Molecular Mechanisms of Cocaine-Induced Alterations in Accumbens AMPA Receptors

描述（由申请人提供）：药物成瘾的特点是极易复发，即使在长期戒断药物后也是如此。复发易感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，药物诱导伏隔核突触可塑性改变的潜在机制尚不完全清楚。最近，细胞粘附分子β a3整合素被发现在维持含有GluR2亚基的AMPA受体的表面表达中起关键作用。我们实验室的数据表明，在可卡因自我给药期间，长期在大鼠伏隔核内输注β 3整合素调节剂，可以减少可卡因启动引起的药物寻求的恢复，并防止可卡因引起的GluR2表面表达的降低。本研究旨在进一步阐明β 3整合素信号通路，以确定可卡因诱导AMPA受体变化的分子机制。我假设正常的β 3整合素信号被可卡因诱导的基质金属蛋白酶（MMPs）的过度活性破坏，从而通过激活Rap1细胞内信号导致β 3整合素介导的glur2 - 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输注MMP或Rap1抑制剂是否会减少消失的可卡因寻求的恢复，就像之前在β 3整合素调节剂中看到的那样。具体目标2：使用对减少恢复行为最有效的治疗剂量，我计划接下来评估每种伏隔核内治疗的生化后果（MMP抑制，Rap1抑制或β 3整合素调节）。对伏隔核蛋白表达水平的分析将有助于揭示行为影响的潜在机制以及假设通路中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的伏隔核谷氨酸传递神经适应的分子机制。

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.