Dopaminergic and Cholinergic Interaction in Cataleptic Responses in Mice

doi:10.1016/S0091-3057(96)00478-9

Pharmacology Biochemistry and Behavior

Volume 58, Issue 1, September 1997, Pages 103-108

https://doi.org/10.1016/S0091-3057(96)00478-9 Get rights and content

Abstract

The cataleptogenic effects of haloperidol, a dopamine D2 receptor antagonist; SCH23390, a D1 receptor antagonist; physostigmine, a cholinesterase inhibitor; and pilocarpine, a muscarinic M1 receptor agonist, were challenged by pretreatment of mice with SKF38393, a dopamine D1 receptor agonist; apomorphine, a dopamine D1/D2 receptor agonist (mainly D2 receptor); pirenzepine, a muscarinic M1 receptor antagonist; and scopolamine, a muscarinic M1/M2 receptor antagonist. The effect of physostigmine and pilocarpine on haloperidol and SCH23390 cataleptic responses was also examined. Each of the challenging agents blocked one or more of the cataleptogenic agents, but only scopolamine blocked all four. Pirenzepine blocked cataleptic responses induced by SCH23390 and pilocarpine, but not those by haloperidol and physostigmine. The results of this study suggest that the action of physostigmine (endogenous acetylcholine) on M2 receptors might be more potent than that on muscarinic M1 receptors. A further interesting observation was that the haloperidol-induced catalepsy was enhanced by physostigmine pretreatment, but not by pilocarpine pretreatment, whereas the SCH23390-induced catalepsy showed the opposite spectrum of enhancement by the two cholinergic agonists. We conclude that, although the four cataleptogenic agents act via the dopaminergic-cholinergic systems, their pharmacological differences may be due largely to the different receptor subtypes that are involved in the mediation of catalepsy produced by each agent. Thus, dopamine receptors not only influence the cholinergic muscarinic receptors, but muscarinic M1 and M2 receptors also might mediate dopamine D1 and D2 receptor responses, respectively. The results suggest that there are, at the least, relationships between muscarinic M1 receptors and dopaminergic D1 receptors, and between muscarinic M2 receptors and dopaminergic D2 receptors. Dopamine D1 and D2 receptors may interact in a synergistic fashion on dopaminergic systems, but act independently of each other in influencing other system such as cholinergic neurons.

Section snippets

Animals

Healthy male ddY albino mice (7 week-old mice; 30–35 g), purchased from Kyudo Animal Laboratory (Kumamoto, Japan), were allowed free access to food and water. The mice were housed and all trials were conducted at an environmental temperature of 23 ± 1°C, with a 12 L:12 D cycle (0700–1900). All experiments were performed by using 8-week-old mice weighing 35–40 g.

Measurement of Catalepsy

Catalepsy responses were measured using the suspended bar method. Mice were placed individually on a plastic board (25 × 35 cm) with a

Effects of Dopamine Receptor Agonists on Cataleptic Responses Induced by SCH23390 or Haroperidol

As shown in Fig. 1, pretreatment with SKF38393 (1.0–10 mg/kg IP) did not affect haloperidol (0.3 mg/kg) catalepsy, but inhibited SCH23390 (0.3 mg/kg) catalepsy in a U-shape fashion, the significant doses being at 1.0, 2.5, and 5.0 mg/kg (Fig. 1A).

Apomorphine (0.01–1.0 mg/kg IP) itself induced cataleptic responses and exhibited a small bell-shaped dose-response curve. Apomorphine at 0.01–0.1 mg/kg altered the haloperidol catalepsy response in a bell-shaped manner, at 0.25 and 0.5 mg/kg

Discussion

The results of this study suggest that SCH23390, haloperidol, physostigmine, and pilocarpine exert their cataleptogenic action via dopaminergic and cholinergic mechanisms, but none of them has the identical mechanism as the others.

Although D1 and D2 receptor antagonists exert synergistic effects between D1 and D2 receptor blockade [24], in this study, SCH23390 catalepsy was altered by SKF38393 in a U-shaped manner, whereas haloperidol catalepsy was not affected. SKF38393 may be a partial

Acknowledgements

This work was supported in part by a grant-in aid for scientific research (no. 06670964) from the Ministry of Education Sciences and Culture, Japan.

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Typical antipsychotics such as the dopamine D₂ receptor antagonist, haloperidol are known to cause movement disorders or catalepsy in experimental animals. Catalepsy is believed to result from blockade of dopamine D₂ receptors. In this study two drugs that differ in antipsychotic potency but are similar in blocking dopamine D₂ receptors were used to investigate the mechanism for catalepsy and its sensitization. Metoclopramide is a strong postsynaptic dopamine D₂ receptor blocker with no antipsychotic potency. At low doses of 5 or 10 mg/kg given subcutaneously (s.c.), metoclopramide did not produce catalepsy or movement disturbance for seven days after drug treatment. Also metoclopramide at 10 mg/kg given for five days, failed to induce catalepsy. Haloperidol, another potent dopamine D₂ receptor blocker at 0.5 mg/kg (s.c.) rapidly produced catalepsy and suppressed movement 1 h after a single dose of the drug. Chronic as well as acute treatment with metoclopramide caused sensitization of haloperidol-induced catalepsy. Neurochemical analyses revealed significant dopamine D₂ receptor up-regulation in both frontal cortex and striatum of rats chronically treated with metoclopramide. However, no changes in dopamine D₂ receptor numbers were noted in these areas after chronic treatment with low doses of haloperidol. Significant increases in N-Methyl-d-aspartate (NMDA) receptor numbers were observed in both frontal cortex and striatum of metoclopramide treated animals, while haloperidol elicited significant decreases in NMDA receptor numbers in both brain areas. These observations plus previous reports have led us to propose a model for catalepsy and its sensitization. According to this model the increase in NMDA receptors by metoclopramide sensitizes the brain to haloperidol-induced catalepsy. Thus, catalepsy appears to be elicited by simultaneous activation of glutamatergic NMDA and dopamine D₁ receptors as well as a blockade of dopamine D₂ receptors.
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ArticlesDopaminergic and Cholinergic Interaction in Cataleptic Responses in Mice

Abstract

Section snippets

Animals

Measurement of Catalepsy

Effects of Dopamine Receptor Agonists on Cataleptic Responses Induced by SCH23390 or Haroperidol

Discussion

Acknowledgements

Neuropharmacology

Brain Res.

Neuropharmacology

Prog. Neurobiol.

Life Sci.

Eur. J. Pharmacol.

Neuropharmacology

Neurosci. Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Articles
Dopaminergic and Cholinergic Interaction in Cataleptic Responses in Mice