Role of GluA1 in the Escalation of Alcohol Drinking in Nicotine-Dependent Animals

GluA1 在尼古丁依赖动物饮酒量增加中的作用

• 批准号: 9456050
• 负责人: Scott Edwards
• 金额: $ 20.99万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9456050
• 关键词: AMPA Receptors; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Animals; Antidepressive Agents; Area; Behavior; Behavioral; Brain; Brain region; Categories; Cessation of life; Chronic; Clinical; Cyclic AMP-Dependent Protein Kinases; Data; Development; Drug Addiction; Drug Combinations; Drug usage; Event; Female; Glutamate Receptor; Goals; HSV vector; Heavy Drinking; Individual; Intake; Ketamine; Mediating; Membrane; Methods; Modification; Molecular; Mood Disorders; N-Methylaspartate; Neurobiology; Nicotine; Nicotine Dependence; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Pre-Clinical Model; Prefrontal Cortex; Protein Subunits; Psychological reinforcement; Rattus; Relapse; Reporting; Rewards; Rodent Model; Role; Self Administration; Serine; Signal Transduction; Simplexvirus; Smoker; Substance Use Disorder; Symptoms; Synaptic plasticity; Testing; United States; Withdrawal; Withdrawal Symptom; Work; alcohol effect; alcohol exposure; alcohol use disorder; base; biobehavior; cocaine relapse; drinking; drug of abuse; drug relapse; effective therapy; experience; glutamatergic signaling; insight; interest; male; neuroadaptation; neurobiological mechanism; neurotransmission; nicotine abuse; novel strategies; novel therapeutics; overexpression; preclinical study; reward circuitry; sex; trafficking; treatment strategy; vapor; virtual

Project Summary ______ Drugs of abuse (including alcohol) are frequently used and abused in combination, and there is a substantial association of nicotine and alcohol use disorders in particular. Interest in the biobehavioral mechanisms underlying nicotine and alcohol interactions has recently grown, although information on neuronal signaling and behavioral adaptations that occur in animals exposed to both nicotine and alcohol remains limited compared to the abundance of studies on these substances in isolation. Nicotine use increases alcohol drinking, suggesting that the combination of these drugs may produce synergistic effects in activating brain reward circuitry. Alternatively, use of either of these substances may facilitate the development of cross- tolerance to the other to promote intake escalation. Our preliminary data demonstrates that alcohol self- administration is increased in animals made dependent on nicotine via chronic, intermittent nicotine vapor (CINV) exposure. While these data are consistent with previous reports, the neurobiological mechanisms that underlie this interaction remain largely unknown. Chronic drug-induced modifications of AMPA channel activity alter excitatory neurotransmission that functionally associates with excessive drug use and relapse. Several of these effects occur through phosphorylation of GluA1 AMPA subunits, which increases AMPA channel function via facilitation of membrane trafficking or channel activity. This phosphorylation event is thought to be essential for the modulation of synaptic plasticity that may underlie several key aspects of the persistence of drug addiction. Our preliminary molecular results demonstrate that nicotine exposure and alcohol challenge interactively produce neuroadaptations in GluA1 phosphorylation in a brain region-dependent manner. Alcohol robustly increases PKA-mediated phosphorylation of GluA1 in multiple regions. However, this neuroadaptation is largely absent in two areas (dorsomedial prefrontal cortex and central amygdala) in nicotine-experienced animals. This interactive effect suggests a molecular tolerance to alcohol-stimulated phosphorylation of GluA1 in the context of nicotine dependence. Nicotine may thus facilitate the reinforcing effects of alcohol by altering glutamate signaling in a region-specific manner, thereby leading to increased drinking in heavy smokers. The goal of this proposal is to test the central hypothesis that escalated drinking in nicotine-dependent male and female rats will be reduced by increasing AMPA signaling via local, HSV-mediated GluA1 overexpression in specific brain areas (dorsomedial prefrontal cortex and central amygdala) or by pharmacological stimulation of AMPA receptors via hydroxynorketamine (HNK). Results from this R21 will provide valuable insights into the neurobiological mechanisms associated with the co-abuse of nicotine and alcohol. These data may also provide new therapeutic avenues for treating problematic alcohol drinking in nicotine-dependent individuals.

项目摘要______ 经常使用和滥用滥用药物（包括酒精），并且有很多 尼古丁和酒精使用障碍的关联。对生物行为机制的兴趣 尽管有关神经元信号的信息 在暴露于尼古丁和酒精的动物中发生的行为适应仍然有限 与对这些物质的大量研究相比。尼古丁的使用增加了酒精 饮酒，表明这些药物的组合可能在激活大脑中产生协同作用 奖励电路。或者，使用这两种物质都可以促进交叉的发展 宽容对方，以促进摄入升级。我们的初步数据表明酒精自我 通过慢性间歇性尼古丁蒸气，依赖尼古丁的动物的给药增加了 （CINV）暴露。尽管这些数据与以前的报告一致，但神经生物学机制 这种相互作用的基础在很大程度上是未知的。慢性药物诱导的AMPA通道活性的修饰 改变兴奋性神经传递与过度使用和复发相关的兴奋性神经传递。几个 这些影响通过GLUA1 AMPA亚基的磷酸化发生，从而增加AMPA通道功能 通过促进膜运输或通道活动。这个磷酸化事件被认为是必不可少的 为了调节突触可塑性，这可能是药物持续性的几个关键方面的基础 瘾。我们的初步分子结果表明尼古丁的暴露和酒精挑战 以大脑区域依赖性方式在GLUA1磷酸化中交互作用。酒精 稳健地增加了多个区域中GLUA1的PKA介导的磷酸化。但是，这种神经适应 在尼古丁经验丰富的两个区域（背额前额叶皮层和中央杏仁核）中基本不存在 动物。这种互动效应表明对GLUA1的酒精刺激磷酸化具有分子耐受性 在尼古丁依赖的背景下。因此，尼古丁可以通过改变酒精的增强作用 以特定区域的方式传导谷氨酸信号，从而导致吸烟者的饮酒增加。这 该提议的目标是检验中心假设，即尼古丁依赖性男性饮酒升级和 通过通过局部HSV介导的GLUA1过表达来增加AMPA信号传导来减少雌性大鼠 特定的大脑区域（背侧前额叶皮层和中央杏仁核）或通过药理学刺激 通过羟基苯丙胺（HNK）通过AMPA受体。 R21的结果将为您提供宝贵的见解 与尼古丁和酒精共施用的神经生物学机制。这些数据也可能 提供新的治疗途径，用于治疗依赖尼古丁的个体中有问题的饮酒。