N. M. J. Rupniak

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset.

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p.) for 4 days induced dose-dependent parkinsonism in the common marmoset within 48 h. MPTP produced profound akinesia, rigidity of the trunk and limbs, postural abnormalities, loss of vocalization and, in some cases, postural tremor. In a single animal the administration of L-DOPA in conjunction with a peripheral decarboxylase inhibitor, reversed the parkinsonian symptoms. Subsequent biochemical analysis showed a profound loss of dopamine and [3H]dopamine uptake in the caudate-putamen, but no change in specific [3H]spiperone binding.

Acute dystonia induced by neuroleptic drugs

About 2.5% of patients treated with neuroleptic drugs develop acute dystonia within 48 h of commencing therapy. The symptoms remit on drug withdrawal or following anticholinergic therapy. Acute dystonia can also be reliably induced in many primate species by neuroleptic treatment with comparable time course, symptomatology and pharmacological characteristics to those observed in man. In general, New World monkeys appear more susceptible to acute dystonia than Old World primates. It is at present not clear whether all primates, including man, would exhibit dystonia if a sufficiently high dose of neuroleptic was administered. Alternatively, some unknown, possibly species-specific or even genetic, factors may determine an individuals susceptibility to develop dystonia. Use of a rodent model of dystonia might enable more detailed analysis of biochemical correlates of dystonic behaviour. Whilst rodents do not exhibit overt dystonic behaviour after neuroleptic treatment, they may develop oral dyskinesias which bear a close pharmacological similarity to dystonia in man and primates. However, it is not known whether chewing induced by neuroleptic drugs in rats resembles acute dystonia in primates or whether this is another movement disorder possibly unique to rodent species. The pathophysiology of acute dystonia remains unknown, but may involve striatal dopaminergic and cholinergic function. In view of the close similarity between dystonia in man and other primates, studies on the mechanisms whereby neuroleptic drugs cause acute dystonic reactions in monkeys may give some clues to the pathogenesis of spontaneous dystonia in man.

Pharmacological characterisation of spontaneous or drug-associated purposeless chewing movements in rats

Continuous administration of haloperidol, sulpiride, or cis-flupenthixol, but not of domperidone or apomorphine, to Wistar rats for up to 3 weeks caused an increase in spontaneous purposeless chewing movements. Treatment with physostigmine and pilocarpine, but not neostigmine, for up to 3 weeks increased chewing, whilst scopolamine decreased chewing. Metergoline and cyproheptadine, but not quipazine, increased chewing after only 1 and 7 days but not thereafter.Chewing was not altered following treatment with compounds acting on GABA or noradrenaline systems or by a range of non-neuroleptic agents inducing dystonia in man.The enhancement of chewing induced by neuroleptic and cholinomimetic drugs was reduced by acute treatment with scopolamine, and reverted to control levels following drug withdrawal.Neuroleptic-induced purposeless chewing in Wistar rats appears to be primarily influenced by cerebral dopamine and acetylcholine function and may resemble acute dystonia, rather than tardive dyskinesia.

Cholinergic manipulation of perioral behaviour induced by chronic neuroleptic administration to rats

Rats treated continuously for 4 months with haloperidol (1.4–1.6 mg/kg/day), trifluoperazine (4.5–5.1 mg/kg/day), or sulpiride (102–110 mg/kg/day), but not clozapine (23–26 mg/kg/day), exhibited an increased frequency of chewing jaw movements. Chewing in both control and haloperidol-treated rats was increased by acute administration of the cholinergic agents pilocarpine or physostigmine. Physostigmine or pilocarpine also induced abnormal gaping jaw movements; physostigmine-induced gaping was more prevalent in haloperidol-treated rats than control rats receiving physostigmine alone.Acute administration of the anticholinergic agents scopolamine and atropine decreased chewing in control animals and reduced haloperidol-induced chewing to control values or below. The effects of these cholinergic manipulations suggest that neuroleptic-induced perioral responses in rats do not resemble tardive dyskinesia in man.

Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 months haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.

Changes in apomorphine-induced stereotypy as a result of subacute neuroleptic treatment correlates with increased D-2 receptors, but not with increases in D-1 receptors.

Administration of haloperidol (5 mg/kg i.p.), cis-flupenthixol (2.5 mg/kg i.p.) or sulpiride (2 X 100 mg/kg i.p.) daily for 21 days followed by a 3-day drug withdrawal period caused equivalent cerebral dopamine receptor supersensitivity as judged by enhanced apomorphine-induced stereotypy. These treatments also produced equivalent rises in the number of adenylate cyclase-independent dopamine receptors (D-2) in both striatal and mesolimbic tissue as assessed by specific [3H]spiperone and [3H]N,n-propylnorapomorphine (NPA) binding. No change in the dissociation constant (KD) was apparent in response to neuroleptic treatment. However, only repeated administration of cis-flupenthixol caused an increase in the number of adenylate cyclase-linked dopamine receptors (D-1) in striatum as assessed by enhanced [3H]piflutixol binding and increased dopamine-stimulated cyclic AMP formation. The dissociation constant for [3H]piflutixol binding was unchanged by cis-flupenthixol administration. No change in D-1 receptor numbers or dopamine stimulation of adenylate cyclase occurred in mesolimbic tissue. Repeated treatment with sulpiride or haloperidol was without effect on either [3H]piflutixol binding to D-1 receptors or cyclic AMP formation. In conclusion, increased apomorphine-induced stereotypy following subacute neuroleptic treatment correlates with changes in D-2 receptor numbers, but not with changes in D-1 receptors.

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol, sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.Bmax values for striatal 3H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in Bmax for striatal 3H-piperone binding.Bmax values for striatal 3H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in Bmax for 3H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in Bmax for 3H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.

Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat.

Administration of haloperidol (1.4–1.6 mg/kg/day) for up to 12 months or sulpiride (102–109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25–2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, sterotypy induced by high doses of apomorphine (0.5–1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats.Bmax for specific striatal 3H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. Bmax for 3H-NPA binding was elevated only after 12 months of both haloperidol and sulpiride treatment. Bmax for 3H-piflutixol binding was not alfered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride.Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.

Alterations in cerebral glutamic acid decarboxylase and 3H-flunitrazepam binding during continuous treatment of rats for up to 1 year with haloperidol, sulpiride or clozapine

Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4–1.6 mg/kg/day), sulpiride (102–109 mg/kg/day) or clozapine (24–27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and3H-flunitrazepam binding. Administration of haloperidol, but not sulpiride or clozapine, for 6 or 12 months increased striatal GAD activity. None of the drug treatments altered nigral GAD activity when examined after 1, 3, 6, 9 or 12 months administration. The number of specific3H-flunitrazepam binding sites (Bmax) in striatal membrane preparations were not altered by 12 months administration of haloperidol, sulpiride or clozapine. Surprisingly, Bmax for3H-flunitrazepam binding to cerebellar membrane preparations was decreased-by 12 months administration of all drug treatments. The dissociation constant (Kd) for3H-flunitrazepam binding in striatal and cerebellar preparations was not altered. The ability of GABA (0.25–100 μM) alone, and in conjunction with sodium chloride (200 mM), to stimulate specific3H-flunitrazepam binding in striatal and cerebellar preparations was unaltered by haloperidol, sulpiride or clozapine administration for 12 months. The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of haloperidol, but not sulpiride or clozapine, to induce striatal dopamine receptor supersensitivity in the same animals. The actions of haloperidol may reflect its greater ability to induce tardive dyskinesia compared to sulpiride or clozapine.

Repeated administration of sulpiride for three weeks produces behavioural and biochemical evidence for cerebral dopamine receptor supersensitivity.

Administration of sulpiride (2 X 100 mg/kg i.p.) or haloperidol (5 mg/kg i.p.) to rats for 3 weeks with subsequent withdrawal for 3 or 4 days induced cerebral dopamine receptor supersensitivity. Apomorphine-induced stereotyped behaviour after drug withdrawal was enhanced by pretreatment with either haloperidol or sulpiride both of which increased the number of specific striatal binding sites (Bmax) for [3H]spiperone, [3H]N,n-propylnorapomorphine and [3H]sulpiride. Neither drug altered the dissociation constant (KD) for the ligand binding assays. Striatal dopamine sensitive adenylate cyclase activity was unaltered by such a pretreatment with either haloperidol or sulpiride. The data show that sulpiride, like haloperidol, is capable of inducing behavioural and biochemical supersensitivity of cerebral dopamine receptors.