The incidence of methamphetamine (METH) abuse has risen sharply over the past few years: hence, its neurochemical effects on central monoaminergic neurons warrant investigation. High-dose METH administration to rodents and primates results in short- and long-term deficits in monoaminergic systems. This laboratory reported recently the novel finding that METH administration causes a rapid and reversible decrease in dopamine transporter (DAT) function which is distinct from degeneration of dopamine terminals. Because DAT are essential for clearing dopamine from the extraneuronal environment, this rapid and reversible change in DAT may be a regulatory phenomenon of importance. Hence, the hypothesis will be tested that METH acutely and selectively alters the nature and function of DAT in a reversible manner by achieving the following Specific Aims: A. Assess the selectivity of the METH effect on DAT by: 1) confirming that this phenomenon is not due to dopamine neuronal degeneration; 2) comparing METH actions on DAT with effects on vesicular monoamine and glutamate transporters; and 3) assessing brain regional and species differences in the METH effect on DAT. B. Elucidate the nature of the reversible effect of METH on DAT by investigating whether: 1) METH treatment alters DAT protein structure; 2) dopamine D2 receptors modulate DAT function; 3) de novo protein synthesis is necessary for DAT recovery; and 4) antioxidants restore DAT activity after METH administration. C. Demonstrate functional consequences of METH-affected DAT by assessing the effect of METH-impaired DAT on dopamine reuptake in vivo, and subsequent uptake of METH in vitro. D. Evaluate whether the METH effect on DAT is selective to METH by assessing the response of DAT to: 1) agents that block dopamine reuptake (cocaine, nomifensine), or increase dopamine release (i.e., amphetamine, MDMA, MDE and fenfluramine); and 2) an agent which increases dopamine synthesis (L-dopa). Results of these studies will elucidate the importance of the rapid and reversible METH-induced decrease DAT activity. An understanding of this phenomenon has important implications regarding the mechanism of action of METH and other psychostimulants, as well as for the physiological regulation of dopaminergic systems. Such understanding could help develop better strategies for treating drug abuse and dopamine-related neurological and psychiatric disorders.
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