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

阿片戒断的躯体、动机和情感方面性别差异的神经生物学特征

• 批准号: 10515136
• 负责人: Linda Irene Perrotti
• 金额: $ 43.89万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515136
• 关键词: Abstinence; Acute; Address; Adverse effects; Affect; Analgesics; Antidepressive Agents; Anxiety; Area; Attenuated; Aversive Stimulus; Behavior; Behavior assessment; Behavioral; Benzodiazepines; Brain region; COVID-19 pandemic; CREB1 gene; Cell Nucleus; Chronic; Clinical Research; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Distress; Drops; Drug Exposure; Emergency department visit; Emotional; Environment; Epidemic; Estrous Cycle; Female; Funding; Future; Gene Expression; Gonadal Hormones; Grant; Health; Human; Institution; Ketamine; Knowledge; Mediating; Mental Depression; Minority-Serving Institution; Molecular; Moods; Motivation; NMDA receptor antagonist; Nature; Neurobiology; Neurons; Neurosciences; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid agonist; Pain; Pain management; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Process; Property; Rattus; Regulation; Reporting; Research; Research Training; Risk; Rodent; Role; Science; Severities; Sex Differences; Signal Transduction; Simplexvirus; Students; Substance Withdrawal Syndrome; Substance abuse problem; Symptoms; Tail; Technology Transfer; Testing; Therapeutic; Time; Treatment Efficacy; Treatment outcome; Underrepresented Populations; United States National Institutes of Health; Ventral Tegmental Area; Viral; Viral Vector; Withdrawal; Withdrawal Symptom; Woman; Work; acute symptom; base; career; comorbidity; emotional symptom; experience; experimental study; gene transfer vector; gonad function; improved; male; men; mu opioid receptors; negative affect; neuromechanism; novel therapeutics; opiate tolerance; opioid agonist therapy; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; overexpression; pre-clinical research; relating to nervous system; sex; symptomatology; training opportunity; translational potential; treatment program; treatment strategy

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.

阿片类药物使用障碍 (OUD) 已达到流行病的程度，每天急诊室就诊人数超过 1,000 人次， 在美国，每天约有 130 人因阿片类药物过量服用而丧生。Covid-19 大流行只会让情况变得更糟。 阿片类药物对男性和女性的影响显着不同，但大多数关于阿片类药物依赖和 戒断现象是从专门针对男性的研究得出的，然后推断到女性；和参数 用于描述阿片类药物戒断 (OW) 综合征的神经生物学是使用男性开发的 科目。这表明我们的理解存在重大差距；填补这些空白将有助于设计出更好的、性的 为基础，制定治疗策略。我们的长期目标是了解基本的行为和神经过程 潜在的 OW 将为制定策略提供信息，以改善治疗结果，有一天 可以促进患者与治疗的匹配。为此，本申请概述的研究目标 将开始填补我们知识中的三个重要空白。第一个差距：OUD 研究表明，女性患有以下疾病 与男性相比，情感和身体退缩更为严重，但评估性的基础研究很少 OW 的差异表明结果不一致。我们将描述发病、表达和发展方面的性别差异。 男性和女性急性和长期 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 作为男性和女性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 症状是导致治疗减少的主要原因。女性面临更高的风险 退学；现有的治疗方法会产生不良影响，尤其是在处方或与其他药物联合使用时 苯二氮卓类药物，一种高度为女性开处方并被女性使用的治疗药物。因此，新的药物治疗方法 非常需要。我们将开始通过评估氯胺酮 (KET) 在缓解 OW 方面的功效来填补这一空白 症状学。我们假设 KET 将有效改善 OW 症状。第三个缺口： 对 OW 潜在神经机制的了解源自对男性的研究，表明 cAMP 激活的 CREB ​​对于导致 OW 的基因表达改变至关重要。 OW对的影响 腹侧被盖区/喙内侧被盖核尾部的 cAMP-PKA-CREB ​​活性 （tVTA/RMTg），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，我们实验室只对女性进行了一项研究。我们将开始建立因果关系 通过检查 OW 期间 tVTA/RMTg 中 CREB ​​表达的功能意义来研究关系， 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 使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 开始更好地了解性的系统影响和基本途径 OW 的差异。