MODULATION OF METHYLENEDIOXYMETHAMPHETAMINE-INDUCED STRIATAL DOPAMINERELEASE BY THE INTERACTION BETWEEN SEROTONIN AND GAMMA-AMINOBUTYRIC-ACID IN THE SUBSTANTIA-NIGRA

The effects of the amphetamine analog, 3,4-methylenedioxymethamphetami ne (MDMA) were compared to the effects of d-amphetamine on the in vivo release of dopamine and tau-aminobutyric acid (GABA) in the striatum and substantia nigra. The brain region-dependent role of the 5-HT2 rec eptors in the striatum and substantia nigra in regulating MDMA-induced dopamine and GABA release also was studied. Changes in the extracellu lar concentration of dopamine, 5-HT and GABA were measured simultaneou sly in the awake rat by in vivo microdialysis. The increase in striata l dopamine produced by systemic administration of MDMA was attenuated by infusion of TTX into the striatum. Infusion of the 5-HT2A/2C antago nist ritanserin into the striatum or the ipsilateral substantia nigra also significantly attenuated MDMA-induced dopamine release in the str iatum. At the doses used in this study, MDMA but not d-amphetamine inc reased the extracellular concentrations of 5-HT and decreased GABA eff lux in the substantia nigra. The ability of MDMA to decrease nigral GA BA efflux also was blocked by the local infusion of ritanserin into ei ther the substantia nigra or the striatum. Overall, these data provide evidence that MDMA increases dopamine release partly through an impul se-mediated mechanism. Furthermore, this increase in striatal dopamine efflux produced by MDMA is regulated, in part, by 5-HT2A/2C receptors in the striatum and the substantia nigra and ultimately by GABAergic input into the substantia nigra.