Mu-opioid receptors in the habenulo-interpeduncular circuit in opioid dependence

阿片类药物依赖性缰核-脚间回路中的μ阿片受体

• 批准号: 10309782
• 负责人: Thomas Hnasko
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10309782
• 关键词: Acetylcholine; Acute; Affective Symptoms; Animals; Behavior; Behavioral; Biochemical; Brain; CRISPR/Cas technology; Cholinergic Receptors; Chronic; Cocaine; Cocaine Dependence; Data; Dependence; Development; Electrophysiology (science); Future; Glutamate Receptor; Glutamates; Habenula; Ligands; Literature; Maintenance Therapy; Medial; Mediating; Morphine; Morphine Dependence; Mus; Naloxone; Neurons; Neuropeptides; Neurotransmitters; Nicotine; Nicotine Dependence; Opiate Addiction; Opioid; Opioid agonist; Pharmaceutical Preparations; Physiological; Physiology; Play; Process; Public Health; Receptor Activation; Receptor Signaling; Relapse; Research; Role; Signal Transduction; Site; Slice; Synapses; Synaptic Transmission; Testing; Therapeutic; Viral; Withdrawal; Work; addiction; base; behavioral response; cholinergic; drug withdrawal; interpeduncular nucleus; mu opioid receptors; neural circuit; novel therapeutic intervention; novel therapeutics; opioid abuse; opioid withdrawal; optogenetics; physical symptom; receptor; receptor expression; relating to nervous system; response; small molecule; tool; transmission process

PROJECT SUMMARY Withdrawal is a major obstacle in overcoming opioid dependence and addiction. Identifying the neural circuits involved and how opioids modulate their activity is essential for developing new therapeutic strategies. The medial habenula (MHb) expresses particularly high levels of mu-opioid receptor (MOR) and emerging evidence implicates the MHb as a hotspot for the physical and affective symptoms of opioid withdrawal and relapse. Despite this, there is remarkably little information on how MOR signaling influences MHb projection neurons, or how chronic MOR signaling could induce physiological changes in MHb circuits that contribute to withdrawal. MHb neurons project principally to the interpeduncular nucleus (IPN) where they can release acetylcholine (ACh) or glutamate; and some of these neurons can co-release both glutamate and ACh. While cholinergic- and glutamatergic-defined MHb neurons have been implicated in processes underlying addiction, the respective roles and relative importance of these co-transmitters remain unclear. Based on prior literature and preliminary data we posit an important role for glutamate and ACh co-release from MHb to IPN in mediating effects of opioid dependence, including withdrawal. In this exploratory proposal we aim to test how acute and chronic MOR activation influences activity in MHb and synaptic transmission in IPN and contributes to opioid dependence.

项目概要 戒断是克服阿片类药物依赖和成瘾的主要障碍。识别神经回路 以及阿片类药物如何调节其活性对于制定新的治疗策略至关重要。这 内侧缰核 (MHb) 表达特别高水平的 mu-阿片受体 (MOR) 和新出现的证据 暗示 MHb 是阿片类药物戒断和复发的身体和情感症状的热点。 尽管如此，关于 MOR 信号如何影响 MHb 投射神经元的信息却非常少，或者 慢性 MOR 信号传导如何引起 MHb 回路的生理变化，从而导致戒断。 MHb 神经元主要投射到脚间核 (IPN)，在那里它们可以释放乙酰胆碱 (ACh) 或谷氨酸；其中一些神经元可以同时释放谷氨酸和乙酰胆碱。虽然胆碱能和 谷氨酸能定义的 MHb 神经元与成瘾的潜在过程有关，各自的作用 这些共同发射体的相对重要性仍不清楚。基于先前文献和初步数据 我们认为谷氨酸和乙酰胆碱从 MHb 到 IPN 的共同释放在阿片类药物的介导作用中发挥着重要作用 依赖，包括戒断。在这个探索性提案中，我们的目的是测试急性和慢性 MOR 激活影响 MHb 的活性和 IPN 的突触传递，并导致阿片类药物依赖。