The Influence of Gonadal Hormones on Opioid Use

项目摘要 临床前、临床和流行病学研究一致显示， 物质使用的差异和物质使用障碍的发展。许多性行为 差异可以归因于性腺激素，卵巢激素的影响在整个过程中， 发情/月经周期已被充分记录用于可卡因、甲基苯丙胺和其他 兴奋剂很少有研究探讨雄激素对药物敏感性的作用， 相对较少的研究探讨了卵巢激素在海洛因自我给药中的作用 其他阿片类药物。这代表了现有文献的局限性，因为有证据表明性腺 激素改变对阿片类药物滥用相关效应的敏感性， 改变对兴奋剂敏感性的方式。拟议项目的科学目标是 描述卵巢和雄激素对海洛因自我给药的影响， 成熟的雄性和雌性大鼠，同时确定阿片类药物使用的基于生殖的治疗干预措施 紊乱为此，目标1将检查外源性雌二醇、孕酮及其 联合用药对去势雄性和雌性大鼠海洛因自我给药的影响。目标2将检查 内源性卵巢激素在海洛因自我给药抑制中的作用 通过受体选择性拮抗剂诱导发情前期。目的3将检查外源性雌二醇的作用 和孕酮对性腺完整雌性大鼠海洛因自我给药的影响。目标4将审查 外源性睾酮对去性腺大鼠海洛因自我给药的影响 最后，目标5将检查雄激素类固醇抑制剂对海洛因自我给药的影响， 性腺完整的雄性大鼠。这些研究的最终目的是更好地预测与性别相关的差异 并确定阿片类药物滥用的新的和性别特异性治疗干预措施， 成瘾

PROJECT SUMMARY Preclinical, clinical, and epidemiological studies have consistently revealed sex- and gender-related differences in substance use and the development of substance use disorders. Many of these sex differences can be attributed to gonadal hormones, and the effects of ovarian hormones across the estrous/menstrual cycle have been well documented for cocaine, methamphetamine, and other stimulants. Far fewer studies have examined the role of androgen hormones on drug sensitivity, and relatively few studies have examined the role of ovarian hormones on the self-administration of heroin and other opioids. This represents a limitation of the existing literature, given evidence that gonadal hormones alter sensitivity to the abuse-related effects of opioids in a manner very differently from the way they alter sensitivity to the effects of stimulants. The scientific objective of the proposed project is to characterize the effects of ovarian and androgen hormones on heroin self-administration in sexually mature male and female rats, while identifying hormonally based treatment interventions for opioid use disorders. To this end, Aim 1 will examine the effects of exogenous estradiol, progesterone, and their combination on heroin self-administration in gonadectomized male and female rats. Aim 2 will examine the role of endogenous ovarian hormones in the suppression of heroin self-administration during proestrus through receptor-selective antagonists. Aim 3 will examine the effects of exogenous estradiol and progesterone on heroin self-administration in gonadally intact female rats. Aim 4 will examine the effects of exogenous testosterone on heroin self-administration in gonadectomized male and female rats. Finally, Aim 5 will examine the effects of an androgen steroid inhibitor on heroin self-administration in gonadally intact male rats. The ultimate goal of these studies is to better predict sex-related differences in opioid use disorders and to identify novel and sex-specific treatment interventions for opioid abuse and addiction.