Separate and Combined Effects of Progesterone and Triazolam in Healthy Women

描述（由申请人提供）：越来越多的证据表明，性别在药物滥用中起着关键作用。生物因素，包括性腺性激素，对药物滥用方面的性别差异起着重要的作用，尽管人们对其了解还不完全清楚。女性性激素已被证明能影响中枢神经系统功能并调节药物滥用的效果。例如，GABAA受体功能可被黄体酮和包括苯二氮卓类药物在内的许多镇静药物正向调节。临床前体外和体内研究以及一些临床研究表明，黄体酮及其代谢物可能增强苯二氮卓类药物的行为作用。第一个拟议的研究将利用受试者内设计来检查在低循环性激素条件下健康绝经前妇女的主观、精神运动和生理影响方面，微粉化舌下黄体酮（0、50、150和250）和口服三唑仑（0.00、0.12和0.25 mg/70 kg）的剂量范围的单独和联合效应。第二项研究也是一项受试者内设计，将在同样处于低循环性激素条件下的健康绝经前妇女中，研究孕酮预处理对三唑仑（0.00、0.06、0.12和0.25 mg/70 kg）的鉴别刺激效应的影响。要测试的孕酮剂量将根据最初研究的结果来确定（即，在隔离状态下无活性的剂量，它能最有力地增强三唑仑的作用）。拟议的研究将有助于阐明卵巢激素黄体酮调节镇静药物三唑仑的行为作用的方式。此外，这些研究将为进一步研究奠定基础，以进一步阐明与黄体酮调节苯二氮卓类药物作用有关的机制，从而进一步了解健康和行为中的性别差异。因此，这些研究将有助于制定针对性别的干预和（或）预防战略以及保健管理办法。

DESCRIPTION (provided by applicant): There is accumulating evidence from many directions indicating that gender plays a critical role in drug abuse. Biological factors, including gonadal sex hormones, contribute in a significant although incompletely understood manner, to gender differences in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, GABAA receptor function is positively modulated by both progesterone and many sedative drugs, including the benzodiazepines. There is evidence from preclinical in vitro and in vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines. The first proposed study will utilize a within-subject design to examine the separate and combined effects of a range of doses of micronized sublingual progesterone (0, 50, 150 and 250) and oral triazolam (0.00, 0.12 and 0.25 mg/70 kg) on the subjective, psychomotor and physiological effects of healthy premenopausal women under conditions of low circulating sex hormones. The second study, also a withinsubject design, will examine the effect of progesterone pretreatment on the discriminative stimulus effects of triazolam (0.00, 0.06, 0.12 and 0.25 mg/70 kg) in healthy, premenopausal women, also under conditions of low circulating sex hormones. The progesterone dose to be tested will be determined based on the results of the initial study (i.e., the dose, inactive in isolation, that engenders the most robust potentiation of triazolam effects). The proposed studies will help to clarify the manner in which the ovarian hormone progesterone modulates the behavioral effects of the sedative drug triazolam. In addition, these studies will establish a foundation for additional studies designed to further elucidate mechanisms associated with progesterone modulation of benzodiazepine effects, thereby further informing gender differences in health and behavior. As such, these studies will contribute towards the development of gender-specific intervention and/or prevention strategies and health management approaches.