Behavioural and biochemical alterations following haloperidol treatment and withdrawal: The animal model of tardive dyskinesia reexamined

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BMAVIOURAL AND BIOCHEMICAL ALTERATIONS FOLLOWING HALOPERIDOL TREATMENT AND WITHDRAWAL: THE ANIMAL MODEL OF TARDIVE DYSKINESIA REEXAMINED

SANTOSH

K. RASTOGI,

RAM B. RASTOGI,

RADHEY

L. SINGHAL

and WON

D. LAPIERRE

Departments of Pharmacology and Psychiatry Universitv of Ottawa and Royal Ottawa Hospital Ottawa, Ontario

(Final form, December

1982)

Abstract Rastogi, Santosh K., Ram B. Rastogi, Radhey L. Singhal and Yvon D. Lapierre: Behavioural and biochemical alterations following haloperidol treatment and withdrawal; the animal model of tardive dyskinesia reexamined. Prog. neuro-Psychopharmacol. & Biol. Psychiat. 1983, 7(2/3): 153-164. 1. 2.

3.

4. 5.

6.

Behavioural and biochemical studies were carried out in rats given a single daily dose (1 mg/kg, i.p.) of haloperidol for 30 days and subsequently withdrawn for 7 days. Long-term administration of haloperidol resulted in supersensitivity of dopamine receptors. This was manifested by enhanced stereotypic biting, rearing, locomotor and floor activity of haloperidol withdrawn rats when challenged to a low dose of apomorphine (0.5 mg/kg, s.c.) on the 8th day. Chronic haloperidol treatment significantly decreased dopamine synthesis and release as evidenced by low activity of tyrosine hydroxylase and low level of homovanillic acid in striatum. Dopamine levels did not change in the frontal cortex, striatum and midbrain. Haloperidol treatment significantly increased striatal y-aminobutyric acid content and glutamic acid decarboxylase activity by 17X and 16% respectively. The decreased tyrosine hydroxylase activity and homovanillic acid level in corpus striatum might, in part, be due to an inhibitory effect of GABAergic neurons on dopaminergic system. Rats withdrawn from chronic haloperidol treatment showed significant increases in GABA level and glutamic acid decarboxylase activity. This probably resulted in further inhibition of dopamine release as evidenced by marked accumulation of dopamine in the corpus striatum and midbrain. No significant alterations in the endogenous levels of norepinephrine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in haloperidol-treated and subsequently withdrawn rats. These data suggest that chronic haloperidol treatment and subsequent withdrawal results in the development of behavioural dopamine supersensitivity as well as biochemical alterations in dopaminergic and GABAergic system. The changes in these two neuronal systems seem to be interrelated.

dopamine, y-aminobutyric Keywords: norepinephrine, stereotyped biting,

Abbreviations: 5-hydroxyindoleacetic

norepinephrine

dopmine

acid, haloperidol, tardive dyskinesia

homovanillic

acid, 5-hydroxytryptamine

(DA);

y-aminobutyric acid (GABA); glutamic acid decarboxylase (GAD); (5-HIAA); 5-hydroxytryptamine (5-HT); homovanillic acid (HVA); (TH). (NE); tardive dyskinesia (TD); tyrosine hydroxylase acid

Introduction Tardive dyskinesia or ABC syndrome (athetosis, bucco-oral facial, chorea syndrome) characterized by involuntary movements, particularly cephalic ones (i.e. the tongue,

153

is lips

S.K. Rastogi

154

et al.

It typically occurs in about 20% of patients after continuous, prolonged treatand jaw). ment for 2 years or more with neuroleptics such as the phenothiazines and haloperidol. Tardive dyskinesia persists even after withdrawal of these drugs. It is thought to result from a disruption of the antagonistic GABAergic and/or cholinergic-dopaminergic balance in the striatum (Ansel, 1981; Baldessarini and Tarsy, 1980). However, there is as yet no compelling evidence for the above pathophysiological mechanisms. Pharmacotherapeutic trials employing cholinergic and GABAergic drugs in the treatment of TD have yielded equivocal data Worsening of TD has been reported with L-DOPA (Palatucci, (Mackay and Sheppard, 1979). 1974; Gerlach et al., 1974; Hippius and Logemann, 1970). However, other authors (Alpert 1977; Carroll et&., 1977) have reported that L-DOPA may e al., 1976; Fixhoff, occasionally improve TD in a small number of patients. It has been suggested that bromocriptine may be of value in TD (Barnes et al., 1978), but this has not been borne out in a recent double-blind study (Chase and T&iGa, 1980). Hence, the role of other neurotransqitters in TD cannot be ruled out. In the present study, we thought it worthwhile to examine the effect of chronic treatment with haloperidol for 30 days and subsequent withdrawal for 7 days on biochemical alterations in specific areas of rat brain. Furthermore, the sensitivity of DA receptors was studied by quantifying the stereotyped biting in haloperidol withdrawn rats challenged with apomorphine.

Methods Animals. Male Sprague-Dawley rats (150-175 g) were maintained in groups of 3 per cage under constant environmental conditions (24'C, 60% relative humidity and regular alternate cycles of 12 hours light and darkness) with free access to food and water. Drug Treatment: Groups of rats were treated with haloperidol at a dose of 1 mg/kg, i.p., Control animals received an equivalent volume of the vehicle (0.1 M once daily for 37 days. Other groups of rats were treated with haloperidol for 30 days and tartaric acid). subsequently withdrawn for 7 days during which they received the vehicle. On day 38, both the haloperidol withdrawn group and vehicle treated group were divided into 3 subgroups of 6 rats; one was challenged with a low dose of apomorphine (0.5 mg/kg, s.c.) for behavioural studies, while the other two subgroups were sacrificed for biochemical studies. Behavioural

Testing

Behavioural response to apomorphine was evaluated in an open field A. Open-Field Test. apparatus containing an array of infra-red beams filled with photocells, the interruptions of which were recorded by computerized systems. A piece of black cardboard containing holes of 1 cm diameter, was placed on the plexiglass floor of each rectangular case (18 x 10 x 8 The apparatus was illuminated with white light bulbs in 10 inch reflectors which inches). On the day of testing, animals were located approximately 1 meter above the apparatus floor. were placed individually in each cage an hour before the drug administration for acclimitization. The animals were challenged with freshly prepared solution of apomorphine hydrochloride (Merck Co.) at the dose of 0.5 mg/kg S.C. The following activities were recorded every 10 set for an overall period of 1 hour. Rearing

- when rat got up on his hindlimbs

Floor activity beam interruption.

- any lateral or horizontal

and interrupted displacement

Locomotor activity - each cage was quadrisected number of times an animal crossed any of the beams.

the beam.

of the animal resulting

by three photocells

in a

that recorded

the

Stereotyped behaviour was assessed by two observers, blind to B. Stereotyped Behaviour. Each animal was rated for 30 set periods every 10 min the treatment regimen of the animals. interval, beginning from 5 min after the apomorphine injection and continued for 60 min. The assessment of stereotyping has been previously described (RastogieJ al., 1982).

Tardive dyskinesia: Behavioural and biochemical alterations reexamined

155

Sample Preparation and Enzyme Assays Animals were sacrificed 24 hr after the last injection of drug or vehicle by the unearfreezingr technique of Takahashi and Aprison (1964). The brains were rapidly excised and stripped of adherent membrane and grossly visible blood vessels and dissected into specific brain areas according to the procedure of Glowinski and Iversen (1966) while resting on crushed ice. Norepinephrineand dopamine were extracted simultaneously from tissue in 3 ml of acidified butanol, whereas 5-hydroxytryptamineand 5-hydroxyindoleaceticacid were estimated by the method of Curzon and Green (1970). Levels of norepinephrine were measured according to the method of Maickel et al. (1968) and those of dopamine by the method of Spano and Neff (1971), with modificziz described previously (Hrdina et al., 1975). The tyrosine hydroxylase activity in striatum was determined under the kinziFconditions in presence of tetrahydrobiopterin(BH4) according to the procedure of Rastogi c &. (1977). For determining the concentration of homovanillic acid, the striata were pooled from 3 rats and assays were carried out fluorometricallyaccording to the method of Murphy et al. (1969) with minor modifications. y-Aminobutyric acid was determined by the fluorometricmethod of Okada et al. (1971) which involves the formation of NADPH using the GABA transaminase succinic semixdxyde dehydrogenase system. Glutamic acid dehydrogenase activity was determined by a procedure similar to that reported by Chalmers -et al. (1970), and depended upon the measurement of 14C02 produced by the incubation of L-(l-14C) glutamic acid (Amersham)with tissue homogenates. Statistical Analysis The results were subjected to statistical evaluation by Student's t-test and significant difference between the means (calculatedas p value) is shown. No statistical significance is indicated when the p value was >0.05.

Results Apomorphine-InducedBehavioural Activity in Rats Chronically Treated With Haloperidol and Subsequently Withdrawn Chronic administration of haloperidol and subsequent withdrawal resulted in the development of marked supersensitivityof DA receptors as evidenced by the exaggerated behavioural response to apomorphine. As can be seen in Fig. 1, following apomorphine administration, there was a significant increase in rearing and locomotor activity (112% and 94%, respectively) in haloperidol withdrawn rats as compared to controls. The floor activity, caused by the lateral and horizontal movement of the animals, was also markedly increased by 186% in rats withdrawn from haloperidol (Fig. 1). Apomorphine-inducedstereotyped biting behaviour in animals previously exposed to haloperidol is shown in Fig. 2. There was a significant difference in the severity of stereotyped biting scores at 20, 30 and 40 min following apomorphine administrationwhen control animals are compared to haloperidol withdrawn rats. Also, the onset of biting behaviour and its duration was significantly different in control and haloperidol withdrawn animals (onset: control = 9.5t0.96 min, haloperidol withdrawn = 4.88tC.27 min, p ~0.05; duration: control = 37.10+2.83 miz, haloperidol withdrawn = 56.00t0.27 mTn, p ~0.05). Effect on Brain DA and NE Metabolism Data in Table 1 show that administration of haloperidol for 37 days significantlydecreased TH activity and HVA level by 24% and 29%, respectively in the corpus striatum. TH activity remained unchanged in the corpus striatum of haloperidol-withdrawnrats. Similarly, no significant effect on HVA levels was reported in rats subsequentlywithdrawn from haloperidol treatment. Daily injection of haloperidol (1 mg/kg) for 37 days produced no effect on DA levels in cortex, corpus striatum and midbrain (Table 2). Similarly, no change in DA concentration was seen after 7 days of haloperidol withdrawal in the frontal cortex. However, the DA

S.K. Rastogi

156

Rearing

et al.

Locomotor Activity

Floor Activity

behavioural activity in control and haloperidol withdrawn rats. Fig. 1. Apomorphine-induced Control animals received vehicle (0.1 M tartaric Each value is the mean + S.E.M. of 6 rats. (1 rag/kg i.p.) daily acid) i.p. for 37 days.- Haloperidol withdrawn rats received haloperidol On day 38, apomorphine (0.5 mg/kg s.c.) was for 30 days, followed by vehicle for 7 days. Figures in parenadministered and behavioural activity recorded as described in the text. Statistically significant difference as theses show values as percent of control (100%). compared to control (*p ~0.05; **p
*

*

3i 25k 8 ln20-

5

1

-

control

t--*

Haloperidol Withdrawn

t

J , ,

O0”TIME20FROM

‘v 30 AFOMORPHINE

SO 40 ADMINISTRATION

I

hid

‘

60

in haloperidol withdrawn Fig. 2. Stereotyped biting following apomorphine administration Each point is the mean + S.E.M. of 6 rats. For experimental details, see Fig. 1. rats. Statistically significant difference when compared to control (*p ~0.05; **p ~0.01).

Tardive dyskinesia: Behavioural and biochemical alterations reexamined

157

Table 1 Effect of Haloperidol Treatment and Subsequent Withdrawal on TH Activity and HVA Levels in the Corpus Striatum of Rats

Parameters

TH (nmoles DOPA/g/hr)

HVA (ug/g)

Control

HaloperidolTreated

11.94to.34 (100) 1.55_+0.11 (100)

Haloperidol Withdrawn

9.21kO.25 (76)*

12.78tO.54 (107)

1.1oco.15 (71)*

1.79+0.10 (116)

Each value is the mean + S.E.M. of 6 animals in the group. Groups of rats were treated with haioperidol (1 mg/kg, i.p.) for 30 days and subsequently withdrawn for 7 days during which vehicle was injected. The controls received an equivalent volume of vehicle (0.1 W Tartaric acid). Animals were killed 24 hr after the last injection. Data in parentheses express results in percentages taking the values for control animals as 100%. *Statistically significant difference when compared with the values of control rats (p cO.05).

content was found to be significantly increased in the corpus striatum and midbrain of haloperidol withdrawn rats by 17% and 71%, respectively of control values. Chronic haloperidol treatment tended to lower NE levels in midbrain and corpus striatum; however, the change was statistically non-significant (p ~0.05) (Table 2). Haloperidol withdrawal produced no significant effect on NE levels. Effect on Brain 5-RT and 5-HIAA Daily injection of haloperidol (1 mg/kg) for 37 days did not significantlyaffect the endogenous level of 5-HT (Table 3). Similarly, 5-HIAA content remained unaltered in all brain regions examined. No appreciable changes in 5-HT and 5-HIAA levels were recorded in rats treated with haloperidol for 30 days and subsequentlywithdrawn for 7 days (Table 3). Effect of Brain GAD and GABA Data in Table 4 demonstrate that daily injections of haloperidol for 37 days at the dose of 1 mg/kg produced no effect on GAD and GABA content in the frontal cortex and midbrain. However, in the corpus striatum, GAD activity and GABA levels were significantly increased by 16% and 17%, respectively of control values. Similarly, no change in GAD activity was observed in frontal cortex and midbrain after 7 days of hafoperidol withdrawal. The GABA content was found to be significantly elevated in midbrain and corpus striatum by 19% and 22%, respectively in haloperidol withdrawn rats. In frontal cortex, GABA content was raised by 20%, but the change was statistically non-significant. Discontinuationof haloperidol for 7 days elevated the GAD activity in the corpus striatum by 17% of control values (Table 4).

Discussion Our neurochemical data suggest that repeated administration of haloperidol produced no accelerating effect on DA turnover which is generally seen after short-term treatment with neurolepties (Rastogiet$., 1980). In fact, chronic haloperidol treatment decreased the DA synthesis and release as evidenced by reduced TH activity and HVA level in striatum. The diminished release probably resulted in accumulation of DA which became more conspicuous in

19.49+1.13 (112)

1,91+0.13 (79)

2.29kO.21 (95)

Haloperidol Treated

Haloperidol Withdrawn

0.27tO.02 (84) 0.25+0.05 (79)

0.31+0.04 (91) 0.29*0.02 (84)

2.9320.36 t171>*

1.71io.07 (100) 2.01+0.13 (118)

Corpus Striatum 0.3220.03 (100)

Frontal Cortex 0.34-to.03 (100)

Midbrain

NE (UP/P)

F z Gz +.

0.4920.06 (99)

*Statisticallysignificantdifference when compared with the values of control rate (P <0.05).

(0 i+ R

rJ ;:

0.43iO.06 (86)

0.50+0.04 (100)

Midbrain

Each value represents the mean + S.E.M. of 6 animals in the group. For experimental details, see legend for Table 1. Data in parentheses express resulTs in percentages taking the values for control animals as 100%.

20.281t1.05 (117)*

17.36kO.71 (100)

Corpus Striatum

2.41rtO.22 (100)

Frontal Cortex

DA (uglg)

Control

Treatment

Effect of Haloperidol Treatment and Subsequent Withdrawal on DA and NE Contents in Certain Brain Areas

Table 2

Tardive

dyskinesia:

Behavioural

and biochemical

alterations

reexamined

159

16.70+0.36 (100) 19.4OkO.32 (116)* 19.53iO.60 (117)"

14.70+0.43 (100)

11.121-0.34 (76)

12.60+1.06 (86)

Control

Haloperidol Treated

Haloperidol Withdrawn

23.50i0.48 (111)

22.08kO.58 (105)

21.1o-to.o2 (100)

Midbrain

2.71iO.07 (122)*

2.65kO.14 (1201

3.95+0.15 (119)*

3.5110.12 flO5)

(100) 2.60?0.05 c1171*

3.33io.09

* (iOOj

Midbrain

2 2:,+006

Corpus Striatum

2.15+0.09 (98)

2.2OfO.06 (100)

Frontal Cortex

*Statisticallysignificant difference when compared with the values of control rats (p
Each value represents the mean _+ S.E.M. of 6 animals in the group. For experimental details, see legend to Table 1. Data in parentheses express results in percentages taking the control values as 100%.

Corpus Striatum

Frontal Cortex

Treatment

GABA (nMole/g)

Effect of Haloperidol Treatment and Subsequent Withdrawal on GAD and GABA in Certain Brain Areas

Table 4

Tardive

dyskinesia:

Behavioural

and biochemical

alterations

reexamined

161

midbrain and striatum (but not in cortex) of rats withdrawn from haloperidol treatment. This could be due to tolerance to DA receptor blockade and/or development of supersensitivity of (1979). This DA receptors, as suggested by Lerner et al. (1977) and Tissarietg. tolerance however, fails to develop incerebral DA systems in non-human primates after Decreased HVA levels in CSF of schizochronic neuroleptic treatment (Roth s al., 1980). phrenic patients have been reported after a few weeks treatment w'th neuroleptic (Post and H spiroperidol and 3HGoodwin, 1975). Similarly, increased binding of DA receptors by 3_ apomorphine has been reported in striatum and mesolimbic DA areas of rats as well as in autopsied brain samples of patients treated with neuroleptics over a prolonged period (Nagy The supersensitivity of DA 1978; Muller and Seeman, 1977; Burt et al., 1977). "al., receptors in the nigrostriatal tract is beli=edto be responsible for involuntary movements seen in TD patients. A marked increase in behavioural supersensitivity to apomorphine occurred in rats following chronic haloperidol administration and subsequent withdrawal, which corroborates earlier Stereotyped behaviour induced by apomorphine is believed findings of Racagni et al. (1980). to reflect dopaminerzcactivity at striatal DA receptors and has been considered as a model for TD (Klawans and Rubovits, 1972). Low dose apomorphine has been shown to induce behavioural sedation , presumably due to preferential stimulation of DA autoreceptors However, low dose apomorphine in haloperidol withdrawn rats (DiChiara s al., 1977). increased the biting scores, rearing, floor activity and locomotor activity in the present study, It is likely that these behavioural changes are the result of magnifying the effect of low dose apomorphine by hypersensitive DA post- and possibly pre-synaptic receptors. Indeed, the sensitivity of autoreceptors has also been shown to be affected in animals treated with haloperidol. Nowycky and Roth (1977) observed that DA autoreceptors became supersensitive following chronic haloperidol treatment as evidenced by biochemical and electrophysiological testings. Recently, behavioural supersensitivity to DA agonists applied locally to limbic DA system of the forebrain has been described after haloperidol treatment (Baldessarini and Tarsy, 1980). In fact, this brain region has been hypothesized Although we to mediate the antipsychotic effect of the drug (Chouinard and .Iones, 1980). did not examine DA turnover in the mesolimbic system, it is likely that stereotyped biting seen in haloperidol withdrawn rats challenged with low dose of apomorphine could be due to its DA stimulating effects in mesolimbic areas in addition to the nigrostriatal region. It should be noted that DA supersensitivity in animals following chronic haloperidol treatment is a functional phenomenon which disappears shortly after neuroleptic withdrawal (Rastogi _ et _** al 1982). On the contrary, the involuntary movements seen in patients continue to persist for a long time after neuroleptic withdrawal. Furthermore, not every patient treated with phenothiazine or butyrophenone-type drugs develop TD. It seems that functional supersensitivity, which probably follows in all cases of neuroleptic treatment, is not the only cause of TD, but that a more permanent neurological and/or neurochemical change is probably involved. It is likely Elderly patients are more prone to develop TD. that due to existing disturbances in modulating neuronal system(s) such as cholinergic and/ or GABAergic neurons which control DA system, the brain is less apt to compensate for the consequences of temporary increases in DA receptor sensitivity. This derives support from the present study in which striatal GABA level and GAD activity were significantly increased in rats treated chronically with haloperidol as well as those subsequently withdrawn, indicating an attempt by GABAergic neurons to inhibit DA functioning, probably in nigral DA cell body as demonstrated in previous studies (e.g. Bartholini, 1980). A similar rise in GABA level and GAD activity in brain tissues has been reported in recent post-mortem studies of patients suffering from TD (Ansel, 1981). The clinical trials with drugs modifying the functions of GABA containing neurons, such as muscimol (Chase and Tamminga, 1979) and sodium valproate (Nair JZJ s., 1980) and baclofen (Simpson etg., 1978) further suggest the involvement of this neurotransmitter in TD. Our data on other neurotransmitters such as NE do not provide any conclusive evidence for their involvement in TD. Previous researchers have reported enhanced activity of the enzyme dopamine beta-hydroxylase and NE levels in autopsied brain tissue and its metabolite in the CSF of schizophrenics , particularly those with paranoid features (Lake etc., 1980). Haloperidol treatment for 30 days tended to decrease NE levels in striatum and midbrain by 16% and 14%, respectively; however, the change was statistically non-significant. There is evidence to suggest that in TD there is supersensitivity of beta-adrenoceptors, and prop-

162

S.E. Rastogi

et ni.

ranolol,

a beta-adrenoceptor blocking agent, elicits beneficial effects in alleviating the symptoms of this iatrogenic disorder (Moreira and Karniol, 1979; Bather and Lewis, 1980). More recently, Wilbur and Kulik (1981) reported that propranolol (30-60 rag/day), given for 1 to 3 months , produced marked relief of buccal oral facial symptoms and tremors in 4 patients with TD. Bupranolol, another beta-receptor blocking agent was found effective in treating neuroleptic-induced tremors (Flora -et A.9 al 1979). Studies have shown beneficial effects following the administration of 5-HT precursors in schizophrenic patients (Pollin et al., 1961; Chouinard et al., 1978). Our own earlier study has shown that daily injection of haloperidol at a relaxvely higher dose (2 mg/kg) for 21 days significantly incrased the level of 5-HT, its synthesizing enzyme tryptophan hydroxyHowever, lase and metabolite 5-HIAA in several discrete brain areas (Rastogi s al., 1981). haloperidol treatment at the dose of 1 mg/kg for 30 days and subsequent withdrawal in the Further studies are required to present study produced no effect on 5-HT and 5-HIAA levels. confirm the role of 5-HTergic system in TD.

Conclusions In conclusion, this animal model of TD seems to provide an analogous picture of biochemical changes in DA and GABA systems as seen in post-mortem brains of TD patients. However, the behavioural changes seen in this animal model do not represent the movement disorder seen in TD patients. The duration of supersensitive responses in most animals is relatively brief, usually involving a return to baseline status within a few weeks after discontinuation of the neuroleptic treatment. The peak occurrence of spontaneous locomotor activity in animals withdrawn from chronic haloperidol is on the 4th day, and gradually the activity decreases (Rastogi et al., unpublished data). However, clinical TD is typically much more enduring The oral facial movements in animals treated with and sometzes virtually irreversible. neuroleptics are not seen, unless neuroleptics have been given for one year or more (Glow et&., 1979). Furthermore, there is no consistent experimental criteria in animals to Brandson et al. (1971) considered oral facial movements to be define dyskinetic movements. the core symptom, while other more perizezl movements (although constituting part of the Hence, the observation of behavioural TD dyndrome) may not be essential for diagnosis. changes and more specifically electromyographic recording of the bucco-lingui-masticarbatory movement during the haloperidol withdrawal period may provide a better understanding of the development of TD in animals treated chronically and subsequently withdrawn from neuroleptics. Acknowledeements This work was supported by grants from the Medical Research Council Health Foundation. Dr. S.K. Rastogi was a Visiting Scientist.

and the Ontario Mental

References ALPERT, M., DIAMOND, F. and FRIEDHOFF, A. (1976) Tremographic studies in tardive dyskinesia. Psychopharmacology 12: 5-7. ANSEL, G.B. (1981) ThFbiochemical background to tardive dyskinesia. Neuropharmacology 20: 311-317. BACHER, N.M. and LEWIS, H.A. (1980) Low-dose propranolol in tardive dyskinesia. Amer. J. Psychiat. 137: 495-497. BALDESSARINIT_ii.J. (1979) The pathophysiological basis of tardive dyskinesia. Trends in Neurosciences BALDESSARINI, R.J. and TARSY, D. (1980) Pathophysiologic basis of tardive dyskinesia. In: Long-Term Effects of Neuroleptics. Advances in Biochemical Psychopharmacology, Vol. 2, F. Cattabeni, G. Racagni, R.F. Spano and E. Costs (eds.), pp. 451-456. Raven Press, New York. BARNES, T., KIDGER, T. and TAYLOR, P. (1978) On the use of dopamine agonists in tardive dyskinesia. Amer. J. Psychiat. 135: 132-133. BARTHOLINI, G. (1980) Interaction of striatal dopaminergic, cholinergic and GABAergic neurons relation to extrapyramidal function. Trends in Pharmacological Sciences _1: 138-140.

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