Translational Neuropsychopharmacology Research of Nicotine Addiction

尼古丁成瘾是一个多方面的过程，涉及到失调的执行控制，奖赏处理和 负面影响。临床前模型显示，自身服用尼古丁会导致皮质纹状体失衡 谷氨酸传递介导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)，一种修饰的半胱氨酸链，调节胶质谷氨酸并使可卡因诱导的突触正常化 可塑性，可能会减弱感知的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 提示NAC在戒酒条件下可能是最有效的预防复发的辅助手段。因此，将一个 促进戒烟的戒烟药物(Varenicline：VRN)，配合复发预防辅助(NAC)， 可能比任何一种单独治疗产生更大的戒烟效果。这项提案的首要目标是使用 临床和临床前神经科学研究与尼古丁有关的边缘-纹状体和皮质纹状体回路 并测定VRN+NAC对正常回路功能和尼古丁治疗的价值 上瘾。有意戒烟的吸烟者将被随机分配到四种安慰剂(PBO)控制条件中的一种，以 检查VRN和NAC在4周内的单独和联合作用。在一周的治疗后， 参与者将接受为期3天的临时戒烟，并接受功能磁共振成像扫描。 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使用了 与临床研究相同的治疗组，我们将采用光遗传策略来检查 VRN+NAC抑制杏仁基底外侧核(BLA)和前额叶核(PL)传入的突触可塑性 伏隔核在线索诱导的尼古丁寻找过程中产生。

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.