Mechanisms underlying opiate-induced neuroplasticity at the synapse

阿片类药物诱导突触神经可塑性的机制

• 批准号: 7591381
• 负责人: Jose A Moron-Concepcion
• 金额: $ 26.43万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591381
• 关键词: AMPA Receptors; Adult; Analgesics; Animal Model; Behavior; Behavior Disorders; Behavioral; Biochemical; Cells; Chronic; Development; Drug Addiction; Drug usage; Electron Microscopy; Exposure to; Functional disorder; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Human; Incentives; Intervention; Investigation; Lead; Learning; Long-Term Effects; Memory; Morphine; Motor; Neuronal Plasticity; Neurons; Opiate Addiction; Opiates; Opioid; Pathway interactions; Pharmaceutical Preparations; Process; Property; Relapse; Research; Role; Stimulus; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Time; addiction; behavioral sensitization; drug of abuse; drug relapse; innovation; insight; interest; neuroadaptation; neurotransmission; novel; novel strategies; opioid abuse; public health relevance; research study; response; synaptic function; tool; trafficking; transmission process; treatment strategy

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.

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。反复使用滥用药物，如吗啡，会导致其运动刺激物的持续致敏和积极的强化作用。吗啡致敏可在停药后持续数月，可作为反复服用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、强迫性觅药和吸毒行为密切相关。最近的证据表明，海马体在控制这些长期的行为适应方面发挥了作用。对阿片类药物致敏的研究有助于我们更好地了解其复发机制，并为药物成瘾的治疗提供新的策略。此外，海马体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，尽管这些影响的机制才刚刚开始被理解。我们建议分析突触AMPA谷氨酸受体在与吗啡重复施用相关的神经元适应中的作用。本实验将验证反复给药吗啡通过改变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；这些适应效应会持续一段时间导致谷氨酸突触功能的神经适应这可能是由反复注射吗啡引起的长期行为致敏的原因。在Specific Aim 1中，我们将分析反复吗啡给药引发的神经适应的突触机制，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致敏的相关性。在Specific Aim 2中，我们将描述在基础突触传递过程中谷氨酸能突触中GluR亚基组成的电生理机制，以及反复给药后海马的可塑性，并确定其持久性。这些研究具有重要意义，因为它们阐明了反复暴露于吗啡后海马突触突触神经传递和行为反应的神经适应性变化的关键机制；此外，它们将提供对神经元适应的见解，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：反复接触药物滥用的长期影响是药物成瘾病理生理学研究的一个主要兴趣点。反复服用各种可能上瘾的药物，如吗啡，会增加它们的运动刺激作用（称为行为致敏）和它们的激励动机特性，这种特性在停止服药后持续数月，从而模仿人类成瘾者对药物的长期敏感性。本研究将通过描述吗啡在突触水平对海马神经传递的调节和改变来分析吗啡致敏的机制。