Metabotropic glutamate regulation of synaptic rewiring in opioid addiction

项目摘要 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 在全球阿片类药物通过激活中脑边缘系统中的阿片受体发挥其作用，以产生 愉悦的效果和减轻疼痛。在三种已知的阿片受体中，μ型（莫尔）广泛地被认为是阿片受体的一种。 表达在大脑的奖赏回路中，多巴胺能神经元和多巴胺能神经元都在那里。 神经元已被确定为阿片类药物奖赏、依赖、耐受和 戒断我们的长期目标是了解阿片类药物对神经细胞的影响的细胞机制。 奖赏相关神经回路中的突触传递和可塑性。亲离子性神经适应 谷氨酸受体对持续的阿片类药物暴露产生反应，新的证据表明， 代谢型谷氨酸受体（mGluR）也是莫尔作用的活性调节剂。mGluRs调节 神经递质的释放，以确保基底神经节的稳态和现有的数据支持的作用，mGluRs， 减少在寻求药物的行为中产生的谷氨酸盐的释放。属于组的受体 III（mGluR 4/7/8）分布在多巴胺能皮质纹状体传入的奖赏回路内， GABA能纹状体苍白球神经元。我们实验室的初步数据提供了mGluR III型受体 与细胞外富含亮氨酸的重复纤维连接蛋白3型结构域蛋白Elfn 1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，并且其消除增加 吗啡的奖励作用在这里，我建议研究Elfn 1蛋白的功能及其参与 在反复暴露于阿片类药物时，纹状体回路的突触重新连接。我会用一个组合 全细胞膜片钳电生理学和行为学研究，以追求以下目标：在目标1，我将 鉴定突触前末端与Elfn 1蛋白相互作用的mGluR亚型，并表征 在奖励系统的特定神经元回路中表达Elfn 1的神经元的突触特性。在目标2 我将研究Elfn 1-mGluRs复合物参与阿片类药物的奖励特性的调节， 研究它们对与阿片类药物暴露相关的突触重新连接的贡献。拟议的研究将 提供了在表达Elfn 1的神经元中mGluRs对突触可塑性的调节与 行为适应与阿片类药物暴露发生，大大拓宽阿片类药物可塑性的知识。 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类药物成瘾治疗方法。

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.