The abuse and addictive power of psychomotor stimulants such as methamphetamine and cocaine continue to be a critical national concern. Much evidence has pointed to the interplay of dopaminergic and nondopaminergic mechanisms in the effects of these drugs; however, mechanistically-based medications are not yet available. Research is proposed along two lines to address this continuing lack of anti-stimulant therapeutics. The first, based on the use of the partial agonist buprenorphine for the management of opioid addiction, pertains to the analogous development of dopamine partial agonists for stimulant addiction. A goal of the present research is to examine the potential value of dopamine partial agonists by examining their anti-stimulant effects in monkeys. This will be done using a novel self-administration choice procedure: in this procedure, subjects learn to distribute their behavior on the basis of the relative reinforcing strengths of an i.v. solution that is available for self-injection and an alternative reinforcer (food). This procedure is especially designed to divorce the reinforcing strength of drugs from their other behavioral effects. Partial agonists at different subtypes of dopamine receptors will be studied for their ability to specifically counter the reinforcing strength of methamphetamine and cocaine. A second line of research is based on the need for a firm grasp of the role of nondopaminergic mechanisms in the behavioral effects of psychomotor stimulants, especially in primate species. In acute studies, psychomotor stimulants will be studied by analyzing the cholinergic and noradrenergic mechanisms that complement dopamine activity in preclinical assays of abuse liability, in chronic studies with different types of dopaminergic drugs, behavioral assays and in vitro autoradiography will be used to describe changes in monoamine transporter and receptor densities that may accompany alterations in pharmacological sensitivity. Overall, this program will strengthen our fundamental understanding of dopamine-mediated behavioral effects of methamphetamine and other psychomotor stimulant drugs. This research should point to novel directions for the development of medications with which to manage the abuse and addictive liabilities of psychomotor stimulant drugs
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