Neurobiological characterization of sex differences in somatic, motivational, and emotional aspects of opiate withdrawal

阿片类药物使用障碍（OUD）已达到流行病的程度，每天有1,000多人急诊， 在美国，阿片类药物过量每天夺去约130人的生命。新冠肺炎大流行只会让事情变得更糟。 阿片类药物对男性和女性的影响显著不同，但大多数关于阿片类药物依赖和 撤药率仅来自男性研究，然后外推至女性;以及参数 用于描述阿片类药物戒断（OW）综合征的神经生物学， 科目这代表了我们在理解上的重大差距;填补这些差距将有助于设计更好的，性别- 基于治疗策略。我们的长期目标是了解基本的行为和神经过程 潜在的OW，这将为制定策略提供信息，以改善治疗结果， 可以促进患者与治疗的匹配。为此，本申请中概述的研究目的 将开始填补我们知识中的三个重要空白。第一个差距：对OUD的研究表明，女性遭受 与男性相比，女性在情感和身体上的退缩更严重，但很少有基础研究评估性行为， OW的差异显示不一致的结果。我们将描述性别差异的发病，表达， 男性急性和迁延性OW综合征的躯体、动机和情绪症状持续时间， 雌性大鼠在发情周期的过程中。我们假设OW症状的严重性和持续性 作为雄性和雌性的性腺激素状态的函数而变化。第二个差距：严重性和管理不善 OW症状是治疗损耗的主要因素。女性面临的风险增加 辍学;和可用的治疗有不必要的影响，特别是当规定，或结合， 苯二氮卓类药物是一种高度开给女性并被女性使用的治疗药物。因此，新的药物方法 非常需要。我们将开始通过评估氯胺酮（KET）缓解OW的疗效来填补这一空白 医学。我们假设KET将有效改善OW病理学。第三个差距： 有关OW神经机制的知识来自于对男性的研究，表明： cAMP激活的CREB是沉淀OW的基因表达改变所必需的。OW对 腹侧被盖区/嘴内侧被盖核尾部cAMP-PKA-CREB活性 (tVTA/RMTg），我们首次描述的对慢性药物暴露和厌恶刺激做出反应的大脑区域， 这才刚刚开始，我们实验室只有一项研究是在女性身上进行的。我们将开始建立因果关系 通过检查OW期间tVTA/RMTg中CREB表达的功能意义， 选择性调节tVTA/RMTg神经元中的CREB活性以评估OW的严重性和持续性 症状的雄性和雌性大鼠使用病毒载体基因转移技术。本文提出的研究将 开始提供一个更好的了解系统的影响和基本途径的基础性 在OW的差异。

Opioid use disorder (OUD) has reached epidemic proportions, with over 1,000 daily emergency room visits, and claiming ~130 lives per day, to opioid overdoses in the U.S. The Covid-19 pandemic has only made matters worse. Opioids significantly affect men and women differently, yet most of what is known about opioid dependence and withdrawal has been derived from studies exclusively in men and then extrapolated to women; and parameters used to delineate the neurobiology of opioid withdrawal (OW) syndrome have been developed using male subjects. This represents significant gaps in our understanding; filling such gaps will help devise better, sex- based, treatment strategies. Our long-term objective is to understand basic behavioral and neural processes underlying OW that will inform the development of strategies to improve treatment outcomes that someday could facilitate the matching of patients to treatments. To this end, the research Aims outlined in this application will begin to fill three important gaps in our knowledge. First Gap: Studies of OUD show that women suffer from more severe emotional and physical withdrawal as compared to men, yet the few basic studies assessing sex differences in OW show inconsistent results. We will characterize sex differences in the onset, expression, and duration of somatic, motivational, and emotional symptoms of acute and protracted OW syndrome in male and female rats over the course of the estrous cycle. We hypothesize that severity and persistence of OW symptoms vary as a function of gonadal hormone status in males and females. Second Gap: Severity and mismanagement of OW symptoms are primary contributors to attrition from treatment. Women are at an increased risk for dropping out; and available treatments have unwanted effects, especially when prescribed, or combined, with benzodiazepines, a therapeutic highly prescribed to, and utilized by, women. Thus, new medication approaches are much needed. We will begin to fill this gap by assessing the efficacy of ketamine (KET) in alleviating OW symptomatology. We hypothesize that KET will be efficacious in ameliorating OW symptomatology. Third Gap: Knowledge of the neural mechanism(s) underlying OW has been derived from studies in males, showing that cAMP-activated-CREB is essential for alterations in gene expression that precipitate OW. The effects of OW on cAMP-PKA-CREB activity in the tail of the ventral tegmental area/rostromedial tegmental nucleus (tVTA/RMTg), a brain region we first described to respond to chronic drug exposure and aversive stimuli, are just beginning, and only one study from our lab has been performed in females. We will begin establishing causal relationships by examining the functional significance of CREB expression in the tVTA/RMTg during OW, selectively regulating CREB activity in tVTA/RMTg neurons to assess the severity and persistence of OW symptoms in male and female rats using viral vector gene-transfer technology. The research proposed here will begin to provide a greater understanding of the systemic effects and fundamental pathways underlying sex differences in OW.