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：
8959706
负责人：
Brett Froeliger
金额：
$ 59.94万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8959706
关键词：
Abstinence Acetylcysteine Adjuvant Analgesic Affect Amygdaloid structure Animal Model Animals Attenuated Behavior Behavioral Biological Neural Networks Brain Brain Diseases Brain region Cessation of life Chemosensitization Chronic Clinical Clinical Research Clinical Treatment 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 Placebo Control Placebos Pre-Clinical Model Prefrontal Cortex Process Prodrugs Psychological reinforcement Randomized Rattus Regulation Relapse Research Rest Rewards Scanning Self Administration Self-Administered Self-control as a personality trait Severities Smoker Smoking Smoking Behavior Synapses Synaptic plasticity Therapeutic Translational Research Translations Withdrawal Withdrawal Symptom addiction analog base behavioral response clinically relevant craving cue reactivity design disorder later incidence prevention executive function insight interest neural circuit neuromechanism nicotine replacement novel open label optogenetics pre-clinical preclinical study premature prevent promoter public health relevance reward processing smoking cessation smoking relapse transmission process treatment effect varenicline

项目摘要

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（由适用提供）：尼古丁成瘾是一个多种过程，涉及执行控制，奖励处理和负面影响的失调。临床前模型表明，尼古丁的自我给药会导致皮质纹状体谷氨酸传播的失衡，从而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）是一种改良的半胱氨酸链，可调节神经胶质谷氨酸并使可卡因诱导的突触可塑性归一化，可能会减弱感知的吸烟奖励和吸烟行为。但是，至关重要的是，我们的临床前数据表明，在禁欲的条件下，NAC可能是预防援助的条件。将促进禁欲的戒烟药物（VARENICLINE：VRN）与救济预防援助（NAC）配对，可能会产生比单独使用任何一种治疗的戒烟结果。该提案的总体目标是使用临床和临床前神经科学来研究参与尼古丁成瘾的边缘 - 纹状体和皮质纹状体回路，并确定VRN+NAC在正常化的电路功能和治疗尼古丁成瘾方面的值。对安静感兴趣的吸烟者将被随机分为四个安慰剂（PBO）受控条件之一，以检查VRN和NAC在4周内的个体和组合效果。经过1周的治疗后，参与者将在3天的戒烟中加强加强，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索。在我们使用与临床研究相同治疗组的类似临床前研究中，我们将采用光遗传策略来检查VRN+NAC在抑制预抑制前BBIC（PL）（PL）和基底外侧杏仁核（BLA）输入的突触可塑性方面的有效性。