The effects of antipsychotics with 5-HT2C receptor affinity in behavioral assays selective for 5-HT2C receptor antagonist properties of compounds

Many antipsychotics have marked antagonist effects at 5-hydroxytryptamine ( 5-HT2C) receptors in vitro, which, however, have been difficult to show in behavioral assays. Here, we used two assays - hypolocomotion and hypophagia induced by the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) - to try to characterize the 5-HT2C receptor antagonist properties of anti psychotics in vivo. Clozapine, olanzapine, pipamperone, and trans-5-chloro- 2-methyl-2,3,3a,12 b-tetrahydro-1H-dibenz-[2,3:6,7]oxepino[4,5-C] pyrrolidi no maleate (ORG 5222), modestly, but significantly, attenuated mCPP (10 mg/ kg)-induced hypolocomotion. In contrast, risperidone and loxapine were inac tive. The putative antipsychotic ORG 5222 significantly attenuated mCPP (5 mg/kg)-induced hypophagia, whereas the other antipsychotics were inactive. Selective antagonists at dopamine D-2-like receptors, alpha(1)-adrenoceptor s, alpha(2)-adrenoceptors, or muscarinic receptors were not able to antagon ize the effects of mCPP in either assay. The results suggest that mCPP-indu ced hypolocomotion can be used to characterize the 5-HT2C receptor antagoni st properties of antipsychotics, whereas mCPP-induced hypophagia appeared t o be sensitive only to compounds highly selective for 5-HT2C receptors. Tog ether, these assays may help to characterize functional, in vivo, 5-HT2C re ceptor antagonist properties of antipsychotics. (C) 2000 Elsevier Science B .V. All rights reserved.