Mechanisms underlying opiate-induced neuroplasticity at the synapse

描述(申请人提供)：虽然鸦片类药物的滥用和成瘾一直是一个长期存在的问题，但最近鸦片类镇痛剂的滥用激增预示着鸦片类药物成瘾率可能会上升。反复服用滥用药物，如吗啡，会导致对其运动刺激物和积极强化作用的渐进和持久的敏感化。停药后对吗啡的敏化可持续数月，可作为一种有用的动物模型，用于研究反复使用具有滥用潜力的阿片类药物的可塑性和神经适应。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方面发挥了作用。研究阿片类药物的致敏作用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的策略。此外，海马区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室在成瘾过程中的作用是至关重要的。谷氨酸能系统被认为参与了阿片类药物诱导的神经元和行为可塑性，尽管这些效应背后的机制才刚刚开始被理解。我们建议分析突触AMPA谷氨酸受体在反复给药吗啡相关的神经元适应中的作用。这些实验将验证一种假说，即重复注射吗啡通过改变AMPA谷氨酸受体的表达和组成来调节海马区突触的突触传递和可塑性；这些适应性效应将随着时间的推移而持续，导致谷氨酸能突触功能的神经适应，这可能是重复注射吗啡导致的长期行为敏化的原因。在具体目标1中，我们将分析反复给药引起的神经适应的突触机制，这些机制导致海马谷氨酸受体GluR亚单位(GluR1/2/3)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。在特定的目标2中，我们将描述在基础突触传递和重复给药后海马区的可塑性过程中，谷氨酸能突触GluR亚单位组成的电生理机制，并确定其持久性。这些研究意义重大，因为它们阐明了海马区突触神经传递的神经适应性变化的关键机制，以及重复使用吗啡时发生的行为反应；此外，它们还将为阿片类药物成瘾的药物治疗干预提供可能导致新方法的神经元适应性的洞察。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中的一个主要问题。重复使用各种潜在的成瘾药物，如吗啡，会增加它们的运动刺激效应(称为行为敏化)，以及它们的激励-激励特性，并在停止给药数月后持续存在，从而模仿人类吸毒者对药物的长期敏感性。本研究将通过在突触水平上表征重复给药对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.