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: 10464731
• 负责人: Jessica Tooley
• 金额: $ 3.27万
• 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/10464731
• 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; Pharmacology; 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; prescription opioid; protein activation; 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.

项目总结 阿片类药物使用障碍是美国一项紧迫的公共卫生危机，大约30%的美国人使用阿片类药物 滥用他们的药物。阿片类药物使用障碍患者继续服用阿片类药物的压倒性原因是 以避免撤资。停用阿片类药物在身体上是痛苦的，在情感上也是疲惫的。尽管本质上是 药物滥用和戒断的慢性复发本质，关于长期使用阿片类药物如何改变厌恶的研究 与那些研究奖赏回路的人相比，大脑的回路令人惊讶地有限。失调症 中脑边缘环，包括腹侧苍白球(VP)及其下游靶点，已被牵连 在广泛的物质滥用障碍中，包括阿片类药物使用障碍，但尚不清楚阿片类药物如何使用- 诱导适应出现在这些大脑区域。一种假设是，停止长期使用阿片类药物 可能会促使厌恶处理电路中对厌恶刺激产生更高敏感性的适应 调节与戒断相关的总体负面情绪状态；从而导致压力增加和 随后复发。VP特别适合于调节阿片类药物中厌恶环路的适应 使用无序。VP神经元接受奖赏和厌恶编码结构的输入并调制厌恶 大脑的中枢，主要输出是外侧缰核(LHb)。此外，最近发现的一个子集 VP神经元(VPGlu)被证明在与奖励相关的环境中编码厌恶。在这项提案中，我计划 用多方面方法研究阿片类药物使用诱导的LHb投射VP(VPGluLHb)的适应 老鼠体内的神经元。我推测VPGlu神经元是过度活跃的，对伤害性刺激更敏感。 阿片类药物的长期戒断，并且阿片类药物的戒断加强了VPGluLHb突触的传递。 最后，我预计VPGlu神经元的活动赋予了对负面结果的敏感性，这种反应是 在阿片类药物戒断后升高。我建议在体内用特定的目标来检验这些假说 和体外电生理学、光遗传学和行为技术来评估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 这些目标的完成将为未来治疗阿片类药物的负面情感状态的治疗干预提供信息 停药，以便成功治疗阿片类药物使用障碍。