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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要______ 滥用药物（包括酒精）经常被联合使用和滥用，并且存在大量的滥用行为。特别是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传导的信息，但潜在的尼古丁和酒精相互作用最近有所增加接触尼古丁和酒精的动物的行为适应仍然有限与对这些物质的大量单独研究相比。使用尼古丁会增加酒精含量饮酒，表明这些药物的组合可能会产生激活大脑的协同作用奖励电路。或者，使用这些物质中的任何一种都可以促进交叉的发展对其他的耐受性促进摄入量升级。我们的初步数据表明，酒精会自我通过慢性、间歇性尼古丁蒸气对尼古丁产生依赖的动物的给药量增加（CINV）曝光。虽然这些数据与之前的报告一致，但神经生物学机制这种相互作用的背后仍然很大程度上未知。药物诱导的 AMPA 通道活性的慢性改变改变与过度吸毒和复发功能相关的兴奋性神经传递。几个这些作用是通过 GluA1 AMPA 亚基的磷酸化来实现的，从而增强 AMPA 通道功能通过促进膜运输或通道活动。这种磷酸化事件被认为是必需的用于调节突触可塑性，这可能是药物持久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暴露和酒精挑战 GluA1 磷酸化以大脑区域依赖性方式交互产生神经适应。酒精显着增加多个区域中 PKA 介导的 GluA1 磷酸化。然而，这种神经适应在经历过尼古丁的人中，两个区域（背内侧前额皮质和中央杏仁核）基本上不存在动物。这种相互作用表明对酒精刺激的 GluA1 磷酸化具有分子耐受性在尼古丁依赖的情况下。因此，尼古丁可能通过改变酒精的浓度来促进酒精的增强作用。以特定区域的方式调节谷氨酸信号，从而导致重度吸烟者饮酒量增加。这该提案的目标是检验以下中心假设：尼古丁依赖男性和女性的饮酒量不断增加雌性大鼠会通过局部 HSV 介导的 GluA1 过表达增加 AMPA 信号来减少特定的大脑区域（背内侧前额皮质和中央杏仁核）或通过药物刺激通过羟基去甲氯胺酮 (HNK) 的 AMPA 受体。 R21 的结果将为我们提供宝贵的见解与尼古丁和酒精共同滥用相关的神经生物学机制。这些数据也可能为治疗尼古丁依赖者的饮酒问题提供新的治疗途径。