Inverse Agonist Activity of Atypical Antipsychotic Drugs at Human 5-Hydroxytryptamine2C Receptors1

Abstract

Clozapine is the prototype atypical antipsychotic drug, producing little or no extrapyramidal side effects, while improving negative symptoms of psychosis. Clozapine's high affinity for serotonin receptors has been hypothesized to confer the unique antipsychotic properties of this drug. Recently, we demonstrated that both typical and atypical antipsychotic drugs are inverse agonists at constitutively active 5-hydroxytryptamine2A (5-HT_2A) receptors. To determine whether inverse agonist activity at 5-HT_2Creceptors plays a role in antipsychotic efficacy, typical and atypical antipsychotic drugs were tested for inhibition of basal inositol phosphate production in mammalian cells expressing rat or human 5-HT_2C receptors. Atypical antipsychotic drugs (sertindole, clozapine, olanzapine, ziprasidone, risperidone, zotepine, tiospirone, fluperlapine, tenilapine) displayed potent inverse agonist activity at rat and human 5-HT_2C receptors. Typical antipsychotic drugs (chlorpromazine, loxapine, thioridazine, prochlorperazine, perphenazine, mesoridazine, trifluperidol, fluphenazine, spiperone, haloperidol, pimozide, penfluridol, thiothixene) were devoid of inverse agonist activity, with the exception of loxapine. We review the evidence that loxapine has unique properties characteristic of both atypical and typical antipsychotic drugs. Several typical antipsychotic drugs (chlorpromazine, thioridazine, spiperone, thiothixene) displayed neutral antagonist activity by reversing clozapine inverse agonism. These data suggest that 5-HT_2C inverse agonist activity is associated with atypical antipsychotic drugs with moderate to high affinity for 5-HT_2C receptors, and imply that effects of atypical antipsychotic drugs on the 5-HT_2C receptor may play a role in their unique clinical properties. These data also imply that dysfunction of brain 5-HT_2C receptor systems may be one of the factors involved in the etiology of psychosis.