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，每天有1000多个急诊室就诊，并且 在美国，每天宣称每天有130人生命，而阿片类药物过量服用过量，这是199年的大流行只会使事情变得更糟。 阿片类药物对男性和女性的影响很大，但大多数对阿片类药物依赖性的了解和 戒断是从男性专门研究的，然后推断为女性的。和参数 用于描述阿片类药物戒断（OW）综合征的神经生物学 主题。这代表了我们的理解差距。填补这样的空白将有助于更好地设计，性爱 - 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 基本的OW将告知制定有一天的策略以改善治疗结果 可以促进患者与治疗的匹配。为此，该应用程序概述了该研究的目的 我们的知识将开始填补三个重要的空白。第一差距：OUD的研究表明，女性患有 与男性相比，更严重的情绪和身体戒断更为严重，但是少数基础研究评估了性 OW的差异显示出不一致的结果。我们将表征发作，表达和 男性和 在发情周期的过程中，雌性大鼠。我们假设OW症状的严重程度和持久性 随着男性和女性的性腺激素状态而变化。第二个差距：严重性和管理不善 OW症状是造成治疗流失的主要因素。妇女的风险增加 辍学；并且可用的治疗具有不良影响，尤其是在开处方或合并时与 苯二氮卓类药物是一种高度处方并由妇女使用的治疗性。因此，新的药物方法 非常需要。我们将通过评估氯胺酮（KET）减轻OW的功效来填补这一空白 症状学。我们假设KET可以有效地改善OW症状。第三间隙： 对基本OW的神经机制的了解是从男性的研究中得出的，表明 cAMP激活的-CREB对于沉淀OW的基因表达改变至关重要。 OW对 cAMP-pka-creb活性在腹侧盖区域/roust膜细胞核的尾部 （TVTA/RMTG）是我们首先描述的脑部区域，以应对慢性药物暴露和厌恶刺激 刚开始，在女性中只有一项来自我们实验室的研究。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，通过 有选择地调节TVTA/RMTG神经元中的CREB活动，以评估OW的严重性和持久性 使用病毒载体基因转移技术的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的差异。