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: 10404586
• 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/10404586
• 关键词: Acetylcysteine; Animal Model; Animals; Astrocytes; Calcium; Cells; Cellular Morphology; Chemosensitization; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Cocaine Users; Cocaine withdrawal; 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; Rattus; Regulation; Relapse; Rodent; Rodent Model; Role; Self Administration; Signal Pathway; Signal Transduction; Structural Protein; Sucrose; Synapses; Synaptic plasticity; Training; Transcranial magnetic stimulation; Transgenic Organisms; Translating; Translations; Validation; Viral; Withdrawal; Work; addiction; cell behavior; cell type; 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.

项目概要-项目3 滥用药物成瘾会导致突触生理学的病理变化， 前额叶皮层（PFC）与脑桥核沟通的能力，并阻止 成功地规范了吸毒行为。阿片类药物和可卡因成瘾中心（COCA）研究了 啮齿类动物PFC和延髓核中复发的遗传、细胞和生理机制 使用功能磁共振成像读取治疗结果的COCA临床研究模型和双向转换 用N-乙酰半胱氨酸（NAC）和PFC跨磁刺激（TMS）在可卡因使用者中进行线索反应。 项目3专门探讨了海洛因和可卡因后突触适应的神经核 小鼠和大鼠的自我给药，以及在线索诱导的药物寻找过程中发生的适应。 我们发现，在线索诱导的海洛因戒断过程中， 可卡因寻求与复发事件的强度相关。这些变化出现在 突触的所有四个区室（突触前和突触后、星形胶质细胞和细胞外基质）。通过 同时检查四分突触的4个突触隔室，我们正在访问 迄今为止，与成瘾有关的研究很少，这可能包含独特的机会， 治疗发展动物和验证核心B将提供经过自我训练的大鼠和小鼠。 注射海洛因或可卡因我们的终点包括细胞形态学、细胞信号传导和生理学。 流程.具体来说，我们将测量形态学的持久和线索诱导的瞬时变化， 突触谷氨酸介导的电流和蛋白质表达在特定类型的细胞在海马 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在细胞核中的表达 伏隔核。最后，根据COCA的总体目标，了解哪种细胞类型和神经元 亚群是介导线索诱导的海洛因和可卡因寻求的影响，我们管理的 临床项目4中使用的治疗（NAC和连续theta爆发刺激）， 项目3中复发相关发现的双向结构有效性。