Dissecting the contribution of glutamatergic ventral pallidal neurons to the aversive state of opioid withdrawal

剖析谷氨酸能腹侧苍白球神经元对阿片类药物戒断厌恶状态的贡献

• 批准号: 10569012
• 负责人: Jessica Tooley
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569012
• 关键词: AMPA Receptors; Abstinence; Acute; Affective Symptoms; American; Anhedonia; Appetitive Behavior; Area; Automobile Driving; Aversive Stimulus; Behavior; Behavioral; Behavioral Assay; Brain; Cells; Chronic; Coupled; Cues; Data; Disease; Drug abuse; Electrophysiology (science); Emotional; Event; Exhibits; Functional disorder; Future; GTP-Binding Proteins; Globus Pallidus; Glutamates; Goals; Habenula; Height; Hyperactivity; Intake; Lateral; Longitudinal Studies; Measures; Mediating; Mus; N-Methyl-D-Aspartate Receptors; Nature; Negative Valence; Neurons; Opioid; Oral; Outcome; Output; Oxycodone; Pain; Pattern; Persons; Pharmaceutical Preparations; Population; Positioning Attribute; Positive Valence; Prevention strategy; Probability; Property; Public Health; Punishment; Relapse; Rewards; Risk Behaviors; Role; Self Administration; Stimulus; Stress; Structure; Substance abuse problem; Synapses; Techniques; Testing; Therapeutic Intervention; Withdrawal; Withdrawal Symptom; Work; allostasis; cell type; drug withdrawal; exhaust; experimental study; in vivo; mu opioid receptors; negative affect; neural circuit; neuromechanism; opioid misuse; opioid use; opioid use disorder; opioid withdrawal; optogenetics; patch clamp; pharmacologic; postsynaptic; prescription opioid; recruit; relapse risk; response; reward processing; targeted treatment; transmission process; treatment strategy

PROJECT SUMMARY Opioid use disorder is an urgent public health crisis in the U.S. and roughly 30% of Americans prescribed opioids misuse their medications. The overwhelming reason people with opioid use disorder continue taking opioids is to avoid withdrawal. Opioid withdrawal is physically painful and emotionally exhausting. Despite the inherently chronic relapsing nature of drug abuse and withdrawal, studies of how long-term opioid use alters the aversion circuits of the brain are surprisingly limited compared to those studying the reward circuits. Dysfunction of mesolimbic circuits, which includes the ventral pallidum (VP) and its downstream targets, has been implicated in a wide range of substance abuse disorders, including opioid use disorder, but it is not known how opioid use- induced adaptations arise in these brain areas. One hypothesis is that withdrawal from chronic use of opioids may prompt adaptations in aversion-processing circuits that generate a higher sensitivity to aversive stimuli and mediate the general negative affective state associated with withdrawal; thus leading to increased stress and subsequent relapse. The VP is especially well-positioned to mediate adaptations of aversion circuits in opioid use disorder. VP neurons receive input from reward and aversion encoding structures and modulate aversion centers of the brain, a primary output being the lateral habenula (LHb). Furthermore, a recently discovered subset of VP neurons (VPGlu) has been shown to encode aversion in reward-related contexts. In this proposal, I plan to use a multi-faceted approach to investigate opioid use-induced adaptations of LHb-projecting VP (VPGluLHb) neurons in mice. I hypothesize that VPGlu neurons are hyperactive and more responsive to noxious stimuli in protracted opioid withdrawal, and that opioid withdrawal potentiates transmission at VPGluLHb synapses. Lastly, I expect that VPGlu neuronal activity confers sensitivity to negative outcomes and that this response is heighted following opioid withdrawal. I propose to test each of these hypotheses in specific aims using in vivo and ex vivo electrophysiology, optogenetics, and behavioral techniques to evaluate VPGluLHb activity and plasticity as potential mechanisms underlying enhanced sensitivity to aversive outcomes and events. Successful completion of these aims will inform future therapeutic interventions to treat the negative affective state of opioid withdrawal to allow for successful treatment of opioid use disorder.

项目摘要 阿片类药物使用障碍是美国的紧急公共卫生危机，大约30％的美国人处方阿片类药物 滥用他们的药物。绿氧​​化物使用障碍的人的压倒性原因是继续服用opioids的原因是 避免退出。阿片类药物的戒断在身体上痛苦和情绪上令人筋疲力尽。尽管有继承 慢性滥用药物和戒断的慢性复发性质，研究长期使用阿片类药物的使用如何改变厌恶 与研究奖励电路的电路相比，大脑的电路令人惊讶地受到限制。功能障碍 包括腹侧颗粒（VP）及其下游目标在内的中唇圆圈已实施 在各种药物滥用障碍中，包括阿片类药物使用障碍，但尚不清楚阿片类药物的使用如何 这些大脑区域引起了诱导的适应性。一个假设是从长期使用阿片类药物中提取 可能会促使对厌恶加工电路的适应，从而产生对厌恶刺激的敏感性和 调解与退出相关的一般负面情感状态；因此导致压力增加和 随后的救济。 VP特别适合OID中的厌恶电路的适应 使用障碍。 VP神经元从奖励和厌恶编码结构中获得输入并调节厌恶 大脑的中心，主要输出是外侧Habenula（LHB）。此外，最近发现的子集 已显示VP神经元（VPGLU）的VP神经元（VPGLU）在与奖励相关的上下文中编码厌恶。在此提案中，我计划 使用多方面的方法研究Ooid使用诱导的LHB项目的适应（VPGLULHB） 小鼠的神经元。我假设VPGLU神经元过度活跃，对有害刺激的反应更大 长期戒断阿片类药物的戒断，阿片类药物的戒断会增强VPGLU的传播。 最后，我希望VPGLU神经元活动承认对负面结果的敏感性，并且这种反应是 阿片类药物提取后高度高。我建议使用体内的特定目的测试每个假设 和体内电生理学，光遗传学和行为技术，以评估VPGLULHB活性和 可塑性作为潜在的机制增强了对厌恶结果和事件的敏感性。成功的 这些目的的完成将为未来的治疗干预措施提供治疗状态的治疗干预措施 提取以成功治疗阿片类药物使用障碍。