This application is in response to a program announcement from NIDA to investigate """"""""Club Drugs."""""""" The substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA; """"""""ecstasy"""""""") is chemically similar to methamphetamine and is one of the """"""""club drugs"""""""" currently popular in youth culture. As recently as December 1999, the National Institute on Drug Abuse issued a Community Drug Alert Bulletin warning of the alarming increase and danger of """"""""club drugs,"""""""" in particular MDMA. The intoxication elicited by MDMA combines the classical stimulant properties of amphetamine with mild psychedelic effects. Serotonin (5-hydroxytryptamine; 5HT) neurotransmission appears to make a unique contribution to the unusual behavioral profile of MDMA. Important roles for 5HT-1B, -2A and -2C receptors are supported by preliminary data and published studies with non-selective 5-HT antagonists. In addition, the dense 5-HT innervation and regional localization of 5-HT-1B, 2A and 2C receptors in mesocorticoaccumbens and nigrostriatal dopamine (DA) circuits which mediate the behavioral effects of psychostimulants suggest these circuits as sites of action for the neuropsychopharmacological effects of MDMA. The present series of experiments are planned to systematically test hypotheses concerning the role of specific 5-HT receptor subtypes in mediating the hypermotive and discriminative stimulus effects of MDMA. To this end, the role of 5-HT-1B, -2A and -2C in the acute locomotor stimulant effects of (+)-MDMA will be investigated using novel, selective receptor antagonists. The site of action for brain 5-HT-1B, -2A and 2C within mesocorticoaccumbens and/or nigrostriatal circuits to control spontaneous and (+)-MDMA-evoked behaviors will be explored using highly localized microinfusions of the selective 5-HT antagonists and antisense oligonucleotides directed against specific 5-HT receptors. The ability of 5-HT-1B, -2A and -2C antagonists to block or enhance the development and/or expression of sensitization to (+)-MDMA will be analyzed. Modifications in abundance of 5-HT-1B, -2A, and -2C receptors will also be established via levels of receptor mRNA and protein expression as well as behaviors induced by selective 5-HT receptor agonists at 3, 7, 14 and 28 days of withdrawal from chronic (+)-MDMA. The generality of observations to a model of the human subjective effects of (+)-MDMA will be assessed in drug discrimination assays in rats. Thus, the role of 5-HT-1B, -2A, and -2C receptors in the discriminative stimulus effects of (+)-MDMA will be investigated using novel, selective receptor antagonists administered both systemically and intracranially. The experiments outlined will further elucidate the unique roles that each receptor plays in modulating the in vivo effects of MDMA and how these receptors may control the MDMA-stimulated output of the mesocorticoaccumbens and nigrostriatal circuitry. These data will lend understanding not only to the actions of the abused drug MDMA and approaches to pharmacotherapy for MDMA dependence, but also to the potential involvement of 5-HT receptors in disorders characterized by DA dysfunction and/or the imbalance between 5-HT and DA systems, such as schizophrenia, depression and anxiety.
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