THE INTERACTIONS OF TYPICAL AND ATYPICAL ANTIPSYCHOTICS WITH THE (-)2,5,-DIMETHOXY-4-METHAMPHETAMINE (DOM) DISCRIMINATIVE STIMULUS

The present study was designed to test the hypothesis that atypical, b ut not typical, antipsychotics produce a functional in vivo blockade o f 5-HT2A receptors. The magnitude of functional in vivo 5-HT2A recepto r blockade elicited by representative compounds from each of the six m ajor structural classes of typical antipsychotics, and the representat ive atypical antipsychotics clozapine and risperidone, was indicated b y their respective abilities to block the stimulus effects of the phen ylalkylamine hallucinogen (-)DOM in the rat. Chlorpromazine, thioridaz ine, fluphenazine, thiothixene and haloperidol did not produce a signi ficant antagonism of the (-)DOM stimulus. The benzoxapine, loxapine (6 0%), and the atypical dibenzodiazepine, clozapine (62%), partially blo cked and risperidone fully blocked (100%) the (-)DOM stimulus. None of these agents elicited significant levels of (-)DOM-appropriate respon ding when administered alone. These results indicate that the typical antipsychotics, with the exception of lozapine, fail to produce effect ive in vivo antagonism of 5-HT2A receptors at doses compatible with th e preservation of operant behavior. In contrast, the atypical antipsyc hotics clozapine and risperidone elicit effective in vivo antagonism o f 5-HT2A receptors without severe behavioral disruption. Thus, these d ata are supportive of the hypothesis that the mechanism of action of a typical, but not typical, antipsychotics involves the antagonism of 5- HT2A receptors in vivo.