Mechanisms underlying opiate-induced neuroplasticity at the synapse

描述（由申请人提供）：虽然阿片类药物的滥用和成瘾一直是一个长期存在的问题，但最近阿片类镇痛药滥用的激增预示着阿片类药物成瘾率可能上升。重复施用滥用药物，例如吗啡，会导致其运动兴奋剂和正强化作用逐渐且持续的敏化。对吗啡的敏感性可以在停药后持续数月，并可作为可塑性和与重复施用具有滥用潜力的阿片类药物相关的神经适应的有用动物模型。研究表明，致敏与复吸、强迫性寻药、吸毒行为密切相关。最近的证据表明海马体在控制这些持久的行为适应中发挥着作用。对阿片类药物引起的致敏作用的研究可能有助于我们更好地了解复发机制，并为药物成瘾的治疗提供新策略。此外，海马突触在学习和记忆中的关键作用表明，了解其特殊的亚细胞区室在成瘾过程中的作用至关重要。谷氨酸能系统被认为与阿片类药物诱导的神经元和行为可塑性有关，尽管这些作用背后的机制才刚刚开始被了解。我们建议分析突触 AMPA 谷氨酸受体在与吗啡重复给药相关的神经元适应中的作用。拟议的实验将验证重复吗啡给药通过改变 AMPA 谷氨酸受体的表达和组成来调节海马突触的突触传递和可塑性的假设；并且这些适应性效应将随着时间的推移持续存在，导致谷氨酸能突触功能的神经适应，这可能是重复吗啡诱导诱导的长期行为敏化的原因。在具体目标 1 中，我们将分析重复吗啡给药引发的神经适应背后的突触机制，这种神经适应驱动海马突触 AMPA 谷氨酸受体 GluR 亚基 (GluR1/2/3) 的表达和组成的动态变化，并确定它们与长期行为敏化的相关性。在具体目标 2 中，我们将描述重复吗啡给药后基础突触传递过程中谷氨酸能突触 GluR 亚基组成和海马可塑性的电生理机制，并确定其持久性。这些研究意义重大，因为它们阐明了海马突触突触神经传递的神经适应性变化的关键机制以及重复吗啡暴露时发生的行为反应；此外，他们还将深入了解神经元的适应，这可能会导致阿片成瘾药物治疗干预的新方法。公共卫生相关性：反复接触滥用药物的长期影响是药物成瘾病理生理学研究的一个主要关注点。重复服用多种可能成瘾的药物，例如吗啡，会增强其运动刺激作用（称为行为敏化）及其激励动机特性，这种作用在停止给药后持续数月，从而模仿了人类成瘾者对药物的长期敏感性。本提案将通过表征重复吗啡给药后突触水平上海马神经传递的调节和改变来分析吗啡诱导敏化的潜在机制。

DESCRIPTION (provided by applicant): While abuse and addiction to opiates has been a long-standing problem, the recent surge in abuse of opiate analgesics foreshadows the potential for rising rates of addiction to opiates. Repeated administration of drugs of abuse, such as morphine, causes a progressive and persistent sensitization of its locomotor stimulant and positive reinforcing effects. Sensitization to morphine can be sustained for several months after drug cessation and serves as a useful animal model of plasticity and the neuroadaptations associated with repeated administration of opioids having abuse potential. Studies show that sensitization has a close relationship with relapse, compulsive drug-seeking, and drug-taking behavior. Recent evidence suggests a role for the hippocampus in controlling these long-lasting behavioral adaptations. Investigation of an opiate-induced sensitization may help us to better understand the relapse mechanisms and provide new strategies for the treatment of drug addiction. Additionally, the key role of hippocampal synapses in learning and memory suggests that an understanding of the role of its specialized subcellular compartments in addictive processes is essential. Glutamatergic systems are thought to be involved in opiate-induced neuronal and behavioral plasticity although the mechanisms underlying these effects are only beginning to be understood. We propose to analyze the role of synaptic AMPA glutamate receptors in the neuronal adaptations associated with repeated administration of morphine. The proposed experiments will test the hypothesis that repeated morphine administration modulates synaptic transmission and plasticity at hippocampal synapses by altering the expression and composition of AMPA glutamate receptors; and that these adaptive effects will persist over time leading to neuroadaptations in glutamatergic synaptic function which could be responsible for the long-term behavioral sensitization induced by repeated morphine administration. In Specific Aim 1 we will analyze the synaptic mechanisms underlying the neuroadaptations initiated by repeated morphine administration which drive dynamic changes in the expression and composition of GluR subunits (GluR1/2/3) of AMPA glutamate receptors at hippocampal synapses and determine their correlation with long-term behavioral sensitization. In Specific Aim 2 we will characterize the electrophysiological mechanisms contributing to GluR subunit composition at glutamatergic synapses during basal synaptic transmission and plasticity in the hippocampus following repeated morphine administration, and determine their persistence. These studies are significant because they elucidate key mechanisms underlying neuroadaptive changes in synaptic neurotransmission at hippocampal synapses and behavioral responses that occur upon repeated morphine exposure; in addition, they will provide insight into the neuronal adaptations that may lead to novel approaches for pharmacotherapeutic intervention of opiate addiction. PUBLIC HEALTH RELEVANCE: The long-term effects of repeated exposure to drugs of abuse are a major point of interest in the study of the pathophysiology of drug addiction. The repeated administration of a variety of potentially addictive drugs, such as morphine, produces increases in their motor-stimulant effects (called behavioral sensitization) and their incentive-motivational properties that persist many months after cessation of drug administration, thus mimicking long-term sensitivity to drugs observed in human addicts. The present proposal will analyze the mechanisms underlying morphine-induced sensitization by characterizing the modulation and alteration of hippocampus neurotransmission at the synaptic level upon repeated morphine administration.