FURTHER-STUDIES ON N-METHYL-1(3, 4-METHYLENEDIOXYPHENYL)-2-AMINOPROPANE AS A DISCRIMINATIVE STIMULUS - ANTAGONISM BY 5-HYDROXYTRYPTAMINE3 ANTAGONISTS

Using a standard two-lever operant paradigm, male Sprague-Dawley rats were trained to discriminate 1.5 mg/kg N-methyl-1(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) from saline using a variable-interval 15-s schedule of reinforcement for food reward. Tests of stimulus antagonism were conducted to further define the mechanism of action of MDMA as a discriminative stimulus. Low doses of the 5-hydroxytryptamine(1A) (5-HT1A) antagonist NAN-190, the 5-HT2 antagonist pirenperone, and the dopamine antagonist haloperidol were able to somewhat attenuate the MDMA stimulus; however, none of these agents decreased MDMA-appropriate responding to less than 46%. The 5-HT3 antagonists zacopride and LY 278584 (ID50 = 0.02 mug/kg) antagonized the MDMA discriminative stimulus. Zacopride also attenuated the stimulus effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in DOM-trained animals but not those of (+)amphetamine in (+)amphetamine-trained animals. Several possible mechanistic interpretations are provided but it is concluded that MDMA produces its stimulus effects via a complex mechanism involving both dopaminergic and serotonergic components.