Because of recent dramatic increases in the use of amphetamine (AMPH) analogs such as methylenedioxymethamphetamine (MDMA; Ecstasy), it is important that effects of these agents be elucidated. High-dose administrations of such phenylethylamines cause persistent changes in monoaminergic neuronal function, but with varying expressions. For example, multiple injections of AMPH or methamphetamine (METH), but not MDMA, cause dopamine (DA) deficits persisting even years after drug treatment while similar treatments with METH and MDMA, but not AMPH, have persistent effects on 5-hydroxytryptamine (5HT; serotonin) systems. Distinct from these neurotoxic consequences, we reported recently that multiple high-dose injections of these agents also cause a rapid and at least partially reversible decrease in DA transporter (DAT) activity (referred to throughout this proposal as Acute Transporter Response; ATR) that appears unrelated to an acute loss of DAT protein and is mediated by unidentified mechanisms. Since DAT is a principal regulator of intra- and extra-neuronal DA concentrations, we believe that such rapid ATRs may represent important regulatory phenomena and that differences in ATRs effected by METH, AMPH and MDMA administration may contribute to the unique properties of these agents. To better understand both the regulation of DAT and the long-term significance of the ATR induced by these agents, we will test the hypothesis that: the DAT-related ATRs induced by phenylethylamines are associated with the long-term DA consequences of administering these agents. This will be accomplished by completing the following Specific Aims: Identify the features of the DAT-associated ATR related to phenylethylamine treatment by elucidating its dose, temporal and regional profile, as well as its functional significance. Determine the relationship of the components of the DAT-associated ATR to each other and the persistent DA deficits (or lack thereof) caused by phenylethylamine administration. Determine the uniqueness of the DAT-related ATR by identifying the features of the vesicular monoamine and 5HT transporter-associated ATRs and examining their association with the persistent monoaminergic deficits (or lack thereof) caused by phenylethylamine administration. These studies will determine if an association exists between the acute responses to the AMPH analogs and their neurotoxic properties. In addition, they will elucidate factors that regulate DAT and other related transporter systems. Finally, these studies may provide insight into mechanisms associated with DA-related neurological and psychiatric disorders such as Parkinson's disease and psychosis, respectively.
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