Cocaine Abuse and the Role of Gonadal Steroid Hormones

描述(申请人提供)：这是一份新的申请(R01)以供审查 性腺类固醇激素在吸毒相关效应中的作用 临床前模型中的可卡因。多条证据表明，性腺 类固醇激素可能是可卡因行为效应的重要调节器。 发情期高水平的雌二醇似乎可以增强可卡因的运动能力和 对大鼠的补益作用。可卡因行为和行为的性别差异 两者的生物学效应似乎都是由性腺类固醇激素介导的。 临床和临床前研究。行为研究被提议用来确定 如果性腺类固醇激素具有歧视性刺激作用， 增强可卡因的效果，如果急性或慢性给药 性腺类固醇激素改变可卡因的自我给药和辨别能力 剂量-效应曲线。内分泌研究表明，静脉注射可卡因 给药会刺激雌二醇和睾丸素的迅速增加。 此外，雌二醇和睾酮都有改善情绪的作用。 人类。我们建议评估急性或慢性给药的效果。 性腺类固醇激素对可卡因自我给药和辨别的影响。 此外，我们建议研究可能的强化和区别 这些性腺类固醇激素单独的刺激作用。 将对男性和女性进行研究，以确定是否存在显著的 单用可卡因和急性可卡因后行为反应的性别差异 或慢性性腺类固醇治疗。男性和女性将在一项 性腺类固醇治疗条件下的自身对照设计 在卵巢切除和去势后。在正常骑车的女性中， 将检查月经周期中类固醇激素水平的变化。在……里面 摘除卵巢的女性，系统的激素替代研究将 旨在评估荷尔蒙对可卡因的增强作用和 歧视性刺激效应。男性将接受同样的训练 条件和可卡因剂量-效应曲线将同时确定 间隔时间，以便进行有意义的性别比较。中国经济的快速增长 静脉注射后雌二醇和睾酮。可卡因表明任何同时发生的 行为效应可能是由非基因组机制介导的。因此，我们 建议同时研究基因组效应和非基因组效应的影响 类固醇激素对可卡因自我给药和可卡因辨别的影响。 类固醇激素水平的放射免疫分析将允许评估 激素水平与可卡因相关行为的关系。数据 将有助于阐明可卡因滥用的神经生物底物和 可能对开发新的战略具有启发式的意义 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.