Potential role of 5-HT2 and D2 receptor interaction in the atypical antipsychotic action of the novel succimide derivative, perospirone

Ohno, Y.; Ishida-Tokuda, K.; Ishibashi, T.; Sakamoto, H.; Tagashira, R.; Horisawa, T.; Yabuuti, K.; Matsumoto, K.; Kawabe, A.; Nakamura, M.

Polish Journal of Pharmacology 49(4): 213-219

1997


ISSN/ISBN: 1230-6002
PMID: 9437764
Document Number: 1134
The pharmacological profile of the novel serotonin-dopamine antagonists (SDA)-type antipsychotic, perospirone, was compared with other SDA and typical antipsychotics, and a potential role of 5-HT2 and D2 receptor interaction in the atypical antipsychotic property of SDA was discussed based on the findings with selective 5-HT2 antagonists. Our study revealed that perospirone, like other SDA, differed from the typical antipsychotics by exhibiting 1) putative anxiolytic and/or antidepressant actions in some animal models (e.g., conditioned fear stress-induced freezing model and rat social interaction), 2) reduced extrapyramidal side effects (EPS) liability (catalepsy and bradykinesia induction), 3) weaker blocking actions at striatal D2 receptors as revealed by c-fos expression and dopamine turnover and 4) lower propensity to induce supersensitivity of dopamine receptors after repeated treatments (e.g., dopamine agonist-induced stereotyped behavior and vacuous chewing movement). The 5-HT2 antagonists mimicked the action of SDA antipsychotics in the animal models of mood disorder. In addition, combined treatments of 5-HT2 antagonists with typical antipsychotic could attenuate EPS induction and striatal c-fos expression associated with D2 receptor blockade, and could prevent the sensitization of DI receptor function after repeated treatments. These findings suggest that the blockage of 5-HT2 receptors contributes to the broad efficacy profile of SDA (i.e., antipsychotic and mood stabilizing actions) and may counteract the D2 (and/or D1) blocking activities of antipsychotics in the striatum to reduce EPS.

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Potential role of 5-HT2 and D2 receptor interaction in the atypical antipsychotic action of the novel succimide derivative, perospirone