Sex differences in the aversive effects of kappa-opioid receptor activation

描述（由申请人提供）：本R03提案是针对PA-11-049，“药物和酒精滥用/依赖中的妇女和性别/性别差异”而编写的。越来越多的证据表明，药物依赖的女性比男性表现出更大的负面影响（1,2,3,4），而压力和抑郁等负面情绪状态更有可能引发女性的渴望和复发（5,6）。对男性的研究表明，厌恶和抑郁样状态部分是由神经肽运动啡介导的，运动啡是一种内源性配体，作用于kappa阿片受体(7)。长期暴露于药物滥用中会促进dynorphin的合成和释放，这与抑郁样效应的出现是一致的（8,9,10）。本研究旨在探讨大鼠kappa-阿片受体在调节负性情感状态中的调节和作用的性别差异。了解这些差异的生物学基础对于开发更好的男女治疗方法至关重要。Chartoff和他的同事们已经开始使用颅内自我刺激（ICSS）来研究kappa-阿片受体在男性和女性中的作用，ICSS是一种对“实时”奖励功能的增加或减少敏感的操作性条件反射范式。Kappa-阿片受体激动剂增加ICSS的刺激阈值，这表明奖励功能（快感缺乏）减少。初步结果表明，雌性对kappa-阿片受体激动剂U50,488的阈值升高作用不太敏感。鉴于大多数性别差异与循环性腺类固醇激素的作用有关，本研究建议采用两种互补的方法来测试性腺激素在kappa-阿片受体功能中的作用。首先，U50,488对去性腺大鼠ICSS阈值的影响将被确定。如果性腺切除术消除了KOR激活的抑郁样效应的性别差异，那么很可能需要性腺类固醇激素的激活作用。虽然这是一个相当基本的问题，但它是理解药物成瘾中的情绪障碍的基础。其次，性别和性腺类固醇激素对kappa-阿片受体mRNA水平和u50,488诱导的下游效应物偶联的作用将在调节奖励功能的大脑区域内确定。如果受体水平或偶联是由性别或性激素调节的，那么kappa-阿片受体激活的行为效应的差异很可能部分归因于受体药效学。这些研究的数据将有助于更好地理解kappa-阿片受体如何调节男性和女性的情感状态，并为未来研究kappa-阿片受体在药物成瘾中的作用的性别差异奠定基础。

DESCRIPTION (provided by applicant): This R03 proposal was written in response to PA-11-049, "Women and Sex/Gender Differences in Drug and Alcohol Abuse/Dependence". Growing evidence shows that drug-dependent women express greater negative affect than men (1, 2, 3, 4) and negative emotional states such as stress and depression are more likely to trigger craving and relapse in women (5, 6). Research in males has shown that aversive and depressive-like states are mediated, in part, by the neuropeptide dynorphin, an endogenous ligand that acts at kappa opioid receptors (7). Chronic exposure to drugs of abuse promotes the synthesis and release of dynorphin that is coincident with the emergence of depressive-like effects (8, 9, 10). The purpose of this proposal is to examine sex differences in the regulation and role of kappa-opioid receptors in mediating negative affective states in rats. Understanding the biological basis of these differences is crucial to developing better treatments for both men and women. Chartoff and colleagues have begun to examine the role of kappa-opioid receptors in males and females using intracranial self-stimulation (ICSS), an operant conditioning paradigm that is sensitive to increases or decreases in reward function "in real time". Kappa- opioid receptor agonists increase stimulation thresholds in ICSS, which is indicative of a decrease in reward function (anhedonia). Preliminary results show that females are less sensitive to the threshold-increasing effects of the kappa-opioid receptor agonist U50,488. Given that the majority of sex differences have been linked to actions of circulating gonadal steroid hormones, this proposal uses two complementary approaches to test the role of gonadal hormones in kappa-opioid receptor function. First, the effects of U50,488 on ICSS thresholds will be determined in gonadectomized rats. If gonadectomy abolishes the sex difference in the depressive-like effects of KOR activation, then it is likely that activational effects of gonadal steroid hormones are required. Although a fairly basic question, it is fundamental to the understanding of mood dysfunction in drug addiction. Second, the role of sex and gonadal steroid hormones on kappa-opioid receptor mRNA levels and U50,488-induced coupling to downstream effectors will be determined within brain regions that regulate reward function. If receptor levels or coupling are modulated by sex or sex hormones, then it is likely that differences in the behavioral effects of kappa-opioid receptor activation are due, in part, to receptor pharmacodynamics. Data from these studies will lead to a better understanding of how kappa-opioid receptors regulate affective states in males and females and will form a foundation for future research on sex differences in the role of kappa-opioid receptors in drug addiction.