopamine agonists such as bromocriptine (Calne
et al. 1974).
Drug-induced parkinsonism also is due to
dopamine deficiency in the brain. Reserpine, and
its analogue tetrabenazine, prevent dopamine
storage by disrupting intra-neuronal granules
containing the amines (Bertler, 1961; Glowinski
et al. 1966), while neuroleptic drugs antagonize (•ABA
Substance P
cerebral dopamine action by blocking dopamine lincephalins
receptors in the brain (Carlsson & Lindqvist,
1963; Janssen et al. 1965; van Rossum, 1966).
All neuroleptics are dopamine receptor antago-
nists, at least on acute administration. The
evidence that neuroleptic drugs antagonize
cerebral dopamine action comes from a variety
of animal experimental data, which are sum-
marized in Table 1. However, it must be empha-
sized that all of these behavioural effects have
been most clearly demonstrated when such drugs
are given acutely.
Neuroleptic drugs do not greatly affect brain
dopamine concentration, but they cause a com-
pensatory increase in dopamine synthesis and
turnover in all dopamine-containing cerebral Substantia Outflow pathways
areas (Carlsson & Lindqvist, 1963; Laverty &
Sharman, 1965; Ande"n et al. 1969; Gey & FIG. 1. Schematic representation of the mechanisms by which
Pletscher, 1968; Nyback & Sedvall, 1970). This drugs may cause compensatory increases in dopamine (DA)
neuronal activity in the nigro-striatal system. For explanation
biochemical effect is interpreted as an attempt of mechanisms 1-5 see Table 2. The figure does not represent
to compensate for the blockade of post-synaptic the true anatomical relationship of neuronal connections par-
ticularly in the terminal regions. • , DA receptors; Q, non-
dopamine receptors produced by neuroleptic DA receptors.
 Neuroleptic-induced extrapyramidal disease
Table 2. Evidence for feedback control of
dopamine neurones
Neuroleptics block post-synaptic dopamine receptors but
increase dopamine turnover"'1"'"'
Neuroleptics activate tyrosine hydroxylase*
Mechanisms proposed:
(1) Strio-nigral loop'
Neuroleptics increase nigral cell firing, an effect inhibited
by dopamine"1"
Lesions of nigro-striatal pathway attenuate depressant
actions of amphetamine on nigral cell firing'
Kainic acid lesions of striatum prevent neuroleptic acti-
vation of tyrosine hydroxylase*
(Electrical stimulation of nigra causes tyrosine hydroxy-
lase activation)*
(2) Autoreceptors on pre-synaptic dopamine terminals1'1
Neuroleptic-induced increase in dopamine turnover
persists following destruction of strio-nigral pathway"1
Neuroleptic-induced increase in dopamine turnover
persists following kainic acid lesions of striatum"
Neuroleptic-induced increase in dopamine turnover
persists following hemisection or cessation of impulse
flow using y-butyrolactone /'°
Neuroleptic-induced increase in dopamine turnover
occurs in striatal slices and synaptosomes' 1 ''"
(3) Striatal axo-axonal control by inter-neurones
All that evidence for (2) can be explained by (3) (except
probably the synaptosomal work)
Anticholinergics antagonize the increase in dopamine
turnover caused by neuroleptics8''
Acetylcholine and glutamate influence dopamine syn-
thesis and release in striatal synaptosomes or slices"'"'1"
(4) Dopomine receptors on dopamine neurone cell bodies
Neuroleptics cause dendritic release of dopamine from
dopamine neurones 1 and this may inhibit firing"
Local application of dopamine or apomorphine to nigral
cells inhibits firing, an effect blocked by systemic halo-
peridol administration2
Intra-nigral amphetamine (presumably by releasing
dopamine)1* produces a marked inhibition of neuronal
activity in pars compacta of substantia nigra*
Destruction of the nigrostriatal pathway reduces neuro-
leptic binding sites in nigra^
(5) Dopamine receptors on the terminals of non-dopamine
nigral neurones
Dopamine dendrites do not possess dopamine receptors
linked to adenylate cyclasey but lesions of the strio-nigral
pathway markedly reduce nigral dopamine sensitive
adenylate cyclase*
° Carlsson & Lindqvist, 1963;" Laverty & Sharman, 1965;
" Anden et al. 1969; d Gey & Pletscher, 1968; • Zivkovic et
al. 1975; ' Carlsson et al. 1972a; ' Bunney et al. 1973;
* Aghajanian & Bunney, 1977; ' Bunney & Aghajanian,
1976; I Di Chiara et al. 1978; * Roth et al. 1975; 'Carlsson
et al. 19726; m Garcia-Munoz et al. 1977; " Di Chiara et al.
1977; ° Handforth & Sourkes, 1975;» Seeman & Lee, 1974;
0
Farnebo & Hamberger, 1971; r Iversen et al. 1976;
' O'Keefe et al. 1970; ' Anden, 1972; " GiorguiefT et al.
1976; • de Belleroche & Bradford, 1978; » Giorguieff et al.
1977; x Geffen et al. 1976; » Groves et al. 1975; z Aghajanian
& Bunney, 1974; « Paden et al. 1976; » Reisine et al. 1979;
y
Olianas et al. 1978; B Spano et al. 1977.
and Table 2). This is not the place to discuss the
exact details of these various means by which
neuroleptics may promote increased dopaminer-
57
gic activity, but it is important to note that they
may engage either post-synaptic mechanisms
(short intra-striatal feedback circuits or long
strio-nigral feedback loops), or act directly on
the nigro-striatal neurone (on autoreceptors on
the cell body or dendrites, or on pre-synaptic
receptors on axonal terminals).
Neuroleptic drugs antagonize the action of
dopamine in two in vitro biochemical systems.
Thus, neuroleptics prevent dopamine from
stimulating formation of cyclic AMP in striatal
homogenates (or homogenates from other
dopamine containing areas of the brain), i.e.
they prevent stimulation of the enzyme adenylate
cyclase by dopamine (Kebabian et al. 1972;
Clement-Cormier et al. 1974). Neuroleptics also
prevent the specific labelling of dopamine
receptors in such preparations by radioactive
ligands such as tritiated dopamine agonists
or other tritiated neuroleptic drugs themselves
(Seeman et al. 1975; Burt et al. 1976).
Taking all this evidence together, it is clear
that neuroleptic drugs block cerebral dopamine
receptors, thereby producing the equivalent of
brain dopamine deficiency which may be held
responsible for drug-induced parkinsonism
(Hornykiewicz, 1975). However, there are certain
clinical anomalies that require discussion.
Broadly speaking, drug-induced parkinsonism
is dose-dependent. Indeed, it is probable that
everyone would develop obvious clinical features
of the disorder if given a big enough dose of
neuroleptic drug. However, in routine clinical
practice only some 20-40 % of all patients
treated with these agents are reported to exhibit
obvious clinical signs of parkinsonism (Marsden
et al. 1975). In part this is due to the difficulties
of recognizing more subtle and early features
of the condition. Minor degrees of akinesia
often go unnoticed, the earliest changes in facial
expression, gait, and hand-writing are frequently
not detected by cursory examination. Even so,
it is clear that there is individual susceptibility
to development of parkinsonism in response to
a given dose of neuroleptic. Factors determining
such individual susceptibility have not been
worked out. The fact that the age incidence of
drug-induced parkinsonism parallels that of the
idiopathic disease (Ayd, 1961) strongly hints
that a propensity to the latter may determine
the incidence of the former. Indeed, this is not
surprising when it is realized that it requires
58 C. D. Marsden and P. Jenner
a depletion of striatal dopamine to less than
20 % of its normal content before obvious
clinical evidence of idiopathic paralysis agitans
is evident (Bernheimer et al. 1973). The impli-
cation of this observation is that there must be
a large pool of individuals with sub-clinical
degrees of striatal dopamine depletion without
overt evidence of the disease. Such patients
would be more susceptible to the influence of
administration of neuroleptic drugs. Such an
analysis may also explain the occasional patient
who appears to develop permanent drug-induced
parkinsonism.
In most cases parkinsonism appearing in the
course of neuroleptic treatment disappears when
the offending drug is withdrawn. Admittedly,
this may take a long time, in our experience as
long as eighteen months. This long delay is
attributable, at least in part, to the prolonged
persistence of some neuroleptic agents in tissue
after drug withdrawal. Thus, metabolites of
phenothiazines persist in urine at least for three
months after stopping the drug (Forrest &
Forrest, I960). However, most cases of drug-
induced parkinsonism do remit with time, but
a few do not (1 % or so in our experience). The
question is whether this small minority had sub-
clinical idiopathic Parkinson's disease before
starting treatment, or whether the drugs them-
selves can promote permanent parkinsonism.
Since the incidence of idiopathic Parkinson's
disease in the population at large is of the order
of 0-5 % in those over the age of 50, the likeli-
hood is that the small proportion of patients in
whom parkinsonism persists for years after
neuroleptic administration and withdrawal in-
deed did have the idiopathic disease.
There is often a delay in the appearance of
drug-induced parkinsonism after starting treat-
ment. Most cases appear within a few weeks or
months of starting treatment rather than after
a few days. This may be due to the accumulation
of drugs, because the pharmacokinetics of most
neuroleptic agents are characterized by long
half-life and accumulation in tissue stores
(Salzman & Brodie, 1956). Whether this is the
sole explanation remains to be established.
Equally apparent clinically is the fact that
drug-induced parkinsonism having appeared may
gradually disappear despite continuing drugs.
Such tolerance is well established but hitherto
unexplained. Pharmacokinetic causes may ex-
plain this observation, since there is evidence of
increased neuroleptic metabolism with chronic
administration of the drugs (Sakalis et al. 1972;
Loga et al. 1975). A more rational explanation
is that dopamine receptor blockade gradually
decreases with time and very recent experiments
indicate that this is exactly what happens (see
below).
Finally, one must mention the question of
treatment of drug-induced parkinsonism. Anti-
cholinergics are of some benefit (Simpson, 1970),
but there are very potent reasons for not giving
them routinely and for reserving their use solely
for those patients in whom this side-effect is
causing disability (see below). Since neuroleptics
block cerebral dopamine receptors by competitive
antagonism, their effects should be reversed by
dopamine agonists. However, L - D O P A is usually
reported not to be of value in the treatment of
drug-induced parkinsonism (Fleming et al. 1970;
Yaryura-Tobias et al. 1970). Theoretically, if
given in a sufficient dose, it should be effective.
Indeed, our experience is that it is effective,
provided that dosage is not limited by the
appearance of increasing psychotic disturbance
or other mental side-effects. The implication of
this observation is that it is easier to overcome
neuroleptic blockade of those cerebral dopamine
receptors concerned with mental phenomena
than it is to reverse blockade of the striatal
dopamine receptors responsible for drug-induced
parkinsonism.
DRUG-INDUCED AKATHISIA
Akathisia is a paradox. Neuroleptics calm man
and animals producing mental quiet and motor
immobility. Akathisia is manifest by mental
unease and motor restlessness.
One of the consequences of the concept that
there exist pre-synaptic auto-receptors on all
parts of dopaminergic neurones is that their
preferential stimulation may provoke paradoxi-
cal effects (see Carlsson, 1977). The idea is
that, under normal circumstances, dopamine
released from pre-synaptic nerve terminals
activates autoreceptors on the self-same termi-
nals to decrease synthesis and release dopamine
(Carlsson et al. 1972a, b). The recently discovered
dendritic release of dopamine is thought to have
the same effect within the substantia nigra itself
(Nieoullon et al. 1977).
 Neuroleptic-induced extrapyramidal disease
A neuroleptic drug that preferentially blocks
pre-synaptic dopamine receptors in concen-
trations less than those required to antagonize
the post-synaptic receptor would have unex-
pected effects. Its pre-synaptic action would lead
to increased dopamine synthesis and release of
dopamine on to post-synaptic dopamine re-
ceptors not antagonized by the drug. As a con-
sequence, the functional and behavioural effects
of such a drug would be to increase dopaminergic
action rather than decrease it, despite the fact
that its main mechanism of effect was to block
dopamine receptors. Such an action has been
invoked to explain the paradoxical effect of
dopamine agonists such as apomorphine to
inhibit locomotor activity at very low doses while
stimulating it at high doses (Di Chiara et al.
1976; Strombom, 1977), and similar paradoxical
behavioural effects of neuroleptic drugs in animal
experiments (Ahlenius & Engel, 1971).
Selective pre-synaptic dopamine receptor an-
tagonism might be invoked to explain drug-
induced akathisia, but there are reasons to dis-
miss this hypothesis. In the first place, reserpine
and tetrabenazine, both of which deplete dopa-
mine stores and therefore cannot increase
dopamine action, may cause obvious akathisia.
Secondly, akathisia and drug-induced parkin-
sonism commonly co-exist (Marsden et al. 1975).
An alternative hypothesis is that akathisia is
the result of post-synaptic dopamine receptor
blockade in cerebral dopamine-containing areas
other than the corpus striatum (Fig. 2). Recent
discoveries on the function of such brain areas
are relevant in this context. While blockade of
dopamine receptors in the striatum and such
mesolimbic areas as the nucleus accumbens
produces inhibition of locomotion in the form
of akinesia or catalepsy, the reverse occurs on
blockade of meso-cortical dopamine systems
(Iversen, 1971; Tassin et al. 1978; Carter &
Pycock, 1978). The latter were discovered only
relatively recently when it was appreciated that
not all of the catecholamine content of the
cerebral cortex could be attributed to noradrena-
line. Certain cortical areas were found to contain
appreciable quantities of dopamine which lay
in the terminal projections of dopaminergic
pathways arising in the midbrain - the meso-
cortical dopamine system (Thierry et al. 1973;
Berger et al. 1974; Hokfelt et al. 1974; Lindvall
et al. 1974).
59
Anterior
Nucleus
cingulate
caudate-
cortex
putamen
Olfactory
tubercle
Nucleus
accumbens Amygdala
FIG. 2. A sagittal section of the rat brain schematically
illustrating the dopamine innervation of neostriatal, meso-
limbic and mesocortical brain areas. SN, Substantia nigra;
Aio, ventral tegmental nuclei; CC, corpus callosum; ON,
olfactory nuclei.
Destruction of these pathways alone, or of
their terminal projection areas in the medial
frontal and cingulate areas, causes locomotor
hyperactivity in rodents. If it is assumed that
this has a conscious equivalent in man, then
both the mental and physical manifestations of
akathisia might be attributed to blockade of
dopamine receptors in these specific cortical
areas. Further work is required to confirm this
hypothesis.
ACUTE DYSTONIC REACTIONS
Acute dystonic reactions occur in about 2 % of
those who take neuroleptic drugs, usually within
the first few days of starting treatment, often
after the first dose (Marsden et al. 1975).
Virtually nothing is known about the factors
that predispose this small group of patients to
develop the problem. Until recently, little was
known about their pathophysiology, but new
data derived from both animal experiments and
human observation have begun to shed light
on the matter.
Acute dystonic reactions have been observed
in animals treated with neuroleptics (Deneau &
Crane, 1968; Gunne & Barany, 1976; Bedard
60 C. D. Marsden and P. Jenner

et al. 1977; Weiss et al. 1977). In particular,

several species of primates exposed to the acute Table 3. Effect of drugs on acute dystonia
administration of a variety of neuroleptic drugs provoked by haloperidol
have developed a clinical syndrome indistin-
guishable from that seen in human patients
Severity of
experiencing acute dystonic reactions. Of par- Dose subsequent
ticular interest have been the studies of Meldrum Drug (mg/kg) Time (min) dystonia
et al. (1977). In the course of investigating the
Haloperidol
pharmacology of photo-sensitive epilepsy in the alone 1 i.m. 0 + + +
Senegalese baboon, Papio papio, Meldrum and Haloperidol plus
Scopolamine 002 i.v. 55 a 0
his colleagues noted that haloperidol admini- Benztropine 0-2 i.v. 30 a 0
stered systematically occasionally provoked a Physostigmine 0 1 i.v. 20 a + + + +
bizarre movement disorder. Close examination a-m-p-tyrosine 200 i.p. 270 b +++
Reserpine 2 i.p. 24 h b ++
indicated that this was a typical acute dystonic Reserpine plus 2 i.p. 24 h b +/-
reaction with features such as trismus, forced a-m-p-tyrosine 150 x 2 i.p. 30 and 240 b
jaw opening, spasms of tongue with occlusion
a, After; b, before; 0, no dyskinesia apparent; + to + + +
and gnawing, arching of the back and torticollis, represent increasing severity of dyskinetic movements.
as well as bizarre posturing of the limbs.
Screening of a whole colony of 25 such animals
revealed that no fewer than 3 (12 %) developed the enzyme tyrosine hydroxylase had little effect
such acute dystonic reactions when given halo- when given by itself on dystonia provoked by a
peridol (in doses of 0-6-1-2 mg/kg i.m.). A range subsequent injection of haloperidol. But when
of neuroleptics produced such a response in reserpine (2 mg/kg i.p., 24 h previously) and
susceptible animals, including haloperidol, chlor- a-methyl-/?-tyrosine (150 mg/kg i.p., 0-5 and 4 h
promazine, pimozide, and oxypertine; but thio- previously) were given together, the combined
ridazine, a neuroleptic with an exceptionally high treatment abolished or greatly reduced halo-
inherent anticholinergic activity, was ineffective. peridol-induced dystonia (Table 3). These results
Anticholinergic drugs abolish acute dystonic indicate that acute dystonic reactions to neuro-
reactions in man, and scopolamine (0-02 mg/kg leptic drugs are dependent upon some pre-
i.v.) and benztropine (0-2 mg/kg i.v.) also synaptic dopaminergic (and perhaps noradren-
abolished haloperidol (1 mg/kg i.m.) induced ergic) event mediated by both the storage and
acute dystonia in susceptible baboons. Physo- synthesis of catecholamines. The fact that neuro-
stigmine (0-1 mg/kg i.v.) intensified haloperidol- leptics which are relatively specific dopamine
induced dystonia in the baboon (Table 3). Thus, receptor antagonists with little noradrenaline
the acute dystonic reaction in the baboon, like receptor blocking action, such as haloperidol
its human counterpart, appears to be modified and pimozide, are just as capable of producing
by manipulating cholinergic mechanisms, anti- acute dystonic reactions as neuroleptics which
choltnergics improving it and cholinergics making have a greater capacity to block noradrenaline
it worse. as well as dopamine receptors, such as chlor-
Further pharmacological exploration of this promazine, suggests that the important cate-
primate model of neuroleptic-induced acute cholamine is dopamine. The overall conclusion,
dystonic reactions led to the critical observation then, is that acute dystonic reactions are pro-
that disrupting pre-synaptic dopamine (and nor- duced as a result of some effect of neuroleptic
adrenaline) mechanisms could prevent the phe- drugs on pre-synaptic dopamine mechanisms.
nomenon. Pre-treatment of monkeys with re- The obvious candidate for such a mechanism
serpine (2 mg/kg i.p., 24 h previously) to disrupt is the compensatory increased dopamine syn-
granular storage of catecholamines reduced (but thesis and release provoked by acute admini-
did not abolish) dystonia produced by a sub-, stration of neuroleptic drugs. This phenomenon,
sequent injection of haloperidol (1 mg/kg i.m.). discussed above, represents the normal attempt
Pre-treatment of baboons with a-methyl-/?- of dopaminergic neurones to overcome post-
tyrosine (200 mg/kg i.p., 4-5 h previously) to synaptic dopamine receptor blockade by the
prevent catecholamine synthesis by inhibition of neuroleptic. The many different phenomena in-
 Neuroleptic-induced extrapyramidal disease
volved in this feedback control mechanism (see
Table 2 and Fig. 1) all contribute to one final
functional effect, namely increased dopamine
release from pre-synaptic neurones.
In regard to acute dystonic reactions two
phenomena associated with this compensatory
mechanism require emphasis. First, like acute
dystonic reactions themselves, this increased
dopamine release is apparent only on acute
administration of a neuroleptic drug. Repeated
administration is associated with a decline and
eventual disappearance of evidence of increased
dopamine turnover (Asper et al. 1973; Scatton,
1977). Secondly, administration of anticholin-
ergic drugs not only prevents acute dystonic
reactions, but also diminishes the dopamine
release provoked by neuroleptics (O'Keefe et al.
1970; Anddn, 1972; Corrodi et al. 1972).
Is there any evidence that dopamine release
can provoke dystonia? Certainly a proportion
of patients with Parkinson's disease treated with
L - D O P A develop abnormal movements identical
to those of dystonia (Parkes et al. 1976). Stimu-
lation of the abnormal denervated dopamine
receptors in Parkinson's disease thus can cause
dystonia, and administration of even larger
doses of L - D O P A (combined with a peripheral
decarboxylase inhibitor) also can cause dystonic
abnormal movements in normal monkeys (Paul-
son, 1973; Mones, 1973; Sassin, 1975).
All this evidence suggests the hypothesis that
acute dystonic reaction in man and animals may
be due to increased dopamine release resulting
from the acute administration of a neuroleptic
drug. But a paradox is immediately apparent.
How can the dopamine released by this com-
pensatory mechanism stimulate post-synaptic
dopamine receptors, for these are blocked by
the neuroleptic? Two explanations may be in-
voked to overcome this difficulty. First, it is
possible that neuroleptic drugs preferentially act
on pre-synaptic dopamine receptors in concen-
trations which do not affect post-synaptic
receptors. The consequence of such an action
would be to liberate dopamine into the synaptic
cleft as a result of inhibition of pre-synaptic and
autoreceptor function, with consequent stimu-
lation of post-synaptic dopamine receptors which
are not antagonized by that concentration of
neuroleptic. One piece of evidence compatible
with this suggestion is the clinical observation
that acute dystonic reactions occur many hours
61
or even days after the administration of a
single dose of a drug, presumably at a time
of falling brain concentrations of the active
agent. A second explanation draws on the con-
siderable evidence that suggests the presence
of more than one dopamine receptor in the
brain (Klawans, 1973 a; Costall & Naylor, 1975;
Cools & van Rossum, 1976; Cools et al. 1976;
Kebabian & Calne, 1979). It is possible that
the dopamine released as a result of neuro-
leptic administration may act, not only on a
population of dopamine receptors blocked by
that neuroleptic, but also on another population
of dopamine receptors which is not affected by
neuroleptic administration. There is now experi-
mental evidence to support this suggestion, for
Skirboll & Bunney (1979) have identified one
population of striatal neurones inhibited by local
dopamine application whose effect can be
prevented by haloperidol, and another population
on which haloperidol has no effect on the action
of dopamine.
There is another phenomenon that must be
taken into account in assessing the patho-
physiology of acute dystonic reactions. Not only
are there compensatory changes in the activity
of the pre-synaptic dopamine neurone in response
to an acute neuroleptic drug, but it has now
been established that there are changes in the
sensitivity of the post-synaptic receptor. The
acute administration of a single dose of any
neuroleptic has been found to lead to a delayed
appearance of post-synaptic super-sensitivity to
systemically administered dopamine agonists
(Christensen, 1973; Christensen & lvMler-
Nielsen, 1974). Thus, 24 hours or so after the
acute administration of butyrophenone or other
neuroleptic drugs, rodents show enhanced stereo-
typy or climbing behaviour lasting for a matter
of a few days to a week (Meller-Nielsen &
Christensen, 1975; Moller-Nielsen et al. 1976;
Christensen et al. 1976; Martres et al. 1977).
The implication of this finding in relation to
acute dystonic reactions is that, as the neuro-
leptic concentration decreases after acute ad-
ministration, it will leave exposed the super-
sensitive post-synaptic dopamine receptor; at
this point persisting increased dopamine release,
or even perhaps normal or reduced concentra-
tions of dopamine, may provoke an enhanced
dopaminergic response. In other words, the
final functional effect of this complex series of
62 C. D. Marsden and P. Jenner

(a) Levels of HVA, DOPAC and DA in striatum

700-

100-

2 4 72

(fi) Stereotypy
200-

2 4 12 24
Time (h) after butaperazine (400 mg/kg p.o.)

Fie. 3. Modification of (a) striatal homovanillic acid (HVA) 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine
(DA) concentrations; and (b) apomorphine (0-5 mg/kg s.c.)-induced stereotyped behaviour in rats receiving
butaperazine (40 mg/kg p.o.), expressed as a percentage of control values (control values = 100%). *P < 005.
• , HVA; • , DOPAC; A, DA.

changes that occur after the acute administration
of a neuroleptic must take into account not
only changes in pre-synaptic dopamine release
but also changes in post-synaptic dopamine
receptor sensitivity.
The interaction of these various phenomena
can be illustrated from our own studies on the
time course of changes in brain dopamine turn-
over and dopamine receptor sensitivity in rats
treated with the phenothiazine neuroleptic buta-
perazine. We chose this drug for study specifically
because it had been carefully investigated
clinically by Garver et al. (1976a, b) with con-
siderable interest in relation to acute dystonic
reactions. A group of 13 schizophrenics were
given 40 mg of butaperazine as a single oral dose
and no fewer than 8 developed acute dystonic
reactions as a result. The timing of their appear-
ance was of considerable interest. In 7 of the
8 patients the acute dystonic reaction occurred
some 20-28 hours after the administration of
butaperazine, and in the eighth patient it occur-
red around 56 hours later.
We administered a single dose of butaperazine
(40 mg/kg p.o.) to rats, and subsequently fol-
lowed the changes in stereotypy induced by
apomorphine (0-5 mg/kg s.c, 15 min previously),
a behavioural index of cerebral dopamine
stimulation, and of the striatal concentration
of dopamine, homovanillic acid (HVA) and
 Neuroleptic-induced extrapyramidal disease
dihydroxyphenylacetic acid (DOPAC) over the
next 72 hours (see Fig. 3). Apomorphine-induced
stereotypy was virtually abolished for the first
8 hours after butaperazine and was greatly
reduced for up to 12 hours. Concentrations of
HVA and DOPAC in striatum were greatly
increased, with no change in dopamine levels,
for the first 12 hours after butaperazine, indi-
cating an increased turnover and release of
dopamine from striatal terminals. Twenty-four
hours after butaperazine, apomorphine induced
a normal or exaggerated stereotyped behavioural
response and, although concentrations of HVA
and DOPAC in the striatum were falling, they
were still increased by comparison with control
animals. In other words, at this critical time
striatal dopamine receptors responded normally
or in a slightly exaggerated manner to apo-
morphine (as judged by exaggerated stereotypy),
while striatal dopamine turnover and release
were still increased (as judged by HVA and
DOPAC concentrations). The net sum of these
two events would be increased striatal dopamine
activity, and it was just at this critical time
interval of 24 hours after drug administration
that the majority of acute dystonic reactions
occurred in the human studies with this drug.
Seventy-two hours after butaperazine admini-
stration to rats, stereotypy in response to apo-
morphine had returned towards control levels,
and HVA, DOPAC and dopamine concentra-
tions in the striatum were similar to those in
control animals. All the acute dystonic reactions
observed in the human studies had occurred by
this time after drug administration.
A final question to consider is why such a
small proportion of individuals challenged with
a neuroleptic drug develop an acute dystonic
reaction. This may represent an idiosyncratic
reaction of the minority. Alternatively, every-
body might develop the phenomenon if given
a big enough dose of neuroleptic but, in usual
clinical practice, only a small proportion achieve
high enough concentrations of the drug to cause
the problem. There is evidence compatible with
both suggestions and it is impossible to decide
between the two at present.
With regard to idiosyncrasy, the high incidence
in otherwise normal young individuals is strongly
against any obvious degenerative brain pathology
as predisposing to dystonic reactions, but it has
been suggested that they may occur in those who
63
have inherited the gene for dystonia musculorum
deformans. This disease is rare in its florid
clinical manifestation, but the autosomal reces-
sive gene responsible for many hereditary cases
is commoner in the general population, parti-
cularly among Jews, 1 in 65 of whom have been
estimated to carry the gene (Eldridge & Gottlieb,
1976). Even if the gene exists asymptomatically
as frequently as this among Jews, it could not
be held responsible for an incidence of acute
drug-induced dystonic reactions approaching 1
in 50 of the general population. Nor are such
events known to be more prevalent among the
Jewish population.
It has been proposed that acute dystonic re-
action may be dose-dependent in any individual
(Marsden et al. 1975), and further data from
the study of Garver et al. (1976 a, b) lend weight
to this suggestion. These authors measured
plasma and red cell butaperazine concentrations
in this clinical study and were able to compare
levels in those who developed acute dystonic
reactions with those who did not. No differences
were found in any measure of plasma butapera-
zine level, but red cell butaperazine concen-
tration was sixfold higher at the onset of the
dystonic reaction, red cell butaperazine half-
life was greatly prolonged and the area under
the red cell butaperazine absorption curve
was much increased in those who developed
acute dystonic reactions compared with those
who did not (Fig. 4). It was argued that the
red cell blood levels, being in part membrane
bound, gave a better indication of brain buta-
perazine concentrations, and the conclusion was
that the development of dystonic reactions in
response to the drug was related to an increase
in concentration of butaperazine compared with
that achieved in those who escaped the side-
effect.
CHRONIC TARDIVE DYSKINESIA
(Crane, 1968, 1973; Marsden et al. 1975; Tarsy
& Baldessarini, 1976).
Of all the extrapyramidal complications of
chronic neuroleptic treatment, tardive dyskinesia
is potentially the most serious. These abnormal
movements appear after many months or years
of drug treatment. Characteristically, they affect
the face, producing the typical oro-buccu-lingual
dyskinesia, but often they may involve limbs and
64
Plasma
300-|
1
200 A
100-
{b) -
t -
40
c " -
o
ration at
to
o
L
c
o> -
u
,° 0 _
Fio. 4. Plasma and red blood cell (RBC) butaperazine levels in dystonic and non-dystonic patients receiving
a single oral dose of butaperazine (40 mg). (a) Peak drug levels; (6) drug levels at the time of onset of dystonia;
(c) half-life; (d) area under curve (AUC). *P < 005. D, Dystonia patients; • , non-dystonia patients.
trunk. The movements are typically choreiform
in the elderly, but may be frankly dystonic in
the young. Tardive dyskinesia may co-exist with
drug-induced parkinsonism. The same patient
may have the typical oro-facial movements with
distal chorea of the digits, but at the same time
may exhibit a blank face, a stooped posture and
a slow shuffling gait (Gerlach, 1977a, b). Like-
wise, tardive dyskinesia may be accompanied by
profound akathisia.
The abnormal movements that characterize
tardive dyskinesia may occur spontaneously
without prior drug intake. The evidence in-
criminating chronic neuroleptic drug intake as
a common cause of similar abnormal movements
is epidemiological. The incidence of tardive
dyskinesia in those on chronic neuroleptics is
greatly in excess of that of spontaneous oro-
facial dyskinesias. The latter may occur in some-
thing of the order of less than 1 % of the
population, while chronic tardive dyskinesias
occur in between 20 and 40 % of those on long-
term neuroleptic drugs (Degkwitz, 1967; Jus et al.
1976 a, b).
A singular and worrying feature of tardive
dyskinesia is that it frequently persists, or may
even appear for the first time when the offending
C. D. Marsden and P. Jenner
RBC Plasma RBC
24-i
1
0
neuroleptic drug is stopped (Degkwitz & Wenzel,
1967; Crane, 1973). Indeed, it is believed that
this extrapyramidal complication of neuroleptic
therapy may be permanent despite drug with-
drawal (Crane, 1973). There is debate as to how
frequently this occurs, but the risk of permanent
tardive dyskinesias has been estimated at some-
where around 30 % of those who develop the
problem (Marsden et al. 1975).
The clinical pharmacology of tardive dyskine-
sias indicates that they are due to over-stimu-
lation of dopamine mechanisms in the brain
(Klawans, 1973 a, b). The movements themselves
resemble those produced by L - D O P A in patients
with Parkinson's disease. They can be suppressed,
at least partially and temporarily, by drugs that
interfere with dopaminergic neurotransmission.
Drugs that prevent dopamine storage (reserpine
or tetrabenazine) or dopamine synthesis (a-
methyl-/?-tyrosine) decrease tardive dyskinesias,
as do drugs that block dopamine receptors
(Kazamatsuri et al. 1972 a, b; Chase, 1972;
Gerlach et al. 1974). Increasing the dose of the
offending neuroleptic, or substituting a more
powerful neuroleptic, will temporarily suppress
tardive dyskinesias. This is no way to treat the
condition, for it is irrational to use any drug
 Neuroleptic-induced extrapyramidal disease
that has caused the problem and, in any case,
the tardive dyskinesia will soon break through
again as time passes. The appearance of tardive
dyskinesia on neuroleptic drug withdrawal is
another illustration of the influence of dopamine
antagonists on the condition. Finally, there is
general agreement that the movements of tardive
dyskinesia are enhanced by administration of
high doses of dopamine agonists (Chase, 1972;
Gerlach et al. 1974). Lower doses may have the
opposite effect, perhaps by selective stimulation
of pre-synaptic or autoreceptors on dopamine
neurones (Carroll et al. 1977; Smith et al. 1977;
Tolosa, 1978).
A paradox again is immediately apparent.
How can a condition whose pathophysiology is
that of dopaminergic overactivity be produced
by drugs whose prime mode of action is to
block dopamine receptors? Carlsson (1970) and
Klawans (1973 a, b) overcame this problem by
invoking the concept of drug-induced super-
sensitivity.
In the peripheral somatic (Axelsson & Thes-
leff, 1959) and autonomic nervous systems
(Trendelenburg, 1963 a, b), it has long been
known that denervation or pharmacological in-
activation of pre-synaptic neurones will produce
a state of post-synaptic receptor super-sensitivity
to applied transmitter (Langer & Trendelenburg,
1966; Langer et al. 1967). Carlsson and Klawans
argued that blockade of post-synaptic cerebral
dopamine receptors might have a similar effect
by depriving receptor sites of their normal
stimulation by the natural transmitter, dopamine.
Experimental support for this hypothesis soon
came from a variety of studies, demonstrating
that sub-acute administration of neuroleptic
drugs for a matter of a few weeks could lead to
pharmacological super-sensitivity when the ani-
mals were tested to dopamine agonists some days
or weeks after drug withdrawal (Schelkunov,
1967; Tarsy & Baldessarini, 1973, 1974; von
Voigtlander et al. 1975).
In the studies of Tarsy & Baldessarini, for
example, rats were treated with chlorpromazine
(15 mg/kgs.c.) for three weeks and the drug
was then withdrawn. The sensitivity of their
cerebral dopamine receptor mechanisms was
assessed by establishing dose-response curves
for stereotypy provoked by apomorphine. The
stereotypy dose-response curve a week after
withdrawal of chlorpromazine was clearly shifted
65
to the left by comparison with that obtained
in control animals treated with vehicle only,
indicating the development of true pharmaco-
logical super-sensitivity. In the same study, it
was shown that treatment with reserpine (0-25
mg/kg s.c.) and a-methyl-/?-tyrosine (50 mg/kg
s.c.) also led to pharmacological super-sensitivity
to apomorphine when tested a week after with-
drawal, but treatment with phenobarbitone
(50 mg/kg s.c.) or diazepam (5 mg/kg s.c.) had
no effect. Subsequently, many other similar
studies with a range of different neuroleptics
and durations of treatment have shown a similar
phenomenon (see Table 4).
The molecular mechanism of this form of
super-sensitivity produced by short-term ad-
ministration of a neuroleptic followed by drug
withdrawal has been investigated by studying
the activity of dopamine receptor action in vitro.
The number of dopamine receptors identified
by specific tritiated neuroleptic binding sites is
increased in the brains of animals killed a week
or so after drug withdrawal (Burt et al. 1977;
Muller & Seeman, 1977). At this time the
neuroleptic drug has disappeared, so that
affinity constants are unchanged. According
to some authors, the capacity of dopamine to
stimulate brain adenylate cyclase activity in
homogenates from dopamine-rich areas also is
increased at this time, but this is disputed (see
Table 4). Pharmacological super-sensitivity after
short-term neuroleptic administration and drug
withdrawal is thus accompanied by increased
numbers of dopamine receptors and perhaps
by some increase in sensitivity of dopamine
stimulated adenylate cyclase.
This short-term super-sensitivity obtained
after a few days or weeks of neuroleptic admini-
stration is fundamentally different from that
occurring after a single dose of such drugs. As
described above, the pharmacological super-
sensitivity evident in the few days after a single
dose of a neuroleptic (Moller-Nielsen et al. 1976;
Martres et al. 1977) is not accompanied by any
change in receptor binding or dopamine sensitive
adenylate cyclase (Hyttel, 1978).
These studies clearly indicate that short-term
neuroleptic administration produces super-sensi-
tivity of cerebral dopaminergic mechanisms
evident after drug withdrawal. During the short
period of drug administration, however, the
neuroleptic still effectively blocks dopaminergic
66 C. D. Marsden and P. Jenner

Table 4. The effect of repeated neuroleptic administration and subsequent withdrawal on

dopamine-mediated behaviour and in vitro receptor binding and adenylate cyclase
Length of Withdrawal
Drugs used treatment time Enhanced response
06
Behaviour '
Haloperidol "1
Chlorpromazine > 1-4 weeks 1 week Apomorphine-induced stereotypy
Reserpine J
Thioridazinej 6-7 weeks 10 days Apomorphine-induced stereotypy;
Clozapine / spontaneous locomotor activity
Receptor binding"'1'
Haloperidol 1-3 weeks 2-5 days [3H]haloperidol and [3H]apomorphine
binding to striatal and mesolimbic
tissue
3
Reserpine \ 3 weeks 5-7 days [ H]haloperidol binding to striatal tissue
Fluphenazine/
Adenylate cyclase*1*''*1'
Haloperidol \ 20 days 2 weeks Enhanced response to dopamine
(+)-butaclamol/ stimulation
Haloperidol 2 weeks 2 days No change
Chlorpromazine 3-4 days 1 day No change
Reserpine 7 days 0 Enhanced response to dopamine
c t imi IIQ t tr\t\
ollllllilallUIl
Reserpine 2 days 2 days No change

° Tarsy & Baldessarini, 1974; * Smith & Davis, 1976; e Burt et al. 1977; * Muller & Seeman, 1977; ' Gnegy et al. 1977;
f
von Voigtlander et al. 1975; » Rotrosen el al. 1975; * Heal et al. 1976; ' Seeber & Kuchinsky, 1976.

activity. Such animals are incapable of respond-
ing behaviourally to dopamine agonists during
this first few weeks of neuroleptic administration.
This still leaves the question of the cause of
tardive dyskinesia unresolved, for in most cases
the abnormal movements appear while the
patient is still taking the drug. For this reason,
we set up experiments to examine the effects of
really long-term neuroleptic administration in
animals, and the results of these experiments
have resolved this paradox.
Groups of rats were treated with either tri-
fluoperazine (0-7-0-9 mg/kg/day or 2-5-3-5 mg/
kg/day) or thioridazine (6-9 mg/kg/day or
30-40 mg/kg/day) in their drinking water for
a year. Litter-mates were kept under identical
conditions throughout the experiment as control
animals. The two neuroleptics were chosen as
one representing the class of potent dopamine
antagonists with little inherent anticholinergic
activity (trifluoperazine) and the other a weaker
dopamine antagonist with high inherent anti-
cholinergic activity (thioridazine). This choice
was made because there is reasonably compelling
clinical evidence to suggest that anticholinergic
drugs increase the intensity of tardive dyskinesia
and perhaps its frequency (Klawans, 19736;
Klawans & Rubovits, 1974; Fann & Lake, 1974;
Gerlach et al. 1974). The doses administered
were chosen to approximate to those administered
clinically to man in the case of the lower levels,
and a fivefold greater dose to take into account the
more rapid drug metabolizing capacity of the
rat.
At intervals throughout the experiment, drug-
treated and control animals were tested for
cerebral dopaminergic sensitivity by examination
of apomorphine-induced stereotypy (0-5 mg/kg
s.c.). Full dose-response curves to apomorphine
were done at critical periods. Also, throughout
the experiment, animals were sacrificed for
measurement of cerebral dopamine concen-
trations and those of its metabolites, for
estimation of dopamine sensitive adenylate
cyclase activity, and for dopamine receptors as
judged by tritiated spiperone binding activity in
striatal homogenates. At the end of the year,
the drug was withdrawn and animals were fol-
lowed up for a further period of six months
thereafter.
The results, which have been published in full
elsewhere (Clow et al. 1978, 1979 a, b), may be
summarized as follows (Fig. 5). In the first
month or so of drug treatment, all indices of
cerebral dopamine action were antagonized.
Apomorphine induced little or no stereotypy;
dopamine could not stimulate the striatal adenyl-
ate cyclase activity in vitro; and dopamine
 Neuroleptic-induced extrapyramidal disease 67

(a) Stereotypy
200-,
* ***

100- /
/

IWithdrawal

(h). Binding sites

200 -i

Withdrawal

(c) Dissociation constant

„ 500.

300-

100-

(d) Adenylate cyclase

2 200 -i

100-

Witlidrawal

3 6 i: 1 3
Time on drug (months) Withdrawal
FIG. 5. The effect of 12 months' continual administration of trifluoperazinedihydrochloride (2-5-3-5 mg/kg/day p.o.)
to rats and its subsequent withdrawal for 6 months on (a) apomorphine (0-5 mg/kg s.c.) induced stereotyped
behaviour; (6) [sH]spiperone (0-125-40nM) specific striatal binding sites (Bmax); (c) the dissociation constant
(KB) for specific [3H]spiperone striatal binding; and (d) the dopamine (50(IM) stimulation of striatal adenylate
cyclate, expressed as a percentage of control values (control values = 100 %). *P < 005.

receptor affinity was decreased, as expected from
the presence of the antagonist in the homogenate
analysed. Numbers of dopamine receptors
initially were increased, but then returned to
normal.
Between one and six months of drug treatment
a change occurred. Stereotypy to apomorphine
began to reappear; dopamine stimulation of
adenylate cyclase began to return to control
levels; and receptor affinity began to increase,
although receptor numbers were not changed.
These results indicated a disappearance of evi-
dence of dopamine receptor antagonism by the
neuroleptic drugs, despite their continuation and
regular intake.
Between six months and a year of drug ad-
ministration, this gradual disappearance of
dopamine receptor antagonism progressively
changed into a state of dopamine receptor over-
activity. Apomorphine began to provoke greater
stereotypy than in control animals; dopamine
began to produce excessive stimulation of striatal
adenylate cyclase in vitro; and the number of
dopamine receptors identified by tritiated spi-
5-2
 C. D. Marsden and P. Jenner
perone increased above control levels. These
behavioural and biochemical changes clearly
indicated that the animals were developing
dopamine receptor super-sensitivity, despite con-
tinuation of drug intake.
In the six months after drug withdrawal, some
indices of dopamine receptor activity persisted
in an abnormal super-sensitive state. While mean
stereotypy scores to apomorphine returned
towards control levels, some animals continued
to have excessive response. Dopamine stimu-
lation of striatal adenylate cyclase remained
enhanced throughout the whole period of six
months' withdrawal. Dopamine receptor numbers
tended to return towards control levels but were
still elevated up to three months after drug
withdrawal. Thus, the dopamine receptor super-
sensitivity provoked by the year's intake of tri-
fluoperazine or thioridazine persisted for at least
six months after withdrawal of the drugs,
especially as regards adenylate cyclase action.
No difference could be detected between the
effects of trifluoperazine and thioridazine.
These results show that the initial inhibition
of dopamine action on acute administration of
neuroleptic drugs disappears with chronic treat-
ment to be replaced by dopamine super-sensi-
tivity, at least as regards those behavioural and
biochemical indices attributed to striatal dopa-
mine function. Obviously, this is of significance
in regard to tardive dyskinesias which can be
attributed to basal ganglia dysfunction. The
results vindicate Carlsson and Klawans' hypo-
thesis, that dopamine receptor super-sensitivity
provoked by chronic neuroleptic administration
may be the pathophysiological mechanism
responsible for tardive dyskinesia. The fact that
some of the evidence of dopamine receptor
super-sensitivity persisted for at least six months
after withdrawal of drugs in the animal studies
adds weight to the clinical concern that these
agents may provoke long-lasting, perhaps even
permanent, changes in the brain. It should be
remembered that administration of a drug for
a year to a rat represents exposure for approxi-
mately a third of its life-span, while persistence
of a change in the brain for six months may
represent a change lasting some ten years or so
in a human being.
This animal model of tardive dyskinesia is
currently being used to assess the significance of
a number of possible clinical approaches to
management of the problem, for instance the
impact of so-called drug holidays and the pos-
sible use of novel neuroleptics which do not
appear to cause this problem.
These studies also have possible fundamental
relevance to the mode of action of anti-psychotic
drugs. The general hypothesis, that drugs capable
of controlling psychotic thought and behaviour
disturbances act by blocking cerebral dopamine
receptors, rested upon their capacity to do so
in acute experiments. Our studies indicate that
this acute action of the drug disappears on
chronic administration, at least as far as the
striatum is concerned. If a similar tolerance and,
indeed, reversal of the effect of these agents
occur in other dopamine containing areas of the
brain, such as the meso-limbic system and
meso-cortical areas, it would be difficult to sus-
tain the argument that their neuroleptic action
is due to cerebral dopamine receptor blockade.
Indeed, we have some evidence to suggest that
this action does disappear in meso-limbic areas
over six months' administration. Findings such
as these certainly cast doubt on the hypothesis
that neuroleptic drugs act by being dopamine
receptor antagonists and therefore, by impli-
cation, cast doubt on the general dopamine
hypothesis of schizophrenia.
CONCLUSION
The mechanism responsible for the production
of extrapyramidal side-effects by neuroleptic
drugs has been reviewed in the light of new
experimental data. Drug-induced parkinsonism
is held to be due to post-synaptic dopamine
receptor blockade in striatum, while akathisia
may be due to similar blockade of dopamine
receptors in meso-cortical areas. Acute dystonic
reactions appear to be due to the interaction
between the development of post-synaptic dopa-
mine receptor super-sensitivity with increased
dopamine turnover and release provoked by the
acute administration of these drugs. Chronic
tardive dyskinesias appear to result from a
gradual disappearance of dopamine receptor
blockade in the striatum by neuroleptic drugs
and the emergence of striatal dopamine receptor
super-sensitivity, despite continuation of drug
intake. Similar tolerance to the dopamine
receptor blocking action of neuroleptics in
 Neuroleptic-induced extrapyramidal disease
mesolimbic areas may occur, casting doubt on
the general hypothesis that therapeutic anti-
psychotic effect of these drugs is due to their
ability to block dopamine receptors.
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