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）：皮质醇在与复发易感性相关的核内核核心（NAcore）突触可塑性中产生持久改变。具体而言，可卡因自我管理的原因持久增加树突棘头直径，AMPA/NMDA比率，和基质金属蛋白酶（MMP）的活性。在消退后再次暴露于可卡因调节的线索在15分钟内产生进一步快速的、瞬时的突触增强（t-SP），其用这些测量中的任何一个进行定量。然而，当诱导恢复与noncontingent可卡因注射的时间过程中的t-SP的不同之处在于，直到45分钟的最大反应没有观察到。这种差异导致的假设，而线索立即推动药物寻求和t-SP，当恢复是由noncontingent可卡因启动，药物最初抑制药物寻求和t-SP，直到药理作用降低到阈值以下。开发了一个复吸模型来评估线索诱导的可卡因寻求导致可卡因使用建模人类复吸的许多重要特征之间的这种相互作用。初步数据显示，偶然可卡因逆转线索诱导的t-SP，中断这种通路迅速恢复t-SP。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假设有助于可卡因对线索诱导的t-SP的影响。可卡因诱导的腹侧被盖区（VTA）DA传递在t-SP逆转中的作用使用基于病毒的设计者受体（DREADD）和酪氨酸羟化酶-Cre（TH-Cre）来检测转基因大鼠引入解剖和细胞类型的特异性。为了实现这一目标，候选人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颅内显微注射技能在F32 NRSA培训期间获得。在K99目标中，将表征VTA DA在可卡因诱导的NAcore t-SP逆转中的作用。初步数据显示，在VTA TH+细胞中具有Gq-DREADD的可卡因训练的大鼠将恢复到CNO引发注射，并且将进一步评估这种激活是否同样钝化线索诱导的t-SP。将对SP进行检查。在R 00期间，将使用CNO自我给药的慢性Gq-DREADD激活来测试VTA DA活性是否足以重现慢性可卡因产生的增强的神经可塑性（目的3）。此外，将用微透析评估恢复模型中谷氨酸和DA释放的动态调节（目的4）。这些实验有可能有助于开发旨在逆转可卡因诱导的神经生物学改变的新型治疗方案。