Translational Neuropsychopharmacology Research of Nicotine Addiction

 描述（由申请人提供）：尼古丁成瘾是一个多方面的过程，涉及失调的执行控制，奖励处理和负面影响。临床前模型显示，尼古丁自我给药会导致皮质纹状体谷氨酸传输失衡，从而介导线索诱导的尼古丁寻求恢复。先前的研究表明，N-乙酰半胱氨酸（NAC），一种修饰的半胱氨酸链，调节神经胶质谷氨酸和正常化可卡因诱导的突触可塑性，可能会减弱感知吸烟奖励和吸烟行为。然而，至关重要的是，我们的临床前数据表明，NAC可能是最有效的条件下禁欲作为复发预防援助。因此，将促进戒烟的戒烟药物（瓦伦克林：VRN）与复发预防辅助药物（NAC）配对，可能会比单独使用任何一种治疗产生更好的戒烟结果。本提案的总体目标是使用临床和临床前神经科学来研究参与尼古丁成瘾的边缘-纹状体和皮质纹状体回路，并确定VRN+NAC用于使回路功能正常化和治疗尼古丁成瘾的价值。有兴趣戒烟的吸烟者将被随机分配到四种安慰剂（PBO）对照条件之一，以检查VRN和NAC在4周内的单独和联合作用。治疗1周后，参与者将接受3天的戒烟强化，并接受fMRI扫描。将在接下来的3周治疗期间对受试者进行随访，并评估临床相关行为。将探讨功能磁共振成像测量和临床变量之间的关系。在我们使用与临床研究相同的治疗组的模拟临床前研究中，我们将采用光遗传学策略来检查VRN+NAC抑制在线索诱导的尼古丁寻求期间产生的到丘脑核的边缘前系统（PL）和基底外侧杏仁核（BLA）输入中的突触可塑性的功效。

 DESCRIPTION (provided by applicant): Nicotine addiction is a manifold process that involves dysregulated executive control, reward processing and negative affect. Preclinical models reveal that self-administration of nicotine produces an imbalance in corticostriatal glutamate transmission that mediates cue-induced reinstatement to nicotine seeking. Prior research suggests that N-acetylcysteine (NAC), a modified cysteine chain that regulates glial glutamate and normalizes cocaine-induced synaptic plasticity, may attenuate perceived smoking reward and smoking behavior. Crucially however, our preclinical data suggests NAC may be most effective under conditions of abstinence as a relapse prevention aid. Thus, pairing a smoking cessation medication (Varenicline: VRN) that promotes abstinence, with a relapse prevention aid (NAC), may produce greater cessation outcomes than either treatment alone. The overarching goal of this proposal is to use clinical and preclinical neuroscience to investigate limbic-striatal and corticostriatal circuits involved in nicotine addiction and determine the valueof VRN+NAC for normalizing circuitry function and treating nicotine addiction. Smokers interested in quitting will be randomized to one of four placebo (PBO) controlled conditions to examine the individual and combined effects of VRN and NAC over 4-weeks. Following 1-week of treatment, participants will be contingently reinforced for 3 days of smoking abstinence and undergo an fMRI scan. Participants will be followed over the next 3-weeks of treatment and clinically relevant behaviors will be assessed. Relations between fMRI measures and clinical variable will be explored. In our analog preclinical studies that use the same treatment groups as the clinical studies, we will employ an optogenetic strategy to examine the efficacy of VRN+NAC at inhibiting synaptic plasticity in prelimbic (PL) and basolateral amygdala (BLA) inputs to the nucleus accumbens produced during cue-induced nicotine seeking.