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: 9926487
• 负责人: SADE MONIQUE SPENCER
• 金额: $ 0.82万
• 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/9926487
• 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（由适用提供）：可卡因会产生与缓解脆弱性相关的声核（Nacore）突触可塑性的持久变化。具体而言，可卡因自我给药会导致树突状脊柱直径，AMPA/NMDA比和基质金属蛋白酶（MMP）活性的持久增加。延伸后，重新暴露于可卡因的线索会在15分钟内产生进一步的快速，瞬态合成电位（T-SP），并通过这些测量值进行量化。但是，当通过非诱导可卡因注入诱导恢复原状时，T-SP的时间过程有所不同，因为直到45分钟才观察到最大响应。这种差异导致了以下假设：尽管提示立即推动非转化可卡因启动恢复原状的药物，但该药物最初会抑制寻求药物和T-SP，直到药物效应降低到阈值以下。开发了一种评估提示诱导的可卡因之间这种相互作用的恢复模型，从而导致可卡因使用建模人类继电器的许多重要特征。初步数据表明，偶然的可卡因会逆转提示诱导的T-SP，而该通道的停用迅速恢复了T-SP。可卡因增加了突触多巴胺（DA）作为多巴胺转运蛋白的竞争抑制剂，因此假设多巴胺能机制有助于可卡因对提示引起的T-SP的影响。在这里，使用基于病毒的设计器接收器（Dreadd）和酪氨酸羟化酶-CRE（TH-CRE）转基因大鼠引入解剖学和细胞型特异性，使用了可卡因诱导的T-SP中可卡因诱导的DA传播的作用。为此，候选人将学习体内Zymography，以分析MMP活性和贴片夹电生理学（AIM 1），以及在F32 NRSA培训期间获得的雇员树突状脊柱分析和颅内微注射技能。在K99的目标中，将表征VTA DA在可卡因诱导的Nacore T-SP逆转中的贡献。初步数据表明，在VTA TH+细胞中，由可卡因训练的大鼠将带有GQ-DREDD的大鼠将恢复到CNO启动注射中，并且将进一步评估这种激活是否同样钝化提示引起的T-SP。选择性激活（AIM 2B）或VTA DA细胞体的失活（AIM 2A）或末端场区域（AIM 2C）对提示诱导的T-SP和可卡因诱导的T-SP抑制的影响。在R00期间，使用CNO自我给药的慢性GQ-DreadD激活将用于测试VTA DA活性的充分性，以再现慢性可卡因产生的潜在神经可塑性（AIM 3）。此外，将用微透析评估谷氨酸和DA释放的动态调节（AIM 4）。这些实验有可能有助于开发新型热选择，旨在逆转可卡因引起的神经生物学改变。