COCA - Project 3. Tetrapartite Synapses Regulate Cue-induced Drug Seeking

COCA - 项目 3。四方突触调节提示诱导的药物寻求

• 批准号: 10630234
• 负责人: Peter W Kalivas
• 金额: $ 23.23万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630234
• 关键词: Acetylcysteine; Animal Model; Animals; Astrocytes; Calcium; Cells; Cellular Morphology; Chemosensitization; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Cocaine Users; Cocaine withdrawal; Communication; Cues; Data; Dendritic Spines; Drug Regulations; Event; Excitatory Synapse; Extracellular Matrix; Extracellular Space; Functional Magnetic Resonance Imaging; Genetic study; Glutamate Receptor; Glutamates; Goals; Heroin; Integrins; Isoxazoles; Link; Measures; Mediating; Metalloproteases; Molecular Target; Morphology; Mus; Neurons; Nucleus Accumbens; Opiate Addiction; Pathologic; Pharmaceutical Preparations; Physiological; Physiological Processes; Physiology; Population; Prefrontal Cortex; Process; Propionic Acids; Proteins; Rat Transgene; Rattus; Regulation; Relapse; Rodent; Rodent Model; Role; Self Administration; Signal Pathway; Signal Transduction; Structural Protein; Sucrose; Synapses; Synaptic plasticity; Traction; Training; Transcranial magnetic stimulation; Translating; Translations; Validation; Viral; Withdrawal; Work; addiction; cell behavior; cell type; cocaine cue; cocaine seeking; cocaine self-administration; confocal imaging; cue reactivity; drug development; drug of abuse; drug withdrawal; epigenetic regulation; impaired capacity; in vivo; knock-down; neuroadaptation; neuroimaging; optogenetics; pre-clinical; prevent; protein expression; therapeutic development; transgene expression

PROJECT SUMMARY – Project 3 Addiction to drugs of abuse produces pathological changes in synaptic physiology that impair the capacity of the prefrontal cortex (PFC) to communicate with the nucleus accumbens, and impede the successful regulation of drug seeking. The Center for Opioid and Cocaine Addiction (COCA) studies the genetic, cellular and physiological mechanisms of relapse in the PFC and nucleus accumbens rodent models and bidirectionally translates this with COCA clinical studies using fMRI read-out of treatments with N-acetylcysteine (NAC) and PFC transmagnetic stimulation (TMS) for cue reactivity in cocaine users. Project 3 specifically explores the nucleus accumbens for synaptic adaptations after heroin and cocaine self-administration in mice and rats, and the adaptations that occur during cue-induced drug seeking. We find both enduring changes in withdrawal and transient changes during cue-induced heroin and cocaine seeking that are correlated with the intensity of the relapse event. These changes are present in all four compartments of the synapse (pre- and postsynapse, astroglia and extracellular matrix). By simultaneously examining the 4 synaptic compartments of the tetrapartite synapse, we are accessing processes heretofore poorly studied in relation to addiction, which may contain unique opportunities for therapeutic development. Animal & Validation Core B will provide rats and mice trained to self- administer heroin or cocaine. Our endpoints include cell morphology, cell signaling and physiological processes. Specifically, we will measure enduring and cue-induced transient changes in the morphology, synaptic glutamate-mediated currents and protein expression in specific cell types in the accumbens using transgenic rats and mice and cell-specific viral mediated expression of transgenes in the nucleus accumbens. Finally, pursuant to an overarching COCA goal to understand which cell type and neuronal subpopulation is mediating the effects of cue-induced heroin and cocaine seeking, we administer the treatments used in the clinical Project 4 (NAC and continuous theta burst stimulation) to provide bidirectional construct validity for the relapse-related discoveries in Project 3.

项目摘要 - 项目3 对虐待药物的成瘾会导致突触生理的病理变化，从而损害 前额叶皮层（PFC）与伏隔核通信的能力，并阻碍 成功调节毒品。阿片类药物和可卡因成瘾中心（可可）研究 PFC和伏隔核中缓解的遗传，细胞和物理机制 模型和双向使用fMRI读取治疗的可口可乐临床研究将其转换 与可卡因使用者中的提示反应性的N-乙酰半胱氨酸（NAC）和PFC传播刺激（TMS）。 项目3专门探讨了海洛因和可卡因后突触适应的伏隔核 在小鼠和大鼠中进行自我给药，以及在提示引起的药物寻求药物期间发生的适应。 我们发现在提示引起的海洛因期间撤离的持久变化和瞬态变化以及 与继电器事件强度相关的可卡因寻求。这些变化存在于 突触的所有四个隔室（前后，星形胶质细胞和细胞外基质）。经过 类似地检查四斜杆突触的4个突触室，我们正在访问 迄今与成瘾有关的过程较差，这可能包含独特的机会 治疗发展。动物与验证核心B将为自我训练的老鼠和小鼠提供 管理海洛因或可卡因。我们的终点包括细胞形态，细胞信号和生理 特别是，我们将衡量形态学的持久和提示诱导的瞬态变化， 伏隔族特定细胞类型中的突触谷氨酸介导的电流和蛋白质表达 使用转基因大鼠和小鼠以及细胞特异性病毒介导的转基因表达 伏伏尔。最后，根据总体可口的目标，以了解哪种细胞类型和神经元 亚群正在介导提示引起的海洛因和可卡因的影响，我们管理 临床项目4（NAC和连续theta爆发刺激）中使用的治疗方法提供 项目3中与中继相关发现的双向结构有效性。