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.

项目概要 阿片类药物使用障碍是美国的一个紧急公共卫生危机，大约 30% 的美国人服用阿片类药物 滥用药物是阿片类药物使用障碍患者继续服用阿片类药物的主要原因。 为了避免戒断，阿片类药物戒断会带来身体上的痛苦和精神上的疲惫。 药物滥用和戒断的慢性复发性，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功能障碍的人相比，大脑回路的局限性令人惊讶。 中脑边缘回路，包括腹侧苍白球（VP）及其下游目标，与此有关 广泛的药物滥用障碍，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- 一种假设是，戒断长期使用阿片类药物会引起这些大脑区域的诱导适应。 可能会促进厌恶处理电路的适应，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，从而导致压力增加和 VP 特别适合调节阿片类药物的厌恶回路。 VP 神经元接收来自奖赏和厌恶编码结构的输入并调节厌恶。 大脑的中心，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) 已被证明可以在与奖励相关的环境中编码厌恶。 使用多方面的方法研究阿片类药物使用引起的 LHb 投射 VP (VPGluLHb) 的适应 我发现小鼠的 VPGlu 神经元非常活跃，对有害刺激更敏感。 延长阿片类药物戒断，并且阿片类药物戒断增强了 VPGluLHb 突触的传递。 最后，我预计 VPGlu 神经元活动赋予对负面结果的敏感性，并且这种反应是 我建议在体内测试特定目标的每个假设。 和离体电生理学、光遗传学和行为技术来评估 VPGluLHb 活性和 可塑性是增强对不良结果和事件的敏感性的潜在机制。 这些目标的完成将为未来治疗阿片类药物负面情感状态的治疗干预措施提供信息 戒断以成功治疗阿片类药物使用障碍。