Cocaine abuse and dependence remain a major health problem and social concern. In the last decade, the search for effective treatments for cocaine abuse has emphasized pharmacotherapeutic interventions. Despite the considerable progress toward an understanding of the neuropharmacological actions of cocaine and other psychostimulants, there remains no substantially effective pharmacotherapy for psychostimulant abuse. Recent investigations on potential candidates for pharmacotherapy have targeted pharmacological agents that have a preference for the dopamine D# receptor. The D3 receptor is highly concentrated in mesocorticoloimbic regions of the brain. Recent studies in laboratory animals have indicated that D3 receptors may be involved in the positive reinforcing effects of psychostimulants. D3- preferring agonists (e.g., 7-OH-DPAT) appear to enhance the reinforcing effects of cocaine while D3-preferring antagonists (e.g. (+)-AJ76, (+)-UH232 (-)-DS121) attenuate cocaine's reinforcing effects. D3-preferring agonists (7-OH-DPAT, (+)-PD128907) also exhibit stimulus generalization in rats trained to discriminate cocaine, although the D3-preferring antagonists do not substantially block the discriminative stimulus effects of cocaine or amphetamine. The primary goal of the proposed study is to utilize a more selective D3- preferring antagonists, U99194A, to investigate the role of D3 receptors in the discriminative stimulus effects of the psychostimulants, cocaine and amphetamine. U99194A will be tested for substitution, antagonism and potentiation in rats trained to discriminate cocaine or amphetamine from saline in a two-choice, water-reinforced drug discrimination procedure. In a separate experiment, rats will be trained to discriminate U99194A and stimulus generalization tests will be administered with several psychostimulants as well as with the D3-preferring antagonists (+)-UH232 and (-)- DS121. Finally, U99194A and the D2/D3 antagonist sulpiride will be tested in combination with (+)7OH-DPAT, (+)-PD128907 or U91356 in animals trained to discriminate cocaine or amphetamine, in an attempt to determine the importance of D2 vs D3 receptor modulation of the substitution of D3-preferring agonists for psychostimulants.
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