The role of dopamine in modulating relapse-induced transient synaptic plasticity

多巴胺在调节复发引起的瞬时突触可塑性中的作用

• 批准号: 9751826
• 负责人: SADE MONIQUE SPENCER
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751826
• 关键词: Abstinence; Amygdaloid structure; Anatomy; Behavior; Behavioral; Bilateral; Biological Adaptation; Brain; Caliber; Cannulas; Cells; Chemosensitization; Chronic; Clozapine; Cocaine; Cocaine Dependence; Cues; Data; Dendritic Spines; Development; Dopamine; Drug Addiction; Drug usage; Electrophysiology (science); Event; Extinction (Psychology); Glutamates; Head; High Pressure Liquid Chromatography; Human; Impairment; Injections; Intervention; Learning; Matrix Metalloproteinases; Measurement; Measures; Mediating; Mentors; Microdialysis; Microinjections; Modeling; N-Methylaspartate; National Research Service Awards; Neurobiology; Neuronal Plasticity; Nucleus Accumbens; Outcome; Oxides; Pathologic; Pharmaceutical Preparations; Pharmacology; Protocols documentation; Rattus; Regulation; Relapse; Research; Role; Self Administration; Self Stimulation; Slice; Specificity; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic; Time; Training; Transgenic Organisms; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Vertebral column; Viral; addiction; base; brain circuitry; cell type; cocaine exposure; cocaine use; design; designer receptors exclusively activated by designer drugs; dopamine transporter; dopaminergic neuron; experimental study; extracellular; in vivo; inhibitor/antagonist; insight; neuroadaptation; neurobiological mechanism; neurochemistry; neuropathology; neurotransmitter release; novel; novel therapeutics; patch clamp; public health relevance; reinforcer; response; restoration; skills; trait; transmission process

 DESCRIPTION (provided by applicant): Cocaine produces enduring alterations in nucleus accumbens core (NAcore) synaptic plasticity associated with relapse vulnerability. Specifically, cocaine self-administration causes enduring increases in dendritic spine head diameter, AMPA/NMDA ratios, and matrix metalloproteinase (MMP) activity. Re-exposure to cocaine- conditioned cues after extinction produces further rapid, transient synaptic potentiation (t-SP) within 15 min that is quantified with any of these measurements. However, when inducing reinstatement with a noncontingent cocaine injection the time course of t-SP differs in that the maximal response is not observed until 45 min. This discrepancy led to the hypothesis that while cues immediately drive forward drug seeking and t-SP, when reinstatement is initiated by noncontingent cocaine, the drug initially suppresses drug seeking and t-SP until pharmacological effects diminish below a threshold. A reinstatement model to evaluate this interaction between cue-induced cocaine seeking leading to cocaine use modeling many important features of human relapse was developed. Preliminary data show that contingent cocaine reverses cue-induced t-SP and discontinuation of this access rapidly restores t-SP. Cocaine increases synaptic dopamine (DA) as a competitive inhibitor of the dopamine transporter, thus dopaminergic mechanisms were hypothesized to contribute to cocaine's effects on cue-induced t-SP. Here, the role of cocaine-induced ventral tegmental area (VTA) DA transmission in t-SP reversal is examined using viral-based designer receptors exclusively activated by designer drugs (DREADD) and tyrosine hydroxylase-Cre (TH-Cre) transgenic rats to introduce anatomical and cell-type specificity. To accomplish this, the candidate will learn in vivo zymography to analyze MMP activity and patch clamp electrophysiology (Aim 1), as well as employ dendritic spine analysis and intracranial microinjection skills acquired during F32 NRSA training. In the K99 aims, the contribution of VTA DA in cocaine-induced reversal of NAcore t-SP will be characterized. Preliminary data show that cocaine-trained rats with Gq-DREADD in VTA TH+ cells will reinstate to a CNO priming injection and it will be further assessed whether this activation likewise blunts cue-induced t-SP. The impact of selective activation (Aim 2B) or inactivation of VTA DA cell bodies (Aim 2A) or terminal field regions (Aim 2C) on cue-induced t-SP and cocaine-induced suppression of t- SP will be examined. During the R00 period, chronic Gq-DREADD activation with CNO self-administration will be used to test the sufficiency for VTA DA activity to reproduce potentiated neuroplasticity produced by chronic cocaine (Aim 3). Furthermore, the dynamic regulation of glutamate and DA release in the reinstatement model will be assessed with microdialysis (Aim 4). These experiments have the potential to contribute to the development of novel therapeutic options aimed at reversing cocaine-induced neurobiological alterations.

 描述（由申请人提供）：可卡因对与复发脆弱性相关的伏隔核核心（NAcore）突触可塑性产生持久的改变具体来说，可卡因自我施用导致树突棘头部直径、AMPA/NMDA比率和基质金属蛋白酶（MMP）的持久增加。 ) 活动后再次暴露于可卡因条件信号会在 15 分钟内产生进一步的快速、短暂的突触增强 (t-SP)。然而，当用非偶然的可卡因注射诱导恢复时，t-SP 的时间进程不同，直到 45 分钟才观察到最大反应。这种差异导致了这样的假设：虽然提示立即驱动药物。寻找和 t-SP，当最初由非偶然可卡因启动恢复时，药物会抑制药物寻找和 t-SP，直到药理作用减弱到阈值以下。用于评估两者之间相互作用的恢复模型。线索诱导的可卡因寻求导致可卡因使用建模人类复发的许多重要特征已开发出来，初步数据表明，偶然的可卡因可逆转线索诱导的 t-SP，并且停止这种访问可迅速恢复可卡因增加突触多巴胺 (DA)。作为多巴胺转运蛋白的竞争性抑制剂，因此多巴胺能机制被用来促进可卡因对提示诱导的 t-SP 的影响。使用仅由设计药物 (DREADD) 激活的基于病毒的设计受体和酪氨酸羟化酶-Cre (TH-Cre) 转基因大鼠来检查 t-SP 逆转中的被盖区 (VTA) DA 传输，以引入解剖和细胞类型特异性。为了实现这一目标，考生将学习体内酶谱分析 MMP 活性和膜片钳电生理学（目标 1），以及采用树突棘分析和在 F32 NRSA 训练期间获得的颅内显微注射将表征 VTA DA 在可卡因诱导的 NAcore t-SP 逆转中的作用。初步数据表明，经过可卡因训练的大鼠 VTA TH+ 细胞将恢复。到 CNO 引发注射，将进一步评估这种激活是否同样会减弱提示诱导的 t-SP 选择性激活的影响（目的）。 2B) 或 VTA DA 细胞体 (目标 2A) 或末端场区域 (目标 2C) 对提示诱导的 t-SP 和可卡因抑制诱导的 t-SP 的失活将在 R00 期间、慢性 Gq-DREADD 激活进行检查。 CNO 自我给药将用于测试 VTA DA 活性是否足以重现慢性可卡因产生的增强神经可塑性（目标 3）。此外，动态恢复模型中谷氨酸和 DA 释放的调节将通过微透析进行评估（目标 4）。这些实验有可能有助于开发旨在逆转可卡因引起的神经生物学改变的新型治疗方案。