Molecular Mechanisms of Cocaine-Induced Alterations in Accumbens AMPA Receptors

可卡因引起伏隔 AMPA 受体改变的分子机制

基本信息

批准号：
8124267
负责人：
RACHEL J SMITH
金额：
$ 5.13万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-15 至 2013-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8124267
关键词：
AMPA Receptors Animals Behavior Behavioral Behavioral Mechanisms Binding Biochemical Brain CD29 Antigen Cell Adhesion Molecules Chronic Cocaine Cues Data Development Disease Dose Drug Addiction Endocytosis Environment Extinction (Psychology)Extracellular Matrix Proteins Glutamate Receptor Glutamates Infusion procedures Inhibition of Matrix Metalloproteinases Pathway Integrin Signaling Pathway Integrin beta3 Integrins Laboratories Lead Learning Light Link Maintenance Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Membrane Proteins Modeling Modification Molecular Molecular Target N-Methyl-D-Aspartate Receptors Neuronal Plasticity Neurons Nucleus Accumbens Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Play Process Proteins Rattus Receptor Signaling Recording of previous events Regulation Relapse Research Rewards Role Saline Self Administration Signal Pathway Signal Transduction Stimulus Structure Surface Synapses Synaptic Transmission Synaptic plasticity Testing Up-Regulation addiction cocaine exposure drug abstinence drug mechanism extracellular inhibitor/antagonist neuroadaptation neurobiological mechanism novel novel therapeutics postsynaptic prevent protein expression receptor receptor expression research study synaptic function transmission process

项目摘要

DESCRIPTION (provided by applicant): Drug addiction is characterized by a high vulnerability to relapse, even following extended drug abstinence. Relapse vulnerability has been linked to dysregulation in nucleus accumbens synaptic function, including altered AMPA glutamate receptor expression. However, the underlying mechanisms of drug-induced changes in accumbens synaptic plasticity are not fully known. Recently, the cell adhesion molecule beta3 integrin was identified as playing a key role in maintaining surface expression of AMPA receptors containing the GluR2 subunit. Data from our laboratory show that chronic intra-accumbens infusion of beta3 integrin modulators to rats during cocaine self-administration reduced subsequent reinstatement of drug-seeking elicited by a cocaine prime and prevented cocaine-induced reductions in GluR2 surface expression. The current proposal is aimed at further elucidating this beta3 integrin signaling pathway to determine the molecular mechanisms of cocaine- induced AMPA receptor changes. I hypothesize that normal beta3 integrin signaling is disrupted by cocaine- induced overactivity of matrix metalloproteinases (MMPs), which causes beta3 integrin-mediated endocytosis of GluR2-containing AMPA receptors via activation of Rap1 intracellular signaling. Specific Aim 1: Using the self-administration model in rats, I first plan to determine whether intra-accumbens core infusions of MMP or Rap1 inhibitors reduce reinstatement of extinguished cocaine-seeking, as seen previously for beta3 integrin modulators. Specific Aim 2: Using the treatment doses found to be most effective for reducing reinstatement behavior, I plan next to evaluate the biochemical consequences of each intra-accumbens treatment (MMP inhibition, Rap1 inhibition, or beta3 integrin modulation). Analyses of accumbens protein expression levels will help reveal the underlying mechanisms of the behavioral effects and possible interactions among components within the hypothesized pathway. Results from these behavioral and biochemical studies will shed light on the molecular mechanisms of cocaine-induced neuroadaptations in accumbens glutamate transmission. PUBLIC HEALTH RELEVANCE: Drug addiction is associated with long-lasting brain changes that cause heightened relapse vulnerability, even after extended drug abstinence. This research study will investigate a molecular signaling pathway that might underlie cocaine-induced changes in synaptic function in nucleus accumbens, a brain structure critically involved in reward learning and addiction. Determining the processes involved in the development of addiction may lead to novel therapeutic options aimed at reversing drug-induced alterations.

描述（由申请人提供）：药物成瘾的特点是即使在长期戒毒后也很容易复发。复发脆弱性与伏隔核突触功能失调有关，包括 AMPA 谷氨酸受体表达的改变。然而，药物引起的伏隔核突触可塑性变化的潜在机制尚不完全清楚。最近，细胞粘附分子β3整合素被确定在维持含有GluR2亚基的AMPA受体的表面表达中发挥着关键作用。我们实验室的数据表明，在可卡因自我给药期间向大鼠伏隔内长期输注β3整合素调节剂，可减少可卡因引发剂随后引起的药物寻求恢复，并防止可卡因诱导的GluR2表面表达减少。目前的提议旨在进一步阐明β3整合素信号通路，以确定可卡因诱导的AMPA受体变化的分子机制。我假设正常的 β3 整合素信号传导被可卡因诱导的基质金属蛋白酶 (MMP) 过度活性破坏，从而通过激活 Rap1 细胞内信号传导导致 β3 整合素介导的含有 GluR2 的 AMPA 受体的内吞作用。具体目标 1：使用大鼠自我给药模型，我首先计划确定伏隔核内注射 MMP 或 Rap1 抑制剂是否会减少已熄灭的可卡因寻求的恢复，正如之前在 β3 整联蛋白调节剂中所观察到的那样。具体目标 2：使用对减少恢复行为最有效的治疗剂量，我下一步计划评估每种伏隔内治疗（MMP 抑制、Rap1 抑制或 beta3 整合素调节）的生化后果。对伏隔核蛋白表达水平的分析将有助于揭示行为效应的潜在机制以及假设途径内各成分之间可能的相互作用。这些行为和生化研究的结果将揭示可卡因诱导伏隔谷氨酸传输神经适应的分子机制。公共卫生相关性：药物成瘾与长期的大脑变化有关，即使在长期戒毒之后，这种变化也会导致复发风险增加。这项研究将调查可能是可卡因诱导伏核突触功能变化的分子信号通路，伏核是一种与奖励学习和成瘾密切相关的大脑结构。确定成瘾发展过程可能会带来新的治疗选择，旨在逆转药物引起的改变。