Translational Neuropsychopharmacology Research of Nicotine Addiction

尼古丁成瘾的转化神经精神药理学研究

• 批准号: 9753199
• 负责人: Brett Froeliger
• 金额: $ 29.28万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753199
• 关键词: Abstinence; Acetylcysteine; Adjuvant Analgesic; Amygdaloid structure; Animal Model; Animals; Attenuated; Behavior; Behavioral; Brain; Brain Diseases; Brain region; Cessation of life; Chemosensitization; Chronic; Clinical; Clinical Research; Cocaine; Corpus striatum structure; Cues; Cysteine; Data; Dendritic Spines; Equilibrium; Foundations; Functional Magnetic Resonance Imaging; Glutamates; Goals; Human; Individual; Laboratories; Measures; Mediating; Modeling; Moods; Morphology; Motivation; Negative Reinforcements; Neurobiology; Neurocognition; Neurocognitive; Neurophysiology - biologic function; Neurosciences; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Outcome; Participant; Pathway interactions; Patient Self-Report; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Pre-Clinical Model; Prefrontal Cortex; Process; Prodrugs; Psychological reinforcement; Randomized; Rattus; Regulation; Relapse; Research; Rest; Rewards; Self Administration; Self-control as a personality trait; Severities; Smoker; Smoking; Smoking Behavior; Synapses; Synaptic plasticity; Therapeutic; Translational Research; Translations; Withdrawal; Withdrawal Symptom; addiction; analog; clinically relevant; craving; cue reactivity; design; disorder later incidence prevention; executive function; functional MRI scan; human model; insight; interest; negative affect; neural circuit; neural network; neuromechanism; neuropsychopharmacology; nicotine replacement; nicotine seeking behavior; novel; open label; optogenetics; pre-clinical; preclinical study; premature; prevent; promoter; public health relevance; response; reward processing; smoking abstinence; smoking cessation; smoking relapse; transmission process; treatment effect; treatment group; varenicline

 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.

 描述（由申请人提供）：尼古丁成瘾是一个多方面的过程，涉及执行控制失调、奖励处理和负面影响。临床前模型表明，自我施用尼古丁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）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正常化，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，我们的临床前数据表明，在戒烟条件下，NAC 作为预防复发的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）与复发预防辅助剂（NAC）结合使用，可能会比单独使用任何一种治疗产生更好的戒烟效果。该提案的总体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 对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) 对照条件中的一种，以检查 VRN 和 NAC 在 4 周内的单独效果和综合效果。经过 1 周的治疗后，参与者将被随机强化 3 天的戒烟并接受功能磁共振成像扫描。将在接下来的 3 周治疗中对参与者进行随访，并评估临床相关行为。将探讨功能磁共振成像测量与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 在抑制提示诱导尼古丁寻找过程中产生的伏核前边缘 (PL) 和基底外侧杏仁核 (BLA) 输入的突触可塑性方面的功效。