Cocaine, as other indirect sympathomimetics, has reinforcing properties in animals and man. Cocaine is intravenously self- administered by rats, and this model has been used to explore the neural substrates for cocaine reward. Previous work has shown that the forebrain projections of the mesocorticolimbic dopamine (DA) system are critical for cocaine self-administration. Rats will self-administer cocaine directly into the region of the frontal cortex and large 6-hydroxydopamine lesions of the region of the nucleus accumbens and frontal cortex will disrupt intravenous cocaine self-administration. The purpose of this proposal is to characterize further the neural substrates of cocaine reward by examining which DA subsystems are critical for maintaining the reinforcing value of cocaine, by examining the nature of the efferent projections important for processing this reinforcing stimulus, and by comparing the substrates necessary for cocaine reward to those necessary for methamphetamine reward. Rats will be trained to intravenously self-administer cocaine or methamphetamine and treatment effects will be evaluated using a progressive ratio and a discrete trials choice procedure. Studies will involve examining the effects of multiple discrete 6- hydroxydopamine lesions of the terminal projections of the mesocorticolimbic DA systems on intravenous cocaine self- administration. Behavioral measures will be correlated with discrete regional biochemical measures of catecholamine depletion using the regional punch technique. Lesions of the efferent projections of the neurons receiving the terminals of the mesocorticolimbic DA system with the cell body specific neurotoxin, ibotenic acid, will be used to characterize the efferent pathways important for processing the reinforcing stimulus. Those treatments shown to disrupt cocaine self- administration will be tested in rats self-administering methamphetamine. The proposed studies should provide important information for our understanding of the neural substrates for psychomotor stimulant reward but also important basic information about the organization of the neural substrates of reward in general.
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