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

阿片类药物使用障碍(OUD)已经达到流行的程度，每天有超过1000次急诊室就诊，以及 在美国，每天约有130人死于阿片类药物过量。新冠肺炎的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，然而大多数关于阿片类药物依赖和 撤退是从专门针对男性的研究中得出的，然后推论到女性；参数 用于描述阿片类药物戒断综合征(OW)综合征的神经生物学研究已经开发出来，使用的是男性 研究对象。这代表着我们在理解上的重大差距；填补这些差距将有助于设计出更好的性行为-- 以治疗为基础的策略。我们的长期目标是了解基本的行为和神经过程 基础OW将为制定战略提供信息，以改善治疗结果，有朝一日 可以促进患者与治疗的匹配。为此，在本申请中概述了研究目的 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，女性患有 与男性相比，情感和身体上的退缩更严重，但为数不多的评估性的基础研究 OW的差异显示出不一致的结果。我们将在发病、表达和性别差异方面进行表征 急性和迁延性OW综合征的躯体、动机和情绪症状的持续时间 雌性大鼠在发情周期的过程中。我们假设OW症状的严重性和持久性 随着男性和女性性腺激素状况的不同而变化。第二个差距：严重性和管理不善 OW症状的主要因素是治疗过程中的损耗。女性患癌症的风险增加 退出；并且现有的治疗方法有不想要的效果，特别是当处方或与 苯二氮卓类药物，一种女性经常使用的治疗药物。因此，新的药物治疗方法 是非常需要的。我们将开始通过评估氯胺酮(KET)在缓解OW方面的有效性来填补这一空白 症状学。我们假设KET在改善OW症状方面是有效的。第三个差距： 有关失恋的神经机制(S)的知识来自于对男性的研究，表明 CAMP激活的CREB对于导致OW的基因表达变化是必不可少的。OW对以下方面的影响 腹侧被盖区/旋转内侧被盖核尾部cAMP-PKA-CREB活性 (tVTA/RMTg)是我们首先描述的对慢性药物暴露和厌恶刺激做出反应的大脑区域，是 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。我们将开始确定因果关系 通过检测OW期间tVTA/RMTg中CREB表达的功能意义， 选择性调节tVTA/RMTg神经元CREB活性评估OW的严重性和持久性 利用病毒载体基因转移技术研究雄性和雌性大鼠的症状。这里提出的研究将 开始对性行为的系统效应和基本途径有更深入的了解 OW中的差异。

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.