The reinforcing and other behavioral effects of psychomotor stimulants including cocaine and amphetamine involve actions at D1 and D2 brain dopamine receptors. Information about the behavioral effects of agonists and antagonists that act selectively at different subtypes of dopamine receptors is fundamental to understanding the roles of these receptors in the effects of abused drugs. Recent studies have shown that the effects of dopaminergic drugs differ importantly in primate and nonprimate species and that the effects of direct D1 and D2 agonists can be related to the reinforcing and other behavioral effects of psychomotor stimulants in monkeys. We propose to continue our ongoing research in studies involving schedule-controlled performance, drug self-administration, drug discrimination, and unconditioned behavior. In additional studies, we will determine how the effects of full agonists are modified by different types of parallel agonists. The results of these studies will provide fundamental information regarding the pharmacological specificity and quantitative nature of agonist actions at the different types of dopamine receptors and allow us to assess the relative contribution of different dopamine receptor mechanisms in the reinforcing and other behavioral effects of psychomotor stimulants. We also propose to initiate in vivo micro dialysis experiments in conjunction with our-behavioral studies of abuse-related effects of psychomotor stimulants. The combination of these on-line neurochemical sampling techniques and behavioral procedures will enable us to evaluate changes in brain dopamine that are associated with behavior leading to drug self-administration as well as neurochemical effects produced by the self-administered drug. Finally, we will study the effect of chronic administration of D1 and D2 full agonists. Chronic use is a cardinal feature of drug abuse. Our studies to determine how chronic administration alters the effects of dopaminergic agonists differing in receptor selectivity and efficacy will provide information essential for understanding how chronic use of psychomotor stimulants may alter different dopamine brain mechanisms.
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