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

项目摘要--项目4 尽管有大量的研究工作，但可卡因依赖是一种特别困难的物质 用障碍来治疗。该中心的临床前模型表明，神经元减少 腹内侧额前皮质(VmPFC)和腹侧纹状体(即核)的活动 伏隔核)，此后皮质纹状体回路，阻断可卡因线索诱导的复苏性。 项目4的科学和临床前提是靶向抑制皮质纹状体 电路将抑制可卡因线索诱导的可卡因使用者的渴望。连续的theta爆发 刺激(CTB)是一种重复的经颅磁刺激形式，可诱导长时间 长期抑郁样(LTD样)在刺激和刺激区域的神经兴奋性降低 下游的单突触靶标。单剂量的CTB对vmPFC选择性地降低 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)增加皮层纹状体静息状态功能连接(RsFC) 尼古丁吸食者伴随着减少饥饿感。项目4的总体目标是 CTBS联合NAC治疗皮质纹状体成瘾的疗效评价 电路，并将我们的发现与临床前Coca项目进行双向翻译。我们 将确定LTD样CTB是否降低可卡因依赖者的可卡因提示反应性 个体(Aim1)，以及NAC是否增强皮质纹状体rsFC(目标2)。然后呢，我们再来看看 CTBS NAC协同降低药物线索反应性和渴求的有效性(目标3)。这些 AIMS将通过双盲(TMS：TBS与Sham；药物：NAC与 安慰剂：PBO)对96名可卡因依赖者进行的研究。所有人都将接受功能性核磁共振检查 基线扫描，然后随机分为4组之一：1)NAC TBS组，2)NAC Sham组，3)PBO组 TBS，4)PBO Sham)。随着这些数据的出现，我们将与临床前项目1-3密切合作，以 为这些项目提供人体电路数据，帮助指导他们的研究。相反， 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 复发可以解释我们的临床数据，并指导我们的研究 对支撑分子和电路水平的神经生物学有更深入的了解。

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.