COCA: Project 4. Neurocircuit Strategy to Decrease Cocaine Cue Reactivity

项目概要-项目4 尽管进行了大量的研究工作，但可卡因依赖是一种特别困难的物质 该中心的临床前模型表明， 腹内侧前额叶皮层（vmPFC）和腹侧纹状体（即， 皮质纹状体回路，阻断可卡因线索诱导的恢复。 项目4的科学和临床前提是，靶向抑制皮质纹状体 电路会抑制可卡因使用者对可卡因的渴望。连续θ爆发 刺激（cTBS）是一种重复经颅磁刺激， 长期抑郁样（LTD样）的神经兴奋性下降，在该地区的刺激， 下游单突触靶点。对vmPFC单次给予cTBS可选择性降低 腹侧纹状体的活动和自我报告的渴望。最近，我们发现N- 乙酰半胱氨酸（NAC）增加皮质纹状体静息态功能连接（rsFC）， 尼古丁使用者伴随着减少渴望。项目4的总体目标是 评估cTBS+NAC联合治疗对皮质纹状体神经元成瘾病理生理学的疗效。 电路，并与临床前COCA项目双向翻译我们的研究结果。我们 将确定LTD-like cTBS是否降低可卡因依赖者的可卡因线索反应性。 个体（Aim 1），以及NAC是否加强皮质纹状体rsFC（Aim 2）。然后，我们将检查 cTBS+NAC协同降低药物线索反应性和渴求的功效（目的3）。这些 目标将通过双盲（TMS：TBS与SHAM;药物：NAC与 安慰剂：PBO）研究。所有人都将接受功能磁共振成像 基线扫描，然后随机分为4组之一：1）NAC + TBS，2）NAC +假手术，3）PBO + TBS，4）PBO +假手术）。随着这些数据的出现，我们将与临床前项目1-3密切合作， 为这些项目提供人体电路数据，以帮助指导他们的研究。相反地， 我们将收到关于在啮齿动物模型中产生的皮质纹状体机制的数据， 复发，可以告知我们的临床数据的解释，并指导我们的研究， 更深入地了解基础分子和电路水平的神经生物学。

PROJECT SUMMARY – Project 4 In spite of substantial research effort, cocaine dependence is a particularly difficult substance use disorder to treat. Preclinical models in the Center demonstrate that decreasing neuronal activity in the ventromedial prefrontal cortex (vmPFC) and ventral striatum (i.e. nucleus accumbens core), henceforth corticostriatal circuit, block cocaine cue-induced reinstatement. The scientific and clinical premise of Project 4 is that targeted inhibition of the corticostriatal circuit will dampen cocaine cue-induced craving in cocaine users. Continuous theta burst stimulation (cTBS) is a form of repetitive transcranial magnetic stimulation that induces long term depression-like (LTD-like) decreases in neural excitability in the area stimulated and downstream monosynaptic targets. A single dose of cTBS to the vmPFC selectively decreases activity in the ventral striatum and self-reported craving. Recently, we found that N- acetylcysteine (NAC) increases corticostriatal resting state functional connectivity (rsFC) in nicotine users concomitant with reducing craving. The overarching goals of Project 4 are to evaluate the efficacy of combined cTBS+NAC on addiction pathophysiology in corticostriatal circuitry, and to bidirectionally translate our findings with the preclinical COCA Projects. We will determine if LTD-like cTBS decreases cocaine cue reactivity in cocaine dependent individuals (Aim1), and if NAC strengthens corticostriatal rsFC (Aim 2). Then, we will examine the efficacy of cTBS+NAC to synergistically reduce drug cue reactivity and craving (Aim 3). These aims will be evaluated through a double blinded (TMS: TBS vs. SHAM; Medication: NAC vs. Placebo: PBO) study in 96 cocaine dependent individuals. All individuals will undergo an fMRI baseline scan and then randomized to one of 4 groups: 1) NAC + TBS, 2) NAC + Sham, 3) PBO + TBS, 4) PBO + Sham). As these data emerge, we will work closely with preclinical Projects 1-3 to provide these projects with human circuitry data that can help guide their studies. Conversely, we will receive data regarding corticostriatal mechanisms generated in rodent models of relapse that can inform the interpretations of our clinical data and guide our research through greater understanding of the underpinning molecular and circuit level neurobiology.