The onset of addiction to cocaine is more rapid in women than in men. Women begin using cocaine earlier, enter treatment at earlier ages, and are taking more cocaine at intake than men. Furthermore, cocaine cues induce more drug craving in female than male addicts. Basic research on the role of sex and ovarian hormones in the neurochemical and behavioral responses to acute and repeated exposure to cocaine is an important next step to enhance our understanding of the processes involved in gender differences in drug abuse. Experiments proposed will test the hypothesis that female rats are more susceptible to the behavioral effects of cocaine than are males because of organizational effects of gonadal hormones during development as well as activational effects of estrogen in adulthood. As a first step towards determining if there are organizational effects of gonadal hormones during prenatal development, we will look at whether there are sex differences in adulthood independent of circulating gonadal hormones in behavioral and neurochemical responses to cocaine. We will also investigate whether estrogen in adult females further enhances the induction and persistence of these measures. Finally, we will explore whether treatment can ameliorate these sex differences, experiments will test the hypothesis that progesterone can reverse the effect of estrogen on cocaine self-administration. There are 5 specific aims which address these hypotheses: 1) To determine if there are sex differences in or hormonal influences on the persistence of behavioral sensitization to cocaine. 2) To determine if in females, estrogen enhances behavioral sensitization by potentiating the cocaine-stimulated increase in dopamine in dialysate from the dorsal striatum and nucleus accumbens acutely and after sensitization to cocaine. 3) To determine the effect of sex and gonadal hormones on reinstatement of cocaine self-administration. 4) To determine the effect of sex and gonadal hormones on acquisition of cocaine self-administration and breaking point after prior sensitization to cocaine. 5) To determine if progesterone can reverse the effects of estrogen on cocaine self-administration.
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