Translational Neuropsychopharmacology Research of Nicotine Addiction

尼古丁成瘾的转化神经精神药理学研究

基本信息

批准号：
10193286
负责人：
Brett Froeliger
金额：
$ 15.5万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-16 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10193286
关键词：
Translational Neuropsychopharmacology Research Nicotine Addiction

项目摘要

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.

尼古丁成瘾是一个多种过程，涉及执行控制失调，奖励处理和负面影响。临床前模型表明，尼古丁的自助给药会导致皮质纹状体不平衡谷氨酸的传播介导提示引起的恢复到尼古丁寻求。先前的研究表明n- 乙酰半胱氨酸（NAC），一种改良的半胱氨酸链，可调节胶质谷氨酸并归一化可卡因诱导的突触可塑性，可能会衰减感知的吸烟奖励和吸烟行为。但是，至关重要的是，我们的临床前数据建议在禁欲条件下，NAC可能是预防复发的条件。因此，配对戒烟药物（VARENICLINE：VRN），可促进禁欲，预防援助（NAC），可能会产生比单独治疗更大的停止结果。该提案的总体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电路成瘾并确定VRN+NAC在标准化电路函数和治疗尼古丁的值瘾。有兴趣戒烟的吸烟者将被随机分为四个安慰剂（PBO）控制条件之一检查VRN和NAC在4周内的个体和组合效应。在治疗1周之后，参与者将在3天的戒烟中加强3天的加强，并进行fMRI扫描。参与者将在接下来的3周中遵循，并将评估与临床相关的行为。 FMRI测量与临床变量之间的关系将被探讨。在我们的模拟临床前研究中与临床研究相同的治疗组，我们将采用光遗传策略来检查 VRN+NAC在抑制前比（PL）和基底外侧杏仁核（BLA）输入的突触可塑性时在提示引起的尼古丁寻求期间产生的伏拟核。