The objective of the proposed research is to anatomically localize the dopamine receptor subtypes involved in the rewarding and stimulant effects of cocaine in rats. The rewarding effects of cocaine will be assessed using the conditioned place preference paradigm. Animals will be injected with cocaine and placed into a distinctive environment, and on alternate days they will be injected with saline and placed into a different environment. Following these drug-environment pairings, the rewarding properties of cocaine will be evident as an increase in the amount of time animals spend in the drug-paired environment relative to the saline-paired environment when given free-access to both simultaneously. The stimulant properties of cocaine will be assessed by measuring locomotor activity and stereotypy following acute and repeated administrations of cocaine. It is expected that the stimulant properties of cocaine will be enhanced by repeated administration of the drug. Subsequent behavioral tests will examine whether this sensitization response is due to conditioned or unconditioned factors. The first experiment will establish dose-response curves for the effects of cocaine on reward and psychomotor stimulation. The next series of experiments will assess the role of dopamine receptor subtypes in mediating these responses by pretreating the animals with selective D1, D2, D1 and D2, or atypical dopamine antagonists prior to cocaine administration. The last series of experiments will assess the role of dopamine receptor subtypes in specific regions of the mesocorticolimbic system by directly injecting the antagonists into either the ventral tegmental area, nucleus accumbens, or medial prefrontal cortex prior to systemic administration of cocaine. These experiments will help to elucidate the mechanisms of cocaine reward, and will provide crucial information for developing pharmacologic treatment strategies for cocaine abuse.
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