Determinants of transition states in MDMA self-administration

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DESCRIPTION (provided by applicant): Epidemiological reports show that (1)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") continues to be used by large fractions of young adults. Studies have further suggested that up to 40 percent of users become at least temporarily dependent on MDMA, experienced users abuse an array of other substances and may abuse MDMA several times per week or even daily. It is also known that some Ecstasy users exhibit lasting cognitive and mood alterations, even years after discontinuing Ecstasy use. Nevertheless, in comparison with structurally related drugs such as amphetamine and methamphetamine minimal animal research has been devoted to understanding the determinants of repeated MDMA self-administration. Initial work has shown that MDMA appears to be a weak reinforcer compared with other psychomotor stimulants, thus additional study of factors which create a transition to frequent or compulsive MDMA use is needed. The hypothesis that differences in the self administration of MDMA are related to the increased serotonergic agonist properties of MDMA is supported by prior observations that drugs which increase serotonergic tone may decrease self- administration of psychomotor stimulants. Such work will not only contribute to understanding the development of MDMA/Ecstasy abuse but may generalize to understanding factors which influence which of a minority of individuals exposed to other psychomotor stimulants will eventually transition to dependence. The proposed studies will use rat intravenous self-administration models to test factors which may underlie a transition from casual to compulsive Ecstasy use. The experiments will first examine methodological variables such as training dose, route of administration and duration of access session that have not been systematically addressed for MDMA self-administration. Additional studies will examine situational factors intended to model the human user milieu (such as high ambient temperature and hyperthermia, running wheel activity and exposure to a serotonin-depleting high dose regimen of MDMA) which may facilitate a transition to dependence. PUBLIC HEALTH RELEVANCE: Approximately 15-20 percent of young adults have used the recreational drug 3,4-methylenedioxy- methamphetamine (MDMA, known as "Ecstasy") and many of these users become dependent on Ecstasy while using; clinically significant symptoms of depression and anxiety, and poor cognitive performance can persist years after discontinuing Ecstasy use. Furthermore, in the US about 8,500 individuals per year have critical hyperthermia, seizure and other medical symptoms requiring emergency medical intervention after Ecstasy use. The proposed studies seek to determine situational and neurochemical factors which may increase use of this recreational drug and/or facilitate a transition from casual use to dependence.