Methylenedioxymethamphetamine (MDMA) is a drug of abuse that was proposed for use as an adjunct to psychotherapy. Such potential therapeutic benefic was abandoned when the drug was found to have neurotoxic, serotonin-depleting actions. Nevertheless, MDMA is still widely used and abused. Although MDMA-induced toxicity has been an area of considerable research, the long-term effects of MDMA on neuropsychological function remain unknown. Results in animals suggest alterations of function in brain areas thought to subserve cognition, but little alteration in neurobehavioral function has been demonstrated. Sophisticated cognitive testing is critical to examine neuropsychological function in animals that have received repeated administration MDMA under conditions known to cause serotonergic depletion. Testing in non-human primates will allow evaluation of the complex cognitive functions, not testable in rodents, which may be most sensitive to the MDMA-induced neurotoxicity, and allows for data collection both pre- and post-treatment, not possible in drug abusing humans. In addition, monkeys are more sensitive than rodents to the neurotoxic effects of MDMA and metabolize the amphetamines, like MDMA, via the same pathways as humans, whereas rodents metabolize these drugs via an alternate pathway. The purpose of this proposal is to study the neuropsychopharmacological effects of MDMA in rhesus monkeys using a computerized test battery. The hypothesis to be tested is that repeated MDMA administration produces neurochemical changes that have cognitive behavioral correlates. Rhesus monkeys can be trained on the identical neuropsychological tasks as humans using a touch-sensitive computerized apparatus. The test battery includes probes of memory (delayed non-matching to sample, spatial working memory), attention (intradimensional/extra-dimensional shift task) and motor performance, as well as an estimate of relative reinforcement efficacy (progressive-ratio) and reaction-time. These tasks were chosen because they represent psychological processes which are associated with distinct neurological substrates. Drug challenges will be combined with behavioral testing to reveal changes in brain neurochemistry not observable under basal conditions. Further, the ability of MDMA to function as a reinforcer will be examined after repeated administration. Alterations in serotonergic function following repeated MDMA administration may contribute to changes in the potency and efficacy of MDMA, as well as other drugs of abuse, such as cocaine and methamphetamine, to act as reinforcers. These studies will not only provide critical information about the neurotoxic potential of MDMA on a functional level, but the ability of MDMA to selectively destroy certain serotonergic pathways makes it a useful tool to study the role of serotonin in cognitive function and stimulant drug abuse.
