GLUTAMATE RECEPTORS AND OPIOID DEPENDENCE: MOLECULES, CIRCUITS AND BEHAVIOR

谷氨酸受体和阿片类药物依赖性：分子、电路和行为

• 批准号: 7766956
• 负责人: MICHAEL J GLASS
• 金额: $ 24.95万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7766956
• 关键词: AMPA Receptors; Acute; Addictive Behavior; Address; Affect; Amygdaloid structure; Animals; Arts; Attenuated; Behavior; Behavioral; Behavioral Model; Bilateral; Brain region; Cell Nucleus; Chronic; Complex; Cues; Dendrites; Dendritic Spines; Dependence; Development; Dose; Drug Exposure; Drug usage; Gene Deletion; Genes; Genetic; GluR2 subunit AMPA receptor; Glutamate Receptor; Goals; Injection of therapeutic agent; Intervention; Knock-out; Knowledge; Learning; Mediating; Memory; Mentored Research Scientist Development Award; Methodology; Methods; Microinjections; Modeling; Molecular; Morphine; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Naloxone; Neurobiology; Neuronal Plasticity; Neurons; Opiate Addiction; Opioid; Pathway interactions; Physiological; Play; Process; Property; Public Health; Role; Self Administration; Signal Transduction; Signaling Molecule; Site; Source; Symptoms; Synapses; Techniques; Technology; Testing; Withdrawal; addiction; adverse outcome; brain pathway; clinical efficacy; mature animal; mu opioid receptors; neurogenetics; novel; opioid withdrawal; postsynaptic; prevent; psychologic; receptor; relating to nervous system; trafficking

DESCRIPTION (provided by applicant): Opioid dependence is characterized by negative physiological and psychological symptoms that arise following termination of drug exposure. Since these symptoms can be relieved or avoided by continued drug use, dependence contributes to the cycle of addiction. While the neural substrates of dependence are poorly understood, evidence is emerging that functional ionotropic (NMDA and AMPA) glutamate receptors in the central amygdala (CeA) play a critical role in this form of opioid-dependent plasticity. Studies conducted during the PI's current Research Scientist Development Award have shown that Cre-loxP technology can be used to delete the NMDA-NR1 (NR1) receptor subunit gene in CeA neurons and prevent morphine withdrawal-induced aversion, without affecting physical symptoms. The goal of the present proposal is to expand on these findings by testing the following global hypothesis: Central amygdala NMDA receptors play critical roles in both conditioned aversion and AMPA receptor plasticity associated with opioid dependence. This hypothesis will be addressed by the following Specific Aims: Aim 1 will test the hypothesis that CeA knockout of NR1 will produce a specific inhibition of opioid withdrawal aversion. Aim 2 will examine the hypothesis that mu-opioid receptors (OR) and ionotropic glutamate receptors are co-localized in dendrites and dendritic spines (i.e. postsynaptically) in CeA neurons. Aim 3 will test the hypothesis that acute opioid exposure can affect the trafficking of the AMPA-GluR2 receptor subunit at postsynaptic sites in CeA neurons, a process that can be inhibited by local NR1 gene deletion. To address these hypotheses, state-of-the-art technology, including spatial-temporal knockout methods and quantitative ultrastructural analysis of receptor trafficking, will be employed within the context of models of opioid dependence. These studies should elucidate the role of key molecules and intracellular processes involved in both behavioral and neural plasticity associated with morphine use, thus expanding our knowledge of the neurogenetic and neuroanatomical substrates of opioid dependence. Despite the clinical efficacy of opioids, their abuse and addictive liability are a significant source of public health problems. Chronic use of opioids appear to engage a complex network of signaling molecules, particularly glutamate receptors, in limbic brain regions that produce neural changes similar to those involved in normal learning and memory. Using state of the art molecular pharmacological and neuroanatomical techniques, this proposal will identify the role of glutamate receptors in opioid dependence in specific brain pathways. By elucidating the neurobiological processes that mediate the adverse consequences of dependence, we may provide critical information needed to develop pharmacological interventions for reducing these deleterious actions.

描述（由申请人提供）：阿片类药物依赖的特征是在停止药物暴露后出现负面的生理和心理症状。由于这些症状可以通过继续吸毒来缓解或避免，因此依赖性会导致成瘾的循环。虽然人们对依赖性的神经底物知之甚少，但越来越多的证据表明，中央杏仁核 (CeA) 中的功能性离子型（NMDA 和 AMPA）谷氨酸受体在这种形式的阿片依赖性可塑性中发挥着关键作用。在 PI 当前的研究科学家发展奖期间进行的研究表明，Cre-loxP 技术可用于删除 CeA​​ 神经元中的 NMDA-NR1 (NR1) 受体亚基基因，并防止吗啡戒断引起的厌恶，而不影响身体症状。本提案的目标是通过测试以下全球假设来扩展这些发现：中央杏仁核 NMDA 受体在与阿片类药物依赖相关的条件性厌恶和 AMPA 受体可塑性中发挥着关键作用。该假设将通过以下具体目标来解决：目标 1 将测试以下假设：CeA 敲除 NR1 将产生对阿片类药物戒断厌恶的特异性抑制。目标 2 将检验以下假设：mu-阿片受体 (OR) 和离子型谷氨酸受体共定位于 CeA 神经元的树突和树突棘（即突触后）。目标 3 将检验以下假设：急性阿片类药物暴露会影响 CeA 神经元突触后位点的 AMPA-GluR2 受体亚基的运输，这一过程可以通过局部 NR1 基因删除来抑制。为了解决这些假设，将在阿片类药物依赖模型的背景下采用最先进的技术，包括时空敲除方法和受体贩运的定量超微结构分析。这些研究应阐明与吗啡使用相关的行为和神经可塑性中涉及的关键分子和细胞内过程的作用，从而扩大我们对阿片类药物依赖的神经发生和神经解剖学基础的了解。尽管阿片类药物具有临床疗效，但其滥用和成瘾倾向是公共卫生问题的重要根源。长期使用阿片类药物似乎会参与大脑边缘区域的复杂信号分子网络，特别是谷氨酸受体，这些信号分子会产生与正常学习和记忆相似的神经变化。利用最先进的分子药理学和神经解剖学技术，该提案将确定谷氨酸受体在特定大脑通路中阿片类药物依赖中的作用。通过阐明介导依赖性不良后果的神经生物学过程，我们可以提供开发药物干预措施以减少这些有害行为所需的关键信息。