权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8415890
负责人：
MICHAEL J GLASS
金额：
$ 23.23万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415890
关键词：
AMPA Receptors Acute Addictive Behavior Address Affect Amygdaloid structure Animals 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 Opioid Receptor 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

项目摘要

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药物暴露终止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，依赖有助于成瘾的循环。虽然对依赖性的神经基质知之甚少，但有证据表明，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起着关键作用。在PI目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，而不会影响身体症状。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厌恶和AMPA受体可塑性中发挥关键作用。这一假设将通过以下具体目的来解决：目的1将检验CeA敲除NR1将产生特异性抑制阿片类药物戒断厌恶的假设。目的2将检验多阿片受体（OR）和嗜离子性谷氨酸受体在CeA神经元的树突和树突棘（即突触后）共定位的假设。Aim 3将验证急性阿片类药物暴露可以影响CeA神经元突触后位点AMPA-GluR2受体亚基的运输，这一过程可以通过局部NR1基因缺失来抑制。为了解决这些假设，最先进的技术，包括时空敲除方法和受体运输的定量超微结构分析，将在阿片类药物依赖模型的背景下使用。这些研究将阐明与吗啡使用相关的行为和神经可塑性相关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遗传学和神经解剖学基础的认识。尽管阿片类药物具有临床疗效，但它们的滥用和成瘾性是公共卫生问题的一个重要来源。长期使用阿片类药物似乎与一个复杂的信号分子网络有关，特别是谷氨酸受体，它位于大脑边缘区域，产生与正常学习和记忆相关的神经变化。利用最先进的分子药理学和神经解剖学技术，本提案将确定谷氨酸受体在阿片类药物依赖特定脑通路中的作用。通过阐明介导依赖不良后果的神经生物学过程，我们可以为开发减少这些有害行为的药理学干预提供关键信息。