Mechanisms underlying opiate-induced neuroplasticity at the synapse

描述（由申请方提供）：虽然阿片类药物滥用和成瘾是一个长期存在的问题，但最近阿片类镇痛剂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，如吗啡，会导致其运动兴奋剂和积极强化作用的进行性和持续性敏化。对吗啡的致敏作用可在停药后持续数月，并可作为与重复给予具有滥用潜力的阿片类药物相关的可塑性和神经适应性的有用动物模型。研究表明，致敏与复吸、强迫性觅药、吸毒行为有密切关系。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。对阿片类药物致敏的研究有助于我们更好地理解复吸机制，并为药物成瘾的治疗提供新的策略。此外，海马突触在学习和记忆中的关键作用表明，了解其专门的亚细胞区室在成瘾过程中的作用是必不可少的。谷氨酸能系统被认为参与阿片诱导的神经元和行为可塑性，尽管这些作用的机制才刚刚开始被理解。我们建议分析的作用，突触AMPA谷氨酸受体在神经元的适应与重复管理的吗啡。拟议的实验将测试的假设，重复吗啡管理调制突触传递和可塑性在海马突触通过改变AMPA谷氨酸受体的表达和组成，这些适应性的影响将持续随着时间的推移，导致神经适应性突触功能，这可能是负责长期的行为敏化诱导吗啡管理。在具体目标1中，我们将分析由重复吗啡给药引发的神经适应的突触机制，这些机制驱动海马突触AMPA谷氨酸受体GluR亚基（GluR 1/2/3）表达和组成的动态变化，并确定其与长期行为敏化的相关性。在具体目标2中，我们将描述在基础突触传递和可塑性在海马重复吗啡给药后的海马体中的谷氨酸受体亚基组成的电生理机制，并确定其持久性。这些研究是重要的，因为它们阐明了神经适应性变化的关键机制，在海马突触和行为反应，发生在反复吗啡暴露后的突触神经传递;此外，他们将提供深入了解神经元的适应，可能导致阿片类药物成瘾的药物干预的新方法。公共卫生相关性：重复接触滥用药物的长期影响是药物成瘾病理生理学研究中的一个主要兴趣点。重复使用各种可能成瘾的药物，如吗啡，会增加其运动刺激效应（称为行为敏化）和其在停止给药后持续数月的激励-动机特性，从而模仿人类成瘾者对药物的长期敏感性。本研究拟通过观察吗啡重复给药后海马神经传递在突触水平的变化来分析吗啡致敏的机制。

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.