The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment

doi:10.1016/0014-2999(90)94059-7

European Journal of Pharmacology

Volume 186, Issue 1, 4 September 1990, Pages 49-59

https://doi.org/10.1016/0014-2999(90)94059-7 Get rights and content

Abstract

The effects of dopamine D₁ and D₂ receptor agonists and antagonists were studied in eight Cebus apella monkeys previously treated with haloperidol for two years. SKF 81297 (specific D₁ receptor agonist) induced oral hyperkinesia of variable intensity (P < 0.01): some of the monkeys developed extreme lip smacking, tonque protrusions and licking movements while others developed only slight lip movements. A combined treatment of SKF 81297 with LY 171555 (full D₂ receptor agonist) or SCH 23390 (D₁ receptor antagonist) inhibited the oral hyperkinesia induced by SKF 81297 (P < 0.01, P < 0.02, respectively). Raclopride (D₂ receptor antagonist) did not statistically change oral hyperkinesia (P < 0.2), although five monkeys showed increased oral movements; most of these monkeys had pre-existing hyperkinesia. Treatment with SCH 23390 or raclopride resulted in an identical dystonic/cataleptic syndrome. SKF 81297 inhibited the dystonia induced by SCH 23390, while it did not significantly affect raclopride dystonia. The investigation indicates that oral dyskinesia may be related to an imbalance in D₁ receptor and D₂ receptor stimulation in favor of D₁ receptors. The question now is whether D₁ receptor antagonists, which may have antipsychotic potential, will produce tardive dyskinesia after long-term use.

References (20)

J. Arnt
The discriminative stimulus properties of the D-1 agonist SKF 38393 and the D-2 agonist (−)-NPA are mediated by separate mechanisms
Life Sci.
(1988)
A.V. Christensen et al.
Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics
Life Sci.
(1984)
L.M. Gunne et al.
Spontaneous chewing movements in rats during acute and chronic antipsychotic drug administration
Pharmacol. Biochem. Behav.
(1986)
E. Meller et al.
Selective D-2 dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D-1 receptor antagonist
Life Sci.
(1985)
H. Rosengarten et al.
Induction of oral dyskinesias in naive rats by D-1 stimulation
Life Sci.
(1983)
J.L. Waddington
Behavioural correlates of the action of selective D-1 dopamine receptor antagonists
Biochem. Pharmacol.
(1986)
J.L. Waddington
Therapeutic potential of selective D-1 dopamine receptor agonists in psychiatry and neurology
Gen. Pharmacol.
(1988)
J. Arnt et al.
Dopamine D-1 and D-2 receptor differentiation revealed by behavioural studies in rats
J. Arnt et al.
Relative dopamine D-1 or D-2 receptor affinity and efficacy determine whether dopamine agonist induce hyperactivity or oral stereotypy in rats
Pharmacol. Toxicol.
(1988)
V.L. Coffin et al.
Acute extrapyramidal syndrome in Cebus monkeys; devolopment mediated by dopamine D2 but not D1 receptors
J. Pharmacol. Exp. Ther.
(1989)

There are more references available in the full text version of this article.

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While acute dystonia is associated with excessive antagonism of D2 receptors, oral dyskinesia induced by chronic treatment with antipsychotic drugs is believed to involve sensitisation of both D2 and D1 receptors, with a prominent role for D1 receptors (reviewed by Kostrzewa et al., 2007 and Ossowska, 2002). The involvement of D1 receptors in dyskinesia is supported by studies showing that D1-selective agonists induce dyskinesia in rats (e.g. Ellison et al., 1988; Rosengarten et al., 1983) and monkeys (Lublin et al., 1992, Lublin, 1995; Peacock et al., 1990), as well as by recent biochemical and genetic evidence (Carta et al., 2008; Darmopil et al., 2009; Gerfen, 2003). Cannabis is among the most frequently abused drugs by patients with schizophrenia (Kavanagh et al., 2004; Margolese et al., 2004), and hypotheses on self-medication have been proposed (Negrete, 2003).
Antipsychotic drugs may cause extrapyramidal symptoms (EPS), such as dyskinesia and dystonia. These effects are believed to involve dysfunctional striatal dopamine transmission. Patients with schizophrenia show increased prevalence of cannabis abuse and this has been linked to severity of EPS. Endocannabinoids modulate striatal dopamine activity via type 1 cannabinoid (CB₁) receptors, and studies in rats and humans suggest beneficial effects of CB₁ ligands on EPS. The present study explored the effects of CB₁ receptor ligands on oral dyskinesia induced by the dopamine D₁ receptor agonist SKF81297 (SKF) and acute dystonia induced by the dopamine D₂ receptor antagonist haloperidol in Cebus apella monkeys. The monkeys were sensitised to EPS by prior exposure to D₂ receptor antagonists.
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SKF-induced oral dyskinesia was dose-dependently reduced by CP55,940, with no effect of SR141716A. Haloperidol-induced dystonia was not affected by either CP55,940 or SR141716A.
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Several models of dystonia have emerged from clinical studies providing a comprehensive explanation for the pathophysiology of this movement disorder. However, several points remain unclear notably concerning the specific role of brainstem, basal ganglia nuclei and premotor cortex. We review data collected in sub-human primate to see whether they might provide new insights into the pathophysiology of dystonia. As in human patients, lesions of the putamen induce dystonia, as well as pharmacological manipulations of the dopaminergic system. In addition, primate studies revealed that lesions in brain stem areas involved in the control of muscular tone and GABAergic manipulations in various basal ganglia nuclei or thalamus also lead to dystonia. Moreover, there is a dramatic disruption in the processing of proprioceptive information with abnormal large receptive fields in the basal ganglia, thalamus, primary somesthetic cortex and premotor cortex of dystonic monkeys. These data highlight the idea that dystonia is associated with aberrant sensory representations interfering with motor control. Considering that the supplementary motor area (SMAp) is the target of basal ganglia projections within the motor loop, we propose a model of dystonia in which abnormal excitability, associated with alteration in sensory receptive fields within the SMAp, leads to an abnormal synchronization between primary motor cortex columns. Such a phenomenon might account for the co-contractions of antagonist muscles favored by action and the abnormal postures observed in dystonia.
The differential effects of 5-HT<inf>1A</inf> receptor stimulation on dopamine receptor-mediated abnormal involuntary movements and rotations in the primed hemiparkinsonian rat
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Thus the paramount goal of the present study was to characterize the effects of 5-HT1AR stimulation on D1R- and D2R-mediated behaviors. In order to accomplish this goal, we employed the D1R agonist, SKF81297 (Peacock et al., 1990) and the D2R agonist, quinpirole (Tsuruta et al., 1981) at doses that appear to produce equivalent AIMs expression. Numerous studies have implicated D1 receptors in dyskinesia expression and development.
Serotonin 1A receptor (5-HT_1AR) agonists have emerged as valuable supplements to l-DOPA therapy, demonstrating that they can decrease side effects and enhance motor function in animal models of Parkinson’s disease (PD) and human PD patients. The precise mechanism by which these receptors act remains unknown and there is limited information on how 5-HT_1AR stimulation impacts striatal dopamine (DA) D1 receptor (D1R) and D2 receptor (D2R) function. The current study examined the effects of 5-HT_1AR stimulation on DA receptor-mediated behaviors. Male Sprague–Dawley rats were rendered hemiparkinsonian by unilateral 6-OHDA lesions and primed with the D1R agonist SKF81297 (0.8 mg/kg, i.p.) in order to sensitize DA receptors. Using a randomized within subjects design, rats received a first injection of: Vehicle (dH₂O) or the 5-HT_1AR agonist ± 8-OH-DPAT (0.1 or 1.0 mg/kg, i.p.), followed by a second injection of: Vehicle (dimethyl sulfoxide), the D1R agonist SKF81297 (0.8 mg/kg, i.p.), the D2R agonist quinpirole (0.2 mg/kg, i.p.), or l-DOPA (12 mg/kg + benserazide, 15 mg/kg, i.p.). On test days, rats were monitored over a 2-h period immediately following the second injection for abnormal involuntary movements (AIMs), analogous to dyskinesia observed in PD patients, and contralateral rotations. The present findings indicate that 5-HT_1AR stimulation reduces AIMs induced by D1R, D2R and l-DOPA administration while its effects on DA agonist-induced rotations were receptor-dependent, suggesting that direct 5-HT_1AR and DA receptor interactions may contribute to the unique profile of 5-HT_1AR agonists for the improvement of PD treatment.
Neuroleptic-induced acute dystonia and tardive dyskinesia in primates
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Neuroleptic-Induced Acute Dystonia and Tardive Dyskinesia in Primates
2004, Movement Disorders: Genetics and Models: Second Edition
The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia
2004, Pharmacology Biochemistry and Behavior
Tardive dyskinesia (TD), a serious complication of antipsychotic dopamine (DA) antagonist treatment, has been hypothesised to develop due to a dominant DA D1 relative to DA D2 receptor function. Recent genetic and pharmacological studies implicate the DA D3 receptor in TD. The present study examined the role of the DA D3 receptor in relation to the DA D1/D2 imbalance hypothesis of TD in nonhuman primates. Eight Cebus monkeys displaying mild to severe TD due to previous chronic exposure to DA D2 antagonists were acutely injected with SKF 81297 (DA D1 agonist) 0.3 and 0.6 mg/kg, pramipexole (DA D3>D2 agonist) 0.025–0.1 mg/kg, CIS-8-OH-PBZI (DA D3 agonist) 5–10 mg/kg and SB-27701-A (DA D3 antagonist) 1–5 mg/kg and rated for oral dyskinesia. SKF 81297, 0.3 and 0.6 mg/kg, exacerbated TD. Pramipexole and CIS-8-OH-PBZI reduced SKF 81297-induced TD, while SB-27701-A had no effect. When administered alone, SB-27701-A increased TD relative to placebo, while pramipexole and CIS-8-OH-PBZI had no significant effect. Pramipexole did, however, ameliorate TD in those monkeys with severe TD. These results point towards a role of the DA D3 receptor in TD, but indicate that the DA D2 receptor may also play an essential role.

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The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment

Abstract

Life Sci.

Life Sci.

Pharmacol. Biochem. Behav.

Life Sci.

Life Sci.

Biochem. Pharmacol.

Gen. Pharmacol.

Dopamine D-1 and D-2 receptor differentiation revealed by behavioural studies in rats

Relative dopamine D-1 or D-2 receptor affinity and efficacy determine whether dopamine agonist induce hyperactivity or oral stereotypy in rats

Pharmacol. Toxicol.

Acute extrapyramidal syndrome in Cebus monkeys; devolopment mediated by dopamine D2 but not D1 receptors

J. Pharmacol. Exp. Ther.

The effects of dopamine D₁ and D₂ receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment