This is a new application (R01) to examine the contribution of gonadal steroid hormones to the abuse related effects of cocaine in pre-clinical models. Several lines of evidence suggest that gonadal steroid hormones may be important modulators of cocaine's behavioral effects. High levels of estradiol at estrus appear to enhance cocaine's locomotor and reinforcing effects in rats. Gender differences in cocaine's behavioral and biologic effects appear to be mediated by gonadal steroid hormones in both clinical and preclinical studies. Behavioral studies are proposed to determine if gonadal steroid hormones share discriminative stimulus effects and reinforcing effects with cocaine, and if acute or chronic administration of gonadal steroid hormones alters cocaine self-administration and discrimination dose-effect curves. Endocrine studies have shown that intravenous cocaine administration stimulates rapid increases in estradiol and testosterone. Moreover, both estradiol and testosterone have mood enhancing effects in humans. We propose to evaluate the effects of acute or chronic administration of gonadal steroid hormones on cocaine self-administration and discrimination. In addition, we propose to examine the possible reinforcing and discriminative stimulus effects of these gonadal steroid hormones alone. Both males and females will be studied to determine if there are significant gender differences in behavioral responsivity to cocaine alone and after acute or chronic gonadal steroid treatments. Males and females will be studied in an own-control design across gonadal steroid treatment conditions, and before and after ovariectomy and castration. In normally cycling females, the influence of changing steroid hormone levels across the menstrual cycle will be examined. In ovariectomized females, systematic hormone replacement studies will be conducted to evaluate hormonal effects on cocaine's reinforcing and discriminative stimulus effects. Males will be trained under the same conditions and cocaine dose-effect curves will be determined at the same intervals to permit meaningful gender comparisons. The rapid increases in estradiol and testosterone after i.v. cocaine suggests that any concurrent behavioral effects may be mediated by non-genomic mechanisms. Accordingly, we propose to study the influence of both genomic and non-genomic effects of steroid hormones on cocaine self-administration and cocaine discrimination. Radioimmunoassay of steroid hormone levels will permit assessment of temporal relationships between hormone levels and cocaine-related behaviors. Data obtained will help to clarify the neurobiologic substrates of cocaine abuse and may have heuristic implications for the development of new strategies for treatment.
