Prior experiments have shown that primates (rhesus monkeys and baboons) will work for intravenous infusions of racemic MDMA at rates greater than or equal to those produced to obtain cocaine infusions. However, the reinforcing effects of the optical isomers of MDMA have not been previously assessed. Drug discrimination experiments suggest that the complex discriminative stimulus profile of racemic MDMA is attributable to the primarily dopaminergic stimulus effects of (+)-MDMA and the primarily serotonergic stimulus effects of (-)-MDMA. These differential effects of the stereoisomers on neurotransmitter systems have been confirmed in pharmacological studies. The objective of the proposed experiments is to further elucidate the differences between the optical isomers of MDMA by assessing their reinforcing effects in terms of (1) response rate under a fixed ratio schedule and (2) break point under a progressive ratio schedule. Additionally, self-administration data for racemic MDMA will be replicated in the fixed ratio study, and extended by means of a break point analysis in the progressive ratio study. In accord with previous self-administration studies, these behavioral endpoints will be compared with those produced by cocaine and saline, as well as methamphetamine (a drug with a more similar time course to MDMA) and LSD (a drug with more similar neurochemical effects to MDMA). Finally, the relationship between the rewarding and serotonin depleting effects of MDMA will be assessed by pharmacologically challenging self- administration behavior with pre-treatments of various neuroprotective agents.
