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, but not typical, antipsychotics produce a functional in vivo blockade of 5-HT_2A receptors. The magnitude of functional in vivo 5-HT_2A receptor blockade elicited by representative compounds from each of the six major structural classes of typical antipsychotics, and the representative atypical antipsychotics clozapine and risperidone, was indicated by their respective abilities to block the stimulus effects of the phenylalkylamine hallucinogen (-)DOM in the rat. Chlorpromazine, thioridazine, fluphenazine, thiothixene and haloperidol did not produce a significant antagonism of the (-)DOM stimulus. The benzoxapine, loxapine (60%), and the atypical dibenzodiazepine, clozapine (62%), partially blocked and risperidone fully blocked (100%) the (-)DOM stimulus. None of these agents elicited significant levels of (-)DOM-appropriate responding when administered alone. These results indicate that the typical antipsychotics, with the exception of lozapine, fail to produce effective in vivo antagonism of 5-HT_2A receptors at doses compatible with the preservation of operant behavior. In contrast, the atypical antipsychotics clozapine and risperidone elicit effective in vivo antagonism of 5-HT_2A receptors without severe behavioral disruption. Thus, these data are supportive of the hypothesis that the mechanism of action of atypical, but not typical, antipsychotics involves the antagonism of 5-HT_2A receptors in vivo.