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

基本信息

批准号：
9760153
负责人：
Stefano Zucca
金额：
$ 6.77万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760153
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

项目摘要

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.

项目概要阿片类药物耐受性和依赖性的发展是一个重大的社会和经济负担全球。阿片类药物通过激活中脑边缘系统中的阿片受体来发挥作用，产生令人愉悦的效果并减轻疼痛。在三种已知的阿片受体中，mu 型 (MOR) 广泛存在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神经元已被确定为阿片类药物奖励、依赖性、耐受性和撤回。我们的长期目标是了解阿片类药物影响的细胞机制奖励相关神经回路中的突触传递和可塑性。离子型神经适应谷氨酸受体的发生是对持续阿片类药物暴露的反应，新出现的证据表明代谢型谷氨酸受体 (mGluR) 也是 MOR 作用的主动调节因子。 mGluR 调节神经递质释放以确保基底神经节稳态，现有数据支持 mGluRs 的作用减少寻求药物行为期间产生的谷氨酸的释放。属于组的受体 III (mGluR4/7/8) 分布在谷氨酸能皮质纹状体传入神经的奖赏回路内 GABA能纹状体苍白球神经元。我们实验室的初步数据证明 mGluR III 型受体与细胞外富含亮氨酸重复序列的纤连蛋白 3 型结构域蛋白 Elfn1 形成复合物。这个反式突触蛋白在纹状体的胆碱能中间神经元中选择性表达，其消除增加吗啡的奖励作用。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发生的纹状体回路突触重新布线中。我将使用一个组合全细胞膜片钳电生理学和行为研究，以实现以下目标：在目标 1 中，我将识别突触前末端与 Elfn1 蛋白相互作用的 mGluR 亚型并表征奖励系统特定神经元回路内表达 Elfn1 的神经元的突触特性。目标 2 我将研究 Elfn1-mGluRs 复合物在阿片类药物奖赏特性调节中的作用，研究它们对与阿片类药物暴露相关的突触重新布线的贡献。拟议的研究将提供 mGluRs 对表达 Elfn1 的神经元突触可塑性的调节与接触阿片类药物后发生的行为适应，极大地拓宽了阿片类药物可塑性的知识。此外，这项研究有可能确定新的细胞靶点，以实现阿片类药物的奖励作用，并促进寻找更好的阿片类药物成瘾治疗方法。