Reinforcing effects of certain serotonin-releasing amphetamine derivatives

The present study was designed to characterize further the rewarding and aversive properties of 3,4-methylenedioxymethamphetamine (MDMA), the alpha-ethyl homologue of MDMA (MBDB), fenfluramine, and the selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan (MMAI) using the conditioned place preference paradigm (CPP). Extracellular dopamine (DA) and its metabolite DOPAC were also measured in the nucleus accumbens after systemic drug administration, using in vivo microdialysis in freely moving rats. MDMA produced a positive dose-dependent effect in the CPP test, which was maximal at doses of 5 and 10 mg/kg. MBDB also induced a positive CPP, with a maximum effect at 10 mg/kg. The conditioning effect of MBDB was more than 2.5-fold weaker compared with MDMA. Fenfluramine evoked place aversion at doses of 4, 6, and 10 mg/kg. This effect of fenfluramine was independent of dose. MMAI at doses of 1.25, 2.5, and 5 mg/kg produced no significant effect on place conditioning. At doses of 10 and 20 mg/kg, MMAI produced an effect similar to fenfluramine: Place aversion was independent of dose. In the microdialysis experiments, MDMA significantly elevated extracellular DA and induced a decrease of DOPAC in the nucleus accumbens. Thus, activation of dopaminergic systems may be responsible for the rewarding properties of MDMA-like drugs. In contrast to the effects seen with MDMA, no difference in extracellular DA or DOPAC was seen after injection of MBDB, fenfluramine, or MMAI, even though MBDB weakly induced a place preference. The mechanism responsible for the development of place aversion by fenfluramine or MMAI is unknown at this time and requires further study.