Role of Alpha2delta-1 in Cocaine Relapse and Gabapentin Mechanisms of Action

Alpha2delta-1 在可卡因复发中的作用和加巴喷丁的作用机制

基本信息

批准号：
8839664
负责人：
SADE MONIQUE SPENCER
金额：
$ 5.42万
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：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8839664
关键词：
Abstinence Affinity Animal Model Animals Astrocytes Behavioral Binding Biochemical Brain Caliber Chemosensitization Chronic Chronic Disease Cocaine Cocaine Dependence Confocal Microscopy Couples Cues Data Dendritic Spines Development Dialysis procedure Dopamine Drug Addiction Drug Exposure Drug usage Excitatory Synapse Extinction (Psychology)FDA approved Genetic Transcription Glutamate Receptor Glutamates Head Kinetics Lead Learning Ligands Light Measurement Measures Mediating Methamphetamine Microdialysis Microinjections Molecular Target Morphology N-Methylaspartate Nucleus Accumbens Pharmaceutical Preparations Prefrontal Cortex Probability Process Property Protein Binding Proteins Recombinants Relapse Research Rewards Role Self Administration Signal Transduction Structure Surface Synapses Synaptic plasticity Technology Testing Therapeutic Therapeutic Agents Thrombospondin 1 Training Vertebral column addiction drug mechanism drug of abuse drug relapse drug reward drug seeking behavior extracellular gabapentin improved in vivo neuroadaptation neurobiological mechanism neuronal excitability neurotransmitter release novel preference presynaptic prevent public health relevance research study scaffold synaptic function synaptogenesis thrombospondin 2 trafficking voltage

项目摘要

DESCRIPTION (provided by applicant): Drug addiction is a chronic disease characterized by high relapse rates, even following extended abstinence from drug use. Altered glutamatergic plasticity at nucleus accumbens (NAc) synapses after chronic cocaine is identified as a key feature underlying relapse vulnerability. Among the important neuroadaptations that have been identified in NAc are enhancement of prefrontal cortex (PFC) release probability, changes in glutamate receptor composition, expression and currents, and alterations in dendritic spine morphology. However, the underlying mechanisms of drug-induced changes in NAc synaptic plasticity are not fully known. The voltage gated Ca2+ channel (VGCC) auxiliary subunit ¿2¿-1 is upregulated by non-contingent administration of multiple drugs of abuse. The ¿2¿-1 subunit couples to various subtypes of VGCCs which control neurotransmitter release, influence neuronal excitability, and modify gene transcription. In addition, astrocyte-derived thrombospondin (TSP) proteins bind to ¿2¿-1 facilitating the formation of excitatory synapses through a Ca2+ channel-independent mechanism. Gabapentin (GBP), an ¿2¿-1 ligand, disrupts the interaction between TSP and ¿2¿-1 and inhibits synapse formation. My preliminary data show that ¿2¿-1 and TSP-1 are increased after extinction from cocaine self-administration. Moreover, I find that intra-NAc delivery of GBP decreases cocaine-induced reinstatement of drug-seeking. The current proposal is aimed at further clarifying GBP's actions at the ¿2¿-1 subunit and determining the mechanism of action of GBP on cocaine-induced drug- seeking. I hypothesize that upregulated ¿2¿-1 promotes relapse to cocaine-seeking after self-administration, and conversely, inhibiting ¿2¿-1 reduces cocaine-induced reinstatement. I further hypothesize that GBP's effects are due to its actions at presynaptic ¿2¿-1 subunits to inhibit neurotransmitter release induced by VGCC activation OR disrupting the scaffolding of TSP proteins thereby interfering with synaptic remodeling. Specific Aim 1: I will knockdown ¿2¿-1 with anti-sense vivo-morpholino to validate the role of ¿2¿-1 in cocaine reinstatement. Specific Aim 2: Using in vivo microdialysis, I will evaluate my hypothesis that GBP's actions involve inhibition of neurotransmitter release by measuring levels of glutamate and dopamine during cocaine- induced reinstatement with reverse-dialysis of GBP. Specific Aim 3: I will determine the effects of recombinant TSP on cocaine reinstatement and identify whether drug-induced dendritic spine changes are modified by GBP or recombinant TSP treatment using quantitative dendritic spine morphology measurements. Results from these behavioral and biochemical studies will shed light on a shared neurobiological mechanism contributing to drug relapse and clarify the mechanism of action of GBP as an anti-addiction agent.

描述（由申请人提供）：药物成瘾是一种以高复发率为特征的慢性疾病，即使在长期戒毒后，伏隔核（NAc）突触的谷氨酸可塑性改变也被确定为潜在复发易感性的关键特征。 NAc 中已发现的重要神经适应包括前额皮质 (PFC) 释放概率的增强、谷氨酸受体组成、表达和电流的变化，以及然而，药物引起的 NAc 突触可塑性变化的潜在机制尚不完全清楚。 2¿ -1 通过非偶然施用多种滥用药物而上调。 2¿ -1 亚基与 VGCC 的各种亚型结合，控制神经递质释放、影响神经元兴奋性并修饰基因转录。此外，星形胶质细胞衍生的血小板反应蛋白 (TSP) 蛋白与 ¿ 2¿ -1 通过 Ca2+ 通道独立机制促进兴奋性突触的形成，加巴喷丁 (GBP) 是 ¿1。 2¿ -1配体，破坏TSP和¿之间的相互作用2¿ -1 并抑制突触形成我的初步数据表明 ¿ 2¿ -1 和 TSP-1 在可卡因自我给药消失后增加，此外，我发现 GBP 的 NAc 内递送减少了可卡因诱导的药物寻求的恢复。 2¿ -1 亚基并确定 GBP 对可卡因诱导的药物寻求的作用机制。 2¿ -1 促进自我给药后复发可卡因寻求，反之，抑制 ¿1 2¿ -1 减少可卡因诱导的恢复。我进一步集中认为 GBP 的作用是由于其在突触前的作用 ¿ 2¿ -1 亚基抑制 VGCC 激活诱导的神经递质释放或破坏 TSP 蛋白的支架，从而干扰突触重塑具体目标 1：我将击倒 ¿ 2¿ -1与反义vivo-morpholino来验证¿的作用2¿ -1 可卡因恢复具体目标 2：使用体内微透析，我将评估我的假设，即 GBP 的作用涉及抑制具体目标 3：我将确定重组 TSP 对可卡因恢复的影响，并确定 GBP 或 GBP 是否会改变药物诱导的树突棘变化。这些行为和生化研究的结果将揭示导致药物复发的定量共享神经生物学机制，并阐明使用树突棘形态测量的重组 TSP 治疗。 GBP作为抗成瘾剂的作用机制。