EFFECTS OF THE SELECTIVE 5-HT2A RECEPTOR ANTAGONIST MDL-100,907 ON MDMA-INDUCED LOCOMOTOR STIMULATION IN RATS

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) releases dopamine and se rotonin in vivo and stimulates locomotor activity. Previous work demon strated that MDMA-stimulated dopamine release could be reduced by the selective 5-HT2A receptor antagonist -1-[2-(4-fluorophenylethyl)]-4-pi peridinemethanol] (MDL 100,907). In the present study MDL 100,907 sign ificantly reduced MDMA-stimulated locomotion without affecting basal l evels of locomotion. Other agents with 5-HT2A antagonist activity (rit anserin, clozapine, MDL 28,133A, or methiothepin), as well as agents t hat block 5-HT1A-(propranolol), D-2-(haloperidol), or D-1 receptors (S CH 23390) also reduced MDMA-stimulated locomotion. Intraventricularly administered 5,7-dihydroxytryptamine decreased regional 5-HT levels an d attenuated MDMA-stimulated locomotion. these data support the conclu sion that serotonin released onto 5-HT2A receptors contributes to MDMA -stimulated locomotion and suggest that MDMA-stimulated locomotion may be useful as an in vivo behavioral measure of 5-HT2A antagonism. The data also support previous reports of contributions of 5-HT1A, D-1 and D-2 receptors to MDMA-stimulated locomotion. A preliminary time-cours e analysis indicating time-dependent contributions of different recept ors to MDMA-stimulated locomotion suggest the potential utility of thi s model for characterizing potential atypical antipsychotic compounds.