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.

项目摘要 阿片类药物使用障碍是美国的一场紧迫的公共卫生危机，大约30%的美国人开了阿片类药物 滥用药物。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 避免撤退。阿片类药物戒断是身体上的痛苦和情绪上的疲惫。尽管固有的 药物滥用和戒断的慢性复发性质，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，大脑回路的局限性令人惊讶。功能障碍 包括腹侧苍白球（VP）及其下游靶点在内的中脑边缘回路已被牵连 在广泛的物质滥用障碍，包括阿片类药物使用障碍，但它是不知道如何阿片类药物的使用- 这些脑区会产生诱导适应。一种假设是，从长期使用阿片类药物中戒断 可能会促使厌恶处理电路的适应性变化，从而对厌恶刺激产生更高的敏感性， 调解与退缩相关的一般负面情感状态;从而导致压力增加， 随后复发。VP特别适合于介导阿片类药物中的厌恶回路的适应。 使用障碍。VP神经元接受来自奖赏和厌恶编码结构的输入并调节厌恶 大脑的中枢，主要输出是外侧缰（LHb）。此外，最近发现的一个子集 VP神经元（VPGlu）已被证明在奖励相关的情况下编码厌恶。在这份提案中，我计划 使用多方面的方法来研究阿片类药物使用诱导的LHb投射VP（VPGlu → LHb）适应 老鼠的神经元我假设VPGlu神经元是过度活跃的，对伤害性刺激反应更敏感。 阿片类药物戒断延长，阿片类药物戒断增强VPGlu → LHb突触的传递。 最后，我预计VPGlu神经元活性赋予对负面结果的敏感性，并且这种反应是 在阿片类药物戒断后升高。我建议在特定的目标测试这些假设中的每一个使用体内 和离体电生理学、光遗传学和行为技术来评估VPGlu β LHb活性， 可塑性作为潜在的机制增强的敏感性厌恶的结果和事件。成功 这些目标的实现将为未来治疗阿片类药物的负性情感状态提供信息。 戒断以允许成功治疗阿片类药物使用障碍。