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Dopamine D2 Receptors in Primate Models of Cocaine Abuse

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This is an A1 submission of a competing renewal to continue research on the effects of novel dopamine D3 receptor compounds in rhesus monkey models of cocaine abuse. The D3 receptor is a subtype of the D2-like superfamily of receptors and because the relative expression of D3 receptors in the striatum is significantly less than that for D2 receptors, it has been hypothesize that preferential blockade of D3 receptors may lead to selective antagonism of the reinforcing and discriminative stimulus effects of cocaine without producing motor side- effects. Specific Aim 1 will utilize several animal models to evaluate the in vivo agonist efficacy of D3 compounds and to determine the potency, efficacy and time course of behavioral effects. With this information, compounds will be evaluated in drug discrimination and drug self- administration models of cocaine (Specific Aim 2) and methamphetamine (MA) (Specific Aim 3) abuse. We hypothesize that partial agonists with the highest D3 affinity will show agonist-like effects on unconditioned behaviors such as drug-induced yawning and locomotor activity. We also hypothesize that full agonists and D3 partial agonists will substitute for the partial agonist CJB 090 in drug discrimination studies, while D3 antagonists will not substitute. In models of drug abuse, we hypothesize that D3-selective partial agonists and antagonists will attenuate the discriminative stimulus effects of cocaine and MA, with an order of potency directly related to their selectivity at D3 vs. D2 receptors. In self-administration studies using a concurrent food- drug schedule, we hypothesize that D3 compounds will decrease drug choice (both cocaine and methamphetamine) and shift preference to food reinforcement, while non-selective D2-like compounds will decrease overall behavior. Finally, we hypothesize that D3-selective compounds will be effective at attenuating cocaine- and MA-induced reinstatement under the concurrent schedule. These studies should add valuable information about in vivo pharmacology related to D3 compounds, as well as how these drugs affect multiple behavioral endpoints related to cocaine and MA abuse. Such knowledge will aid in the development of effective pharmacotherapies for stimulant abuse. PUBLIC HEALTH RELEVANCE: The dopamine D3 receptor has been identified as a novel and important target for pharmacotherapies combating drug addiction. These studies will utilize several compounds with some of the greatest selectivity for this receptor subtype in an effort to better understand how dopamine D3 receptors mediate the high abuse liability of cocaine and methamphetamine using nonhuman primate models.

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