Translational Neuropsychopharmacology Research of Nicotine Addiction

 描述(由申请者提供)：尼古丁成瘾是一个多方面的过程，涉及到失调的执行控制、奖励处理和负面影响。临床前模型显示，尼古丁的自我给药导致皮质纹状体谷氨酸传递的失衡，介导了线索诱导的尼古丁寻求的恢复。先前的研究表明，N-乙酰半胱氨酸(NAC)是一种修饰的半胱氨酸链，它调节胶质谷氨酸并使可卡因诱导的突触可塑性正常化，可能会减弱感知到的吸烟奖赏和吸烟行为。然而，至关重要的是，我们的临床前数据表明，在戒酒条件下，NAC作为复发预防辅助手段可能是最有效的。因此，将促进戒烟的戒烟药物(Varenicline：VRN)与复发预防辅助药物(NAC)搭配使用，可能比单独治疗产生更大的戒烟效果。这项建议的首要目标是利用临床和临床前神经科学来研究与尼古丁成瘾有关的边缘-纹状体和皮质纹状体回路，并确定VRN+NAC在使回路功能正常化和治疗尼古丁成瘾方面的价值。对戒烟感兴趣的吸烟者将被随机分到四种安慰剂(PBO)对照条件之一，以检查VRN和NAC在4周内的单独和联合影响。在为期一周的治疗后，参与者将接受为期3天的临时戒烟，并接受功能磁共振扫描。参与者将在接下来的3周治疗中接受跟踪，并对临床相关行为进行评估。将探讨fMRI测量方法与临床变量之间的关系。在我们的模拟临床前研究中，我们将使用与临床研究相同的处理组，使用光遗传学策略来检查VRN+NAC在抑制在线索诱导尼古丁寻找过程中产生的伏隔核突触可塑性(PL)和杏仁基底外侧核(BLA)输入的有效性。

 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.