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

项目摘要--项目3 滥用药物成瘾会导致突触生理上的病理变化，从而损害 前额叶皮质(PFC)与伏隔核通讯的能力，并阻碍 成功规范了毒品寻人行为。阿片和可卡因成瘾中心(Coca)研究 前额叶核和伏隔核内复发的遗传、细胞和生理机制 通过使用治疗的fMRI读出的Coca临床研究，建立模型并进行双向翻译 用N-乙酰半胱氨酸(NAC)和PFC转磁刺激(TMS)检测可卡因使用者的线索反应性。 项目3专门探索海洛因和可卡因后伏隔核对突触适应的影响 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，线索诱导海洛因戒断过程中的持久变化和短暂变化以及 寻求可卡因与复发事件的强度相关。这些更改出现在 突触的所有四个部分(突触前和突触后、星形胶质细胞和细胞外基质)。通过 同时检查四部分突触的4个突触间隔，我们正在访问 到目前为止，关于成瘾的过程研究很少，成瘾可能包含独特的机会 治疗方面的发展。动物和验证核心B将提供训练成自我 注射海洛因或可卡因。我们的终点包括细胞形态、细胞信号和生理 流程。具体地说，我们将测量形态上的持久和线索诱导的瞬时变化， 伏隔特定细胞类型中突触谷氨酸介导的电流和蛋白表达 利用转基因大鼠和小鼠及细胞特异性病毒介导的转基因在细胞核内的表达 伏伏草。最后，根据Coca的首要目标，了解哪种细胞类型和神经元 亚群正在调节线索诱导的海洛因和可卡因寻找的影响，我们管理 临床项目4中使用的治疗(NAC和持续电刺激)以提供 项目3中与复发相关的发现的双向结构效度。

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.