Anxiolytic Effects and Abuse of BZ Receptor Ligands

说明(由申请人提供)：本申请是竞争性修订，如公告编号NOT-OD-058所述，标题为“NIH宣布恢复法资金可用于竞争性修订申请”。家长资助是R01DA017792-10，“BZ受体配体的抗焦虑作用和滥用”。父母资助的总体目标是使用相关的非人类灵长类动物模型，调查GABAA受体亚型在与苯二氮(BZ)配体相关的抗焦虑效果、自我给药和身体依赖中的差异程度。本应用程序的修订部分是评估BZ自我给药中潜在的性别差异和月经周期影响。在患者群体中，女性与BZ的使用和滥用比率较高有关，我们假设这在一定程度上与性激素及其神经活性类固醇代谢物增强了这些配体的强化作用有关。在父母赠款下，使用静脉注射的累进比率表来评估加强效果。药物自我给药，我们正在要求修改，以包括在雌性和雄性猴子身上的实验。识别潜在的性别差异和月经周期对BZ配体自我给药的影响将为了解这些药物滥用潜力中与性别相关的差异提供基本信息，这反过来应该有助于开发更安全和更广泛有效的抗焦虑药物。 与公共卫生相关：安定片和相关药物被广泛用于治疗焦虑和睡眠障碍，这是美国最常见的两种精神障碍。苯二氮卓类药物被认为是现代医学中最安全的处方药之一，但不幸的是，它们也是滥用药物，女性的发病率高于男性。我们父母拨款的这次修订的目的是揭示苯二氮类药物滥用潜力的性别差异，总体目标是开发更安全的药物来治疗焦虑和睡眠障碍，而不分性别。

DESCRIPTION (provided by applicant): This application is a Competitive Revision, as described in Notice Number NOT-OD-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". The parent grant is R01DA017792-10, "Anxiolytic Effects and Abuse of BZ Receptor Ligands". The overall goal of the parent grant is to investigate the extent to which GABAA receptor subtypes are differentially involved in the anxiolytic effects, self-administration, and physical dependence associated with benzodiazepine (BZ) ligands, using relevant nonhuman primate models. The revised component of this application is to evaluate potential sex differences and menstrual cycle effects in BZ self-administration. In patient populations, women are associated with higher rates of BZ use and abuse, which we hypothesize to involve, in part, enhanced reinforcing effects of these ligands by sex hormones and their neuroactive steroid metabolites. Under the parent grant, reinforcing effects are evaluated using progressive-ratio schedules of i.v. drug self-administration, and we are requesting a revision to include experiments with both female and male monkeys. Identification of potential sex differences and menstrual cycle effects on the self-administration of BZ ligands will provide fundamental information for understanding gender-related differences in the abuse potential of these drugs that, in turn, should aid in developing safer and more broadly effective anti-anxiety medications. PUBLIC HEALTH RELEVANCE: Valium and related drugs, referred to as "benzodiazepines" are prescribed widely for the treatment of anxiety and sleep disorders, two of the most common psychiatric disorders in the U.S. Benzodiazepines are considered to be among the safest prescription drugs in modern medicine, but they unfortunately are also drugs of abuse, with higher prevalence in women than men. The aim of this revision to our parent grant is to uncover sex differences in the abuse potential of benzodiazepines, with the overall goal of developing safer drugs for treating anxiety and sleep disorders regardless of gender.