Gender differences in response to psychostimulants have been reported both in animals and humans; however, the biological mechanisms which underlie these gender differences to psychostimulants remain for the most part, unexplained. The common observation is that females are more sensitive to psychostimulants, such as cocaine. Our hypothesis is: Activational as well as organizational effects of gonadal hormones on dopaminergic systems provide the underlying basis for the gender differences in behavioral sensitization produced by repeated IV cocaine administration. First, we will determine whether pharmacokinetic differences between the sexes result in higher levels of cocaine in the female brain. We have successfully developed a technically simple, economical and practical non-tethered technique for repeatedly administering cocaine IV to freely moving, group-housed, rats. Detailed pharmacokinetic analysis has demonstrated rapidly peaking cocaine levels following IV dosing in rats, which is similar to that observed in humans, as opposed to SC, PO, or IP dosing. Using this clinically relevant IV rodent dosing model, we will determine whether pharmacokinetic factors contribute to the increased sensitivity of female animals to the effects of cocaine. Second, we will determine whether gonadal hormones regulate the expression of gender differences in response to cocaine in adulthood. We will test the ability of gonadal hormones to modulate dopamine receptor responsiveness to chronic cocaine administration. Third, we will determine whether the brain organizational effect of the perinatal hormonal milieu mediates the gender differences in cocaine responsiveness. We have pharmacologically characterized a recently discovered unique dopamine receptor subtype (D3) which is localized to the striatum/nucleus accumbens region of the brain. We hypothesize that alterations in dopaminergic systems, in particular the D3 receptor system, underlie the gender differences produced by repeated IV cocaine administration. Our long-term goal is to determine the role of the dopamine neurochemical system (emphasizing the dopamine D3 receptors) in gender differences following repeated IV cocaine administration. The ultimate goal of this research is to develop pharmacological interventions to assist in correcting the behavioral problems associated with chronic cocaine abuse in humans, and specifically to provide potential insight into effective treatment strategies for women drug abusers.
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