Effects of perospirone (SM-9018), a potential atypical neuroleptic, on dopamine D1 receptor-mediated vacuous chewing movement in rats: a role of 5-HT2 receptor blocking activity.

We compared the acute and subacute effects of perospirone (SM-9018), a novel neuroleptic with potent 5-HT2 and D2 blocking actions, and of haloperidol (HAL) on dopamine D1 receptor-mediated vacuous chewing movement (VCM) in rats. A selective D1 agonist, SKF 38393 (SKF), markedly increased the incidence of VCM, which was blocked by SCH 23390 (a D1 antagonist) but not by sulpiride (a D2 antagonist). Perospirone and HAL inhibited the SKF-induced VCM in a dose-dependent manner. The potency of the inhibitory actions of perospirone was considerably weaker (about 30 times) than that of HAL despite their similar affinities for D1 receptors. Subacute treatment with perospirone for 2 weeks failed to affect the behavioral sensitivity of rats to SKF. However, the HAL treatment markedly enhanced the incidence of the SKF-induced VCM. On the other hand, the selective 5-HT2 antagonists ritanserin and ketanserin significantly reduced the inhibitory actions of HAL and SCH 23390 on the SKF-induced VCM. In addition, combined treatment of ritanserin with HAL for 2 weeks abolished the enhancement of SKF-induced VCM by HAL treatment. These findings suggest that perospirone is weaker than HAL in altering the behavioral sensitivity of D1 receptor-mediated VCM under repeated administration, which may be related to the 5-HT2 blocking activity of perospirone.

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

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 D1 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.

Evaluation of perospirone (SM-9018), a novel serotonin-2 and dopamine-2 receptor antagonist, and other antipsychotics in the conditioned fear stress-induced freezing behavior model in rats.

We studied the effects of perospirone (SM-9018), a novel serotonin-2 (5-HT2) and dopamine-2 (D2) receptor antagonist (SDA), on conditioned fear stress (CFS)-induced freezing behavior in rats and compared its actions with those of other antipsychotics. Exposure of rats to the environment previously paired with foot shock induced marked freezing behavior, which was reduced by the anxiolytic diazepam (0.1-3 mg/kg, p.o.) or antidepressants, desipramine and imipramine (10-100 mg/kg, p.o.). Perospirone at 0.3-3 mg/kg, p.o. significantly attenuated the CFS-induced freezing behavior in a dose-dependent manner, while the effect was reduced at the higher dose of 6 mg/kg. Other SDA-type antipsychotics, clozapine (1-30 mg/kg, p.o.) and risperidone (0.03-1 mg/kg, p.o.), and selective 5-HT2 antagonists, ritanserin (0.1-1 mg/kg, p.o.) and ketanserin (0.3-1 mg/kg, p.o.), all reduced the freezing behavior with U-shaped dose-response curves. However, neither conventional antipsychotic, haloperidol (0.1-3 mg/kg, p.o.), chlorpromazine (3-100 mg/kg, p.o.), thioridazine (3-100 mg/kg, p.o.), mosapramine (3-100 mg/kg, p.o.) nor tiapride (30-1000 mg/kg, p.o.) reduced the CFS-induced freezing behavior. In addition, subacute treatment of rats with perospirone (1-10 mg/kg/day) or imipramine (30 mg/kg/day) for 2 weeks prevented the induction of the freezing behavior by CFS. These findings suggest that SDA-type antipsychotics including perospirone are effective for the treatment of mood disturbances such as anxiety and depressive mood associated with schizophrenia and have a broader efficacy profile as compared with the conventional antipsychotics.