Metabotropic glutamate regulation of synaptic rewiring in opioid addiction

阿片类药物成瘾中突触重新布线的代谢型谷氨酸调节

• 批准号: 10455293
• 负责人: Stefano Zucca
• 金额: $ 7.71万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455293
• 关键词: Ablation; Agonist; American; Amygdaloid structure; Analgesics; Attenuated; Basal Ganglia; Behavioral; Brain; Brain region; Cells; Cessation of life; Chronic; Complex; Corpus striatum structure; Data; Dependence; Development; Disease; Economic Burden; Electrophysiology (science); Ensure; Etiology; Exposure to; Fibronectins; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Homeostasis; Hypersensitivity; Imaging Techniques; Interneurons; Investigation; Knockout Mice; Knowledge; Laboratories; Learning; Leucine-Rich Repeat; Malignant Neoplasms; Medical; Metabotropic Glutamate Receptors; Morphine; Motivation; Mus; Neurobiology; Neuromodulator; Neurons; Opiate Addiction; Opioid; Opioid Receptor; Pain management; Pathology; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Prefrontal Cortex; Presynaptic Terminals; Process; Property; Proteins; Psychological reinforcement; Recording of previous events; Regulation; Relapse; Research; Rewards; Role; Specific qualifier value; Specificity; Structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; System; Tertiary Protein Structure; Testing; Time; Ventral Striatum; Ventral Tegmental Area; Viral; Withdrawal; Work; addiction; base; behavior test; behavioral study; cellular targeting; cholinergic; cholinergic neuron; clinical practice; dopaminergic neuron; drug of abuse; drug seeking behavior; effective therapy; extracellular; glutamatergic signaling; learned behavior; mesolimbic system; metabotropic glutamate receptor 4; metabotropic glutamate receptor 7; morphine administration; motivated behavior; mu opioid receptors; nerve supply; neural circuit; neuroadaptation; neuronal circuitry; neurotransmitter release; novel; opiate tolerance; opioid abuse; opioid epidemic; opioid exposure; opioid misuse; opioid overdose; opioid use disorder; pain relief; patch clamp; pleasure; positive allosteric modulator; postsynaptic; presynaptic; presynaptic neurons; prevent; protein expression; receptor; recruit; relating to nervous system; response; reward circuitry; segregation; selective expression; side effect; social; transmission process

Project Summary The development of opioids tolerance and dependence represents a major social and economic burden globally. Opioids exert their effect by the activation of opioid receptors in the mesolimbic system to produce pleasurable effects and relieve pain. Of the three known opioid receptors, the mu type (MOR) is broadly expressed throughout the reward circuit of the brain where both dopaminergic neurons and glutamatergic neurons have been identified as critical components for the opioids reward, dependence, tolerance and withdrawal. Our long-term goal is to understand the cellular mechanisms underlying the effects of opioids on synaptic transmission and plasticity within reward-related neural circuits. Neuroadaptations of ionotropic glutamate receptors occur in response to persistent opioid exposure and emerging evidences suggest that metabotropic glutamate receptors (mGluRs) are also active regulators of MOR actions. mGluRs regulate neurotransmitter release to ensure basal ganglia homeostasis and available data support a role for mGluRs to reduce the release of glutamate that is produced during drug-seeking behaviors. Receptors belonging to group III (mGluR4/7/8) are distributed within the reward circuitry on glutamatergic corticostriatal afferents and GABAergic striatopallidal neurons. Preliminary data in our lab provided evidences that mGluR III type receptors form complexes with extracellular leucine-rich repeats fibronectin type-3 domain protein, Elfn1. This trans- synaptic protein is selectively expressed in cholinergic interneurons of the striatum and its elimination increases rewarding effects of morphine. Here I propose to investigate the functions of Elfn1 proteins and their involvement in the synaptic rewiring of striatal circuits that occurs during repetitive opioid exposure. I will use a combination of whole-cell patch-clamp electrophysiology and behavioral studies to pursue the following aims: In Aim 1 I will identify the subtype of mGluRs at presynaptic terminals interacting with Elfn1 proteins and characterize the synaptic properties of Elfn1 expressing neurons within specific neuronal circuits of the reward system. In Aim 2 I will examine the involvement of Elfn1-mGluRs complexes in the regulation of rewards properties of opioids and investigate their contribution to the synaptic rewiring associated with opioid exposure. The proposed studies will provide the causality between mGluRs modulation of synaptic plasticity in Elfn1-expressing neurons and the behavioral adaptations occurring with opioid exposure, greatly broadening the knowledge of opioid plasticity. Moreover, this research has the potential to identify novel cellular targets for the rewarding effects of opioids, and facilitate the search for better treatments for opioid addiction.

项目摘要 阿片类药物耐受和依赖的发展是一个重大的社会和经济负担。 全球范围内。阿片类药物通过激活中脑边缘系统中的阿片受体发挥作用 令人愉悦的效果和缓解疼痛。在已知的三种阿片受体中，MU型(MOR)是广泛存在的 在大脑的奖赏回路中表达，其中多巴胺能神经元和谷氨酸能 神经元被认为是阿片类药物奖赏、依赖、耐受和 戒烟。我们的长期目标是了解阿片类药物对 奖赏相关神经回路中的突触传递和可塑性。嗜离子神经的神经适应 谷氨酸受体是对持续的阿片类药物暴露的反应，新的证据表明 代谢性谷氨酸受体(MGluRs)也是MOR作用的活性调节因子。MGluRs调节 神经递质释放以确保基底节内稳态和现有数据支持mGluRs的作用 减少在寻求毒品行为中产生的谷氨酸的释放。属于组的受体 III(mGluR4/7/8)分布于谷氨酸能皮质纹状体传入神经元的奖赏回路内。 GABA能纹状体丘脑神经元。我们实验室的初步数据为mGluR III型受体提供了证据 与胞外富含亮氨酸的重复纤维连接蛋白3型结构域蛋白Elfn1形成复合体。这本书-- 突触蛋白在纹状体胆碱能中间神经元中选择性表达及其清除增加 吗啡的奖赏作用。在这里，我建议研究Elfn1蛋白的功能及其参与 在重复阿片类药物暴露期间纹状体回路的突触重新布线中。我将使用组合 全细胞膜片钳电生理和行为学研究追求以下目标：在目标1中，我将 鉴定突触前终末与Elfn1蛋白相互作用的mGluR亚型 Elfn1在奖赏系统特定神经元回路中表达神经元的突触特性。在AIM 2 我将研究Elfn1-mGluRs复合体参与阿片类药物奖赏特性的调节和 研究它们在与阿片类药物暴露相关的突触重新连接中的作用。拟议的研究将 提供Elfn1表达神经元中mGluRs调节突触可塑性与 与阿片类药物接触发生的行为适应，极大地拓宽了对阿片类药物可塑性的认识。 此外，这项研究有可能为阿片类药物的奖励作用确定新的细胞靶点， 并促进寻找更好的阿片成瘾治疗方法。