AMYGDALA AMPA GLUR2 DELETION AND OPIOID DEPENDENCE

杏仁核 AMPA GLUR2 缺失和阿片类药物依赖性

• 批准号: 7712282
• 负责人: MICHAEL J GLASS
• 金额: $ 8.45万
• 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: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712282
• 关键词: AMPA Receptors; Address; Amygdaloid structure; Arts; Attenuated; Behavior; Behavioral; Bilateral; Biological Models; Calcium; Cell Nucleus; Chronic; Complication; Cues; Dependence; Development; Disease; Drug Addiction; Drug usage; Electron Microscopy; Electrons; Exposure to; Gene Deletion; Gene Expression; Genetic; GluR2 subunit AMPA receptor; Glutamate Receptor; Goals; Immunohistochemistry; In Situ Hybridization; Intervention; Knock-out; Lead; Learning; Light; Link; Mediating; Memory; Messenger RNA; Microinjections; Modeling; Molecular; Morphine; Mus; N-Methyl-D-Aspartate Receptors; Naloxone; Neurobiology; Neuronal Plasticity; Neurons; Opiate Addiction; Opioid; Permeability; Pharmaceutical Preparations; Play; Process; Proteins; Public Health; Receptor Activation; Receptor Gene; Role; Source; Symptoms; Syndrome; Techniques; Testing; Therapeutic; Viral Vector; Withdrawal; Withdrawal Symptom; addiction; aversive conditioning; base; behavior measurement; clinical efficacy; drug seeking behavior; experience; interdisciplinary approach; neuromechanism; neurotropic; opioid withdrawal; postsynaptic; recombinase; relating to nervous system; small molecule; therapeutic gene

DESCRIPTION (provided by applicant): Opioid dependence is a major complication of chronic opioid use that contributes to the syndrome of addiction. In addition to the avoidance of withdrawal symptoms, experience of withdrawal-associated cues may also play an important role in drug taking behavior. Thus, elucidating the neurobiological processes that mediate the adverse consequences of chronic opioid use, particularly involving the role of aversive learning, may provide critical information for managing addictive disease. There is evidence that ionotropic AMPA-type glutamate receptors in the central nucleus of the amygdala (CeA) may be important molecular substrates of opioid dependence. The AMPA-GluR2 (GluR2) receptor subunit is a major component of AMPA receptors, determines calcium permeability, has been implicated in drug dependence, and is expressed in the CeA. The activity of GluR2 expressing AMPA receptors is modulated by NMDA-type glutamate receptors, which are themselves, established molecular substrates of neural and behavioral adaptability. Despite these findings, there is no direct evidence that GluR2 gene expression in the CeA is necessary for the expression of opioid dependence. The primary goal of this application is to develop a spatial-temporal deletion of the AMPA-GluR2 receptor subunit to test the hypothesis that postsynaptic expression of GluR2 in central amygdala neurons is necessary for opioid withdrawal- induced conditioned place aversion (CPA). This hypothesis will be investigated by producing a postsynaptic deletion of GluR2 in central amygdala neurons of floxed GluR2 mice via local microinjection of a neurotropic adenoassociated viral vector expressing Cre recombinase. The viability of local gene deletion will be tested by light and electron immunohistochemistry and in situ hybridization. The phenotypic effects of CeA GluR2 deletion will be determined by behavioral measurements, including withdrawal-induced conditioned place aversion. This project is expected to enhance our understanding of the role of neuronal glutamate receptor gene expression in opioid dependence, particularly with respect to the possible value of AMPA-GluR2 based small molecule or gene therapeutics. Despite the clinical efficacy of opioids, their abuse and addictive liabilities are significant sources of public health problems. Opioids may produce their long-lasting effects by activating amygdala glutamate receptors, molecules that play important roles in neural plasticity, as well as learning and memory. Using state of the art molecular neuropharmacological techniques, this proposal will identify the role of the AMPA-type glutamate receptor GluR2 subunit in the amygdala with respect to opioid dependence. 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）：阿片类药物依赖性是慢性阿片类药物使用的主要并发症，导致成瘾综合征。除了避免戒断症状外，戒断相关线索的经验在吸毒行为中也可能发挥重要作用。因此，阐明介导慢性阿片类药物的不利后果的神经生物学过程，尤其是涉及厌恶学习的作用，可能会为管理成瘾性疾病提供关键信息。有证据表明，杏仁核中央核（CEA）中心核中的离子型AMPA型谷氨酸受体可能是阿片类药物依赖性的重要分子底物。 AMPA-GLUR2（GLUR2）受体亚基是AMPA受体的主要组成部分，确定钙的渗透性已与药物依赖性有关，并且在CEA中表达。 GlUR2表达AMPA受体的活性由NMDA型谷氨酸受体调节，这些谷氨酸受体本身是神经和行为适应性的分子底物。尽管有这些发现，但尚无直接证据表明，CEA中GlUR2基因的表达对于阿片类药物依赖性的表达是必需的。该应用的主要目的是开发AMPA-GLUR2受体亚基的空间暂时性缺失，以测试中央杏仁核神经元中GlUR2的突触后表达的假设对于阿片类药物戒断诱导的条件条件调节位置（CPA）是必不可少的。该假设将通过通过局部微注射表达CRE重组酶的神经性腺苷相关病毒载体的局部显微注射来研究floxed Glur2小鼠的中央杏仁核神经元中的突触后缺失。局部基因缺失的生存力将通过光和电子免疫组织化学和原位杂交测试。 CEA GLUR2缺失的表型效应将由行为测量（包括戒断诱导的条件位置厌恶）确定。预计该项目将增强我们对神经元谷氨酸受体基因表达在阿片类药物依赖性中的作用的理解，尤其是在基于AMPA-GLUR2的小分子或基因疗法的可能值方面。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。阿片类药物可能通过激活谷氨酸受体，在神经可塑性以及学习和记忆中起重要作用的分子来产生其持久作用。使用最先进的分子神经药物技术，该建议将确定AMPA型谷氨酸受体GlUR2亚基在阿片类药物依赖性方面的作用。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。