Cocaine Abuse and the Role of Gonadal Steroid Hormones

描述（由申请人提供）：这是一个新的应用程序（R 01）进行审查 性腺类固醇激素对滥用相关影响的贡献 可卡因在临床前模型中。几条证据表明，性腺 类固醇激素可能是可卡因行为效应的重要调节剂。 发情期高水平的雌二醇似乎可以增强可卡因的运动能力， 对老鼠的强化作用可卡因的行为和行为的性别差异 生物效应似乎是由性腺类固醇激素介导的， 临床和临床前研究。行为研究被建议用来确定 如果性腺类固醇激素具有区别性刺激效应， 加强可卡因的作用，如果急性或慢性给药 性腺类固醇激素改变可卡因自我给药和辨别 量效曲线内分泌研究表明静脉注射可卡因 给药刺激雌二醇和睾酮的快速增加。 此外，雌二醇和睾酮都有情绪增强作用， 人类我们建议评估急性或慢性给药的影响 对可卡因自我管理和歧视的性腺类固醇激素。 此外，我们建议研究可能的强化和歧视 这些性腺类固醇激素单独的刺激作用。 将对雄性和雌性进行研究，以确定是否存在显著性差异。 对可卡因单独和急性给药后行为反应的性别差异 或慢性性腺类固醇治疗。男性和女性将在一个 跨性腺类固醇治疗条件的自身对照设计，以及之前和 在卵巢切除术和阉割后在正常骑自行车的女性中， 将检查整个月经周期中类固醇激素水平的变化。在 卵巢切除的女性，将进行系统的激素替代研究， 进行评估激素对可卡因的强化作用， 区别性刺激效应。男性将接受同样的培训， 条件和可卡因剂量-效应曲线将在相同的条件下确定。 以进行有意义的性别比较。的迅速提升 静脉注射可卡因后的雌二醇和睾酮表明， 行为效应可能由非基因组机制介导。因此我们 建议研究基因组和非基因组效应的影响， 类固醇激素对可卡因自我管理和可卡因歧视。 类固醇激素水平的放射免疫测定将允许评估时间 激素水平和可卡因相关行为之间的关系。数据 这将有助于澄清可卡因滥用的神经生物学基础， 可能对开发新的战略具有启发性意义， 治疗

DESCRIPTION (provided by applicant): 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.