Exploiting endogenous opioids to selectively modulate accumbal synaptic transmission

利用内源性阿片类药物选择性调节累积突触传递

• 批准号: 10456310
• 负责人: Brian Hong Trieu
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2023-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456310
• 关键词: Address; Affect; Angiotensin-Converting Enzyme Inhibitors; Attenuated; Automobile Driving; Basic Science; Bathing; Behavior; Behavioral; Brain; Brain region; Cells; Compulsive Behavior; Corpus striatum structure; Data; Development; Diagnosis; Disease; Dopamine Receptor; Dorsal; Electrophysiology (science); Elements; Enkephalins; Enzyme Inhibition; Excision; Family; Functional disorder; GABA Antagonists; Impairment; Investigation; Knowledge; Lateral; Liquid Chromatography; Long-Term Depression; Lung; Measures; Mediating; Mental Depression; Mus; Naloxone; Neurons; Neuropeptides; Nucleus Accumbens; Opioid; Opioid Antagonist; Opioid Peptide; Opioid Receptor; Pathologic; Pathway interactions; Peptide Hydrolases; Peptides; Peptidyl-Dipeptidase A; Persons; Pharmaceutical Preparations; Pharmacology; Physicians; Physiologic pulse; Physiological; Regulation; Role; Scientist; Signal Transduction; Slice; Substance Use Disorder; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Therapeutic; Thinking; Training; United States; Ventral Striatum; addiction; antagonist; blood pressure regulation; cell type; chronic pain; connective tissue-activating peptide; endogenous opioids; experimental study; genetic manipulation; hypertension control; motivated behavior; neuropsychiatric disorder; new therapeutic target; novel therapeutics; optogenetics; patch clamp; postsynaptic; presynaptic; synaptic depression; synaptic function; tandem mass spectrometry; translational applications

PROJECT SUMMARY A tremendous effort has been undertaken to understand the pathophysiology underlying addiction. In 2017, an estimated 19.7 million people within the United States met criteria for Substance Use Disorder. Disruptions in several interconnected brain regions manifest as behaviors used to diagnose addiction disorders, which includes compulsive drug-seeking as a hallmark symptom. Compulsive behaviors represent a state of impaired control over repetitive actions or thoughts that can be deleterious to normal behavioral function. There is currently no treatment that addresses this symptom in addiction. Implicated in compulsive behavior pathophysiology are disruptions in nucleus accumbens, a central node critical in driving motivated behaviors. These disruptions are specifically associated with excessive activity of medium spiny projection neurons (MSNs) that express the Drd1 dopamine receptor (D1-MSNs), relative to those that express the Drd2 dopamine receptor (D2-MSNs). MSNs comprise the majority of cells within the nucleus accumbens, and strengthening of excitatory synaptic input onto D1-MSNs contributes to addiction-related behavior. This proposal aims to ultimately restore nucleus accumbens function by indirectly engaging a mechanism of synaptic plasticity that will selectively reduce D1-MSN activity. Our preliminary studies inhibited the peptidase activity of angiotensin converting enzyme (ACE), which is highly expressed by D1-MSNs but not by other neuronal cell types or brain regions. ACE has been shown to degrade endogenous opioid peptides released by D2-MSNs called enkephalins. Preliminary findings suggest a unique mechanism where ACE constrains opioid-mediated regulation of D1-MSN function but not D2-MSN function, and ACE inhibition decreases excitatory synaptic input onto D1-MSNs. Thus, we hypothesize that ACE inhibition elevates endogenous levels of enkephalins which activate presynaptic opioid receptors on excitatory terminals, thereby depressing synaptic input selectively onto D1-MSNs. We propose two aims that will 1) directly evaluate the contribution of endogenous enkephalins in regulating D1-MSNs activity and 2) investigate the mechanism underlying this phenomenon mediated by ACE inhibition. The first aim will integrate optogenetics with peptide quantification techniques and whole-cell patch clamp electrophysiology to directly measure the physiological impact of endogenous enkephalins. The second aim will utilize electrophysiology and genetic manipulations to identify the pre- and postsynaptic elements that underly synaptic changes mediated by ACE inhibition. This proposal’s incorporation of interdisciplinary techniques at the intersection of basic science mechanisms and translational application will provide unparalleled training potential towards becoming an independent physician scientist.

项目总结 人们已经做出了巨大的努力来了解成瘾背后的病理生理学。2017年，一个 据估计，美国境内有1970万人符合物质使用障碍的标准。中途中断 几个相互关联的大脑区域表现为用于诊断成瘾障碍的行为，包括 强迫性吸毒是一种标志性症状。强迫行为代表一种控制能力受损的状态 过度重复的行为或想法，可能有害于正常的行为功能。目前没有 在上瘾时解决这种症状的疗法。与强迫症行为有关的病理生理学 伏隔核的中断，这是驱动动机行为的关键中央节点。这些中断是 与表达DRD1的中棘投射神经元(MSN)的过度活动有关 多巴胺受体(D1-MSN)，相对于那些表达DRD2多巴胺受体(D2-MSN)的受体。MSNS 组成伏核内的大多数细胞，并加强兴奋性突触对 D1-MSN有助于成瘾相关行为。这项提议旨在最终恢复伏隔核 通过间接参与突触可塑性的机制，选择性地降低D1-MSN的活性来发挥作用。 我们的初步研究抑制了血管紧张素转换酶(ACE)的肽酶活性，这是高度 在D1-MSN中表达，但不在其他神经细胞类型或脑区表达。Ace已经被证明是降级的 由D2-MSN释放的内源性阿片肽称为脑啡肽。初步研究结果表明， 血管紧张素转换酶抑制阿片类药物对D1-MSN功能的调节而不是D2-MSN功能的机制 抑制血管紧张素转换酶可减少兴奋性突触对D_1-MSN的传入。因此，我们假设ACE抑制 提高脑啡肽的内源性水平，脑啡肽激活兴奋性终末上的突触前阿片受体， 从而选择性地抑制到D1-MSN的突触输入。我们提出了两个目标：1)直接评估 内源性脑啡肽在调节D1-MSN活性中的作用2)探讨其作用机制 这一现象的基础是ACE抑制所介导的。第一个目标是将光遗传学与多肽相结合。 量化技术和全细胞膜片钳电生理学直接测量生理 内源性脑啡肽的影响。第二个目标将利用电生理学和遗传操作来 确定由ACE抑制介导的突触变化的突触前和突触后成分。这 提议将跨学科技术纳入基础科学机制和 翻译应用程序将为成为一名独立医生提供无与伦比的培训潜力 科学家。