It has been estimated that greater than 1% of the population of the U.S. is addicted to cocaine or other psychostimulants, exacting a heavy toll on society. An understanding of the cellular and molecular substrates of addiction could lead to new approaches in the treatment of drug abuse. The reinforcing properties of cocaine and other psychostimulants are mediated through interactions with the dopamine transporter (DAT), a membrane protein that rapidly recaptures released dopamine (DA), thereby controlling synaptic DA levels. Almost nothing is known about the regulation of the DAT. Recent analysis of human DAT expression demonstrates the importance of comparing multiple measures in order to understand net DAT function. In the proposed experiments, DAT gene transcription rate, DAT mRNA and protein abundance and localization, and DAT functional activity within the cell bodies and nerve terminals of rat mesolimbic and nigrostriatal DA neurons will be studied. The effects of treatment with cocaine and other drugs, which interact with the DAT, will be determined. Preliminary data suggest that distinct changes will be seen in these different DA systems. The role(s) of DA receptors and of afferent innervations in mediating psychostimulant effects of DAT expression will be elucidated by a combination of systemic and local drug injections and discrete brain lesions. In summary, the proposed experiments will utilize multiple measures of DAT expression to elucidate the effects of drugs of abuse on DAT function and the potential role of the DAT in addictive disorders.
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