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）：阿片类药物依赖性的特征是在终止药物暴露后出现的负面生理和心理症状。由于这些症状可以通过继续使用药物来缓解或避免，因此依赖有助于成瘾的循环。尽管对依赖性的神经底物的理解很少，但有证据表明，中央杏仁核（CEA）中功能性离子型（NMDA和AMPA）谷氨酸受体（CEA）在这种形式的阿片类依赖性形式中起着至关重要的作用。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，并防止吗啡戒断诱导的厌食，而不会影响身体症状。本提案的目的是通过测试以下全球假设来扩展这些发现：中央杏仁核NMDA受体在条件厌恶和AMPA受体可塑性与阿片类药物依赖性相关的情况下都起着关键作用。该假设将通过以下特定目的来解决：AIM 1将检验以下假设：NR1的CEA敲除将产生特定的阿片类药物戒断厌恶。 AIM 2将检查以下假设：在CEA神经元中，在树突和树突棘（即突触后）中共定位了Mu-阿片受体（OR）和离子型谷氨酸受体。 AIM 3将检验以下假设：急性阿片类药物暴露会影响CEA神经元突触后部位的AMPA-GLUR2受体亚基的运输，这一过程可以被局部NR1基因缺失抑制。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对受体运输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，从而扩展了我们对阿片类药物依赖性神经遗传学和神经解剖学底物的了解。尽管阿片类药物具有临床功效，但它们的虐待和上瘾的责任是公共卫生问题的重要来源。在边缘大脑区域，长期使用阿片类药物似乎参与了复杂的信号分子网络，尤其是谷氨酸受体的网络，产生与正常学习和记忆相似的神经变化。使用最先进的分子药理和神经解剖学技术，该建议将确定谷氨酸受体在阿片类药物依赖性在特定脑途径中的作用。通过阐明介导依赖不利后果的神经生物学过程，我们可以提供开发用于减少这些有害行为的药理干预所需的关键信息。