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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要提取是克服阿片类药物依赖和成瘾的主要障碍。识别神经回路参与以及阿片类药物如何调节其活动对于制定新的治疗策略至关重要。这内侧Habenula（MHB）表达了特别高的Mu-Apioid受体（MOR）和新的证据将MHB视为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投影神经元或慢性信号传导如何诱导导致戒断的MHB电路的生理变化。 MHB神经元主要投射到枝间核（IPN），在那里他们可以释放乙酰胆碱（ACH）或谷氨酸；这些神经元中的一些可以共释放谷氨酸和ACH。而胆碱能和谷氨酸能定义的MHB神经元已与成瘾的过程有关这些共同传播者的相对重要性尚不清楚。基于先前的文献和初步数据我们在阿片类药物的介导作用中提出了谷氨酸和ACH共释放的重要作用依赖，包括提款。在这项探索性建议中，我们旨在测试急性和慢性MOR 激活影响MHB的活性和IPN的突触传播，并有助于阿片类药物依赖性。