Short and long-term effects of MDMA exposure in rodents : physiological, behavioral and neurochemical responses

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Reveron, Maria Elena, 1970-

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3,4-methylenedioxymethamphetamine (MDMA) is a popular abused amphetamine among young adults. The possibility that MDMA intake may be neurotoxic in humans led to a wealth of studies that demonstrated large doses of MDMA cause damage to serononin (5-HT) nerve terminals in rats and non-human primates. However, to date, the exact mechanism of MDMA-induced neurotoxicity in animals is unknown. In the first data set of this dissertation, neurochemical and thermal changes associated with experimenter-delivered repetitive doses of MDMA in mice of two different age groups were investigated. Confirming previous findings with mice, repetitive MDMA administration affected dopamine (DA) system markers. Findings revealed, significant decreases in vesicular monoamine transporter2 (VMAT2) protein and significant increases in rectal temperature in older mice compared to younger counterparts. The data suggest older mice are more sensitive to the toxic effects of MDMA and that hyperthermia might contribute to MDMA neurotoxicity. Few studies have examined MDMA effects using drug self-administration procedures. Therefore, the remaining portion of the dissertation involved a series of studies investigating behavioral and biological changes occurring as the result of shortand long-term MDMA self-administration. MDMA-stimulated lever responses, locomotor activity, thermal effects, in vivo changes in nucleus accumbens (NAcc) DA and 5-HT levels and post-mortem tissue content of DA, and 5-HT were determined after various periods of MDMA abstinence in MDMA-naïve animals, and those selfadministering over 20 daily sessions. In general, experience-dependent changes in MDMA were observed in all assessed measurements. For instance, MDMA-stimulated locomotor activation increased with experience, initial hypothermia induced by MDMA progressively reversed over time, proportional changes in NAcc DA and 5-HT were altered with experience, and depleted tissue levels of 5-HT recovered after MDMA abstinence. An additional study revealed that many of these experience-dependent changes might be mediated through actions at the 5-HT2c receptor. For instance, in animals with a single MDMA experience, the 5-HT2c antagonist SB242084 enhanced MDMA-induced NAcc DA levels and locomotor activity in a manner similar to that observed only in the long-term MDMA experienced rats. In conclusion, these results suggest MDMA intake induces physiological, neurochemical and behavioral responses that change with increased MDMA drug experience.



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