Psychostimulant abuse is a considerable problem in society. Both cocaine and amphetamine are widely used, and the use of methamphetamine on the rise. These psychostimulant drugs produce their reinforcing effects via interactions with the dopamine transporter, cocaine by inhibiting dopamine uptake (the inward flow of dopamine into the neuron), and amphetamines by stimulating dopamine release via reversal of the transporter. These actions result in an increase in extracellular dopamine, which then interacts with dopamine receptors to increase dopaminergic transmission. In order to develop a treatment for the abuse of these substances, it is necessary to find a mechanism by which the activity of the dopamine transporter and dopamine receptors can be regulated. Repeated administration of a selective kappa-opioid agonist produces a down-regulation of the dopamine transporter, and of dopamine D: receptors, suggesting that the kappa-opioid regulation of dopamine neurotransmission might provide a mechanism by which to alter the effects of psychostimulants such as cocaine and amphetamine. The specific hypothesis of this proposal is that the dopamine transporter can be regulated via manipulations of kappa-opioid receptors, and that this will alter the neurochemical, and hence the behavioral effects of psychostimulant drugs such as cocaine and amphetamine. Specifically, the anatomical and pharmacological alterations in the dopamine transporter and dopamine receptors, as well as the associated behavioral changes, will be measured following chronic administration of kappa-opioid receptor agonists. We will measure receptor binding using in vitro autoradiography and homogenate binding. Dopamine transporter function will be measured using dopamine uptake and release assays, and dopamine receptor function will be evaluated using adenylyl cyclase and GTPgammaS binding assays. Behavior will be measured using locomotor activity studies. Understanding of the regulation of dopamine neurotransmission by kappa-opioid receptor agonists will provide leads to the development of a therapeutic agent for treating abuse of psychostimulant drugs. Altered dopamine receptor function has been implicated in numerous neurological disorders including schizophrenia, Parkinson's disease, Tourette's syndrome, and Huntington's chorea, in addition to psychostimulant drug abuse. Treatments for most of these syndromes involve use of agonists and antagonists at particular receptors, a state that often leads to marked side effects. Hence, the ability to regulate dopaminergic transmission via alterations of the dopamine transporter would be useful in the treatment of such syndromes.
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