Women comprise about one third of cocaine addicts. They start using cocaine earlier in life, are more sensitive to some cocaine effects and progress to dependence more rapidly. Rodents show some similarities to this pattern: cocaine elicits greater increases in cocaine-stimulated locomotion, females work harder for cocaine reinforcement and extracellular dopamine rises more than in male rats. Our preliminary findings suggest that developmental exposure to gonadal steroids contributes to sex differences in cocaine action. The purpose of this proposal is to investigate the basis for the organizational effect of gonadal steroids on forebrain dopamine systems and the behavioral response to psychomotor stimulants mediated by these systems. We will test the hypothesis that sex differences in cocaine effects reflect anatomical or functional differences in dopamine neurons established during ontogeny. To determine when steroid effects are exerted, male and female rats will be gonadectomized on postnatal day 2, prepubertally on day 25 or in adulthood, and cocaine-stimulated locomotion and electrically-stimulated dopamine overflow will be determined on postnatal day 70. To evaluate which steroid mediates these effects, rat pups will be treated with vehicle, testosterone or estrogen antagonist ICI82780 (females), an aromatase inhibitor or androgen antagonist flutamide (males) during the early postnatal window or during puberty and the same dependent measures will be assessed. Finally, to evaluate how organizational effects of steroids are manifested, the number of dopamine neurons, density of innervation, dopamine content and electrically-stimulated dopamine release in nucleus accumbens and caudate nucleus will be determined following the same treatments. These studies should provide insight into potential biologic mechanisms that influence gender differences in diseases related to dopamine neuronal function in humans including Parkinson's disease and psychostimulant addiction.
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