MDMA remains a .widespread drug of abuse worldwide, and may be peaking in recreational popularity. In recent years, use of MDMA has dramatically increased, perhaps due to the widespread perception that MDMA is "safer" than other drugs of abuse, such as cocaine and amphetamine. Despite the widespread recreational use of this drug, the reinforcing and neurochemical effects of MDMA have not been extensively characterized in laboratory animals, and the possibility that MDMA may produce enduring behavioral and neurochemical changes in rhesus monkeys as a consequence of chronic exposure in a self-administration paradigm has not been systematically investigated. The current body of evidence suggests that repeated, non-contingent, large doses of MDMA have the capacity to induce substantial decrements in various serotonergic markers in the primate, but the behavioral correlates of such changes are much more subtle and less well-described. The studies outlined in this proposal will utilize drug-naive rhesus monkeys to characterize the effects of acute MDMA on extracellular striatal monoamine concentrations via in vivo microdialysis in awake monkeys and compare them to those of the structurally similar psychostimulant amphetamine, correlate rates of acquisition and stability of MDMA self-administration with various pre-drug measures of monoamine function (ascertained via in vivo microdialysis, PET neuroimaging, and radioimmunoassay), track stability of MDMA-maintained responding over .an extended duration and assess the pharmacological specificity of observed behavioral decrements, and ascertain longitudinal changes in binding potential at dopamine and serotonin transporters associated with chronic MDMA self-administration via PET neuroimaging. Enduring changes in monoamine neurochemistry and hormonal responsiveness to serotonergic challenge associated with long-term MDMA self-administration will also be assessed via in vivo microdialysis and radioimmunoassay. Allowing animals to regulate their own drug intakes thus eliminates the need to rely on controversial models of allometric interspecies dose scaling and has previously resulted in MDMA intakes quite similar to those estimated in human users. Thus, these studies are likely to be more relevant to the potential human condition of MDMA-induced lasting neurochemical alterations and behavioral changes

R21DA020645

2006-04-01

2008-03-31