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差异”而编写的。越来越多的证据表明，吸毒成瘾的女性比男性表现出更大的负面情绪(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，厌恶和抑郁状态部分是由神经肽强啡肽介导的，强啡肽是一种作用于kappa阿片受体的内源性配体(7)。长期接触滥用药物会促进强啡肽的合成和释放，这与抑郁样效应的出现是一致的(8，9，10)。本研究旨在探讨kappa-阿片受体在调节大鼠负性情感状态中的性别差异。了解这些差异的生物学基础对于为男性和女性开发更好的治疗方法至关重要。Chartoff和他的同事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是一种可操作的条件反射范例，对奖励功能的增加或减少非常敏感。Kappa-阿片受体激动剂提高了ICSS的刺激阈值，这表明奖赏功能下降(快感丧失)。初步结果显示，女性对kappa-阿片受体激动剂U50,488的阈值增加效应不太敏感。鉴于大多数性别差异与循环性腺类固醇激素的作用有关，这项建议使用两种互补的方法来测试性激素在kappa-阿片受体功能中的作用。首先，将确定U50,488对去性腺大鼠ICSS阈值的影响。如果性腺切除消除了KOR激活的抑郁样效应中的性别差异，那么很可能需要性腺类固醇激素的激活效应。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，性激素和性腺类固醇激素对kappa-阿片受体mRNA水平的作用以及U50,488诱导的下游效应器的偶联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受性或性激素的调节，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的药效学。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，并将为未来研究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.