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 nicotine. Our hypothesis is: Gonadal hormones in adulthood and development act on dopaminergic systems, providing the underlying basis for the gender differences in behavioral sensitization produced by repeated IV nicotine administration. First, we will determine whether pharmacokinetic differences between the sexes result in higher levels of nicotine in the female brain. We have successfully developed a technically simple, economical and practical non-tethered technique for repeatedly administering IV nicotine to freely moving, group-housed rats. Detailed pharmacokinetic analysis has demonstrated rapidly peaking nicotine levels following IV dosing in rats, which is similar to that observed in humans, as opposed to SC or PO 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 nicotine. Second, we will determine whether gonadal hormones regulate the expression of gender differences in response to nicotine in adulthood. We will test the ability of gonadal hormones to modulate dopamine receptor responsiveness to chronic nicotine administration. Third, we will determine whether the brain organizational (neurodevelopmental) effect of the perinatal hormonal milieu mediates the gender differences in nicotine 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 underlie the gender differences produced by repeated IV nicotine administration. Our long-term goal is to determine the role of the dopamine neurochemical system in gender differences following repeated IV nicotine administration. The ultimate goal of this research is to develop pharmacological interventions to assist in correcting the behavioral problems associated with chronic tobacco use in humans, and specifically to provide potential insight into effective gender-specific treatment strategies for smoking cessation.