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

项目概要_ 滥用药物（包括酒精）经常合并使用和滥用， 尤其是尼古丁和酒精使用障碍之间的联系。对生物行为机制的兴趣 潜在的尼古丁和酒精的相互作用最近有所增加，尽管神经信号的信息， 同时接触尼古丁和酒精的动物的行为适应仍然有限 相比之下，对这些物质的大量研究是孤立的。尼古丁的使用会增加酒精含量 提示这些药物的联合使用可能在激活大脑中产生协同作用， 奖励电路或者，使用这些物质中的任何一种都可能促进交叉- 另一种是容忍，以促进摄入量的增加。我们的初步数据表明，酒精本身- 在通过慢性间歇性尼古丁蒸汽依赖尼古丁的动物中， （CINV）暴露。虽然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仍然未知。慢性药物诱导的AMPA通道活性改变 改变兴奋性神经传递，这在功能上与过度使用药物和复发有关。几 这些作用通过GluA 1 AMPA亚基的磷酸化而发生，磷酸化增加AMPA通道功能 通过促进膜运输或通道活性。这种磷酸化作用被认为是 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 成瘾我们的初步分子结果表明，尼古丁暴露和酒精挑战， 以脑区域依赖性方式在GluA 1磷酸化中交互产生神经适应。醇 在多个区域强烈增加PKA介导的GluA 1磷酸化。然而，这种神经适应 在尼古丁经验者的两个区域（背内侧前额叶皮层和中央杏仁核）中， 动物这种相互作用表明，分子耐受酒精刺激磷酸化的GluA 1 在尼古丁依赖的背景下。因此，尼古丁可以通过改变酒精的作用来促进酒精的强化作用。 谷氨酸信号以区域特异性方式，从而导致重度吸烟者饮酒增加。的 这项提议的目的是检验中心假设，即尼古丁依赖的男性饮酒量增加， 通过局部HSV介导的GluA 1过表达增加AMPA信号传导， 特定的大脑区域（背内侧前额叶皮层和中央杏仁核）或通过药物刺激， AMPA受体通过羟基去甲氯胺酮（HNK）。R21的结果将为以下方面提供有价值的见解： 与尼古丁和酒精共同滥用相关的神经生物学机制。这些数据还可以 提供了新的治疗途径，用于治疗尼古丁依赖个体的问题性饮酒。

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.