Translational Neuropsychopharmacology Research of Nicotine Addiction

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的不平衡， 谷氨酸传输介导的线索诱导恢复尼古丁寻求。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，可调节神经胶质谷氨酸并使可卡因诱导的突触 可塑性，可能会减弱感知吸烟奖励和吸烟行为。然而，关键是，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，配对a 戒烟药物（伐尼克兰：VRN），促进戒烟，与复发预防援助（NAC）， 可能比单独使用任何一种治疗产生更大的戒烟效果。本提案的总体目标是利用 临床和临床前神经科学研究尼古丁参与的边缘-纹状体和皮质纹状体回路 成瘾，并确定VRN+NAC用于使电路功能正常化和治疗尼古丁的价值 成瘾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， 检查VRN和NAC在4周内的单独和联合作用。治疗1周后， 参与者将被临时加强戒烟3天，并接受功能磁共振成像扫描。 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。在我们的模拟临床前研究中， 与临床研究相同的治疗组，我们将采用光遗传学策略来检查 VRN+NAC抑制边缘前核（PL）和基底外侧杏仁核（BLA）输入的突触可塑性， 在线索诱导的尼古丁寻找过程中产生的丘脑核。

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 value of 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.