Molecular Mechanisms of Ethanol Reinforcement

描述（由申请人提供）：酒精中毒是一种复杂的神经精神疾病，其特征是长期饮酒、戒酒和复发。新出现的证据表明，乙醇和其他滥用药物可能会产生细胞信号和基因转录途径的适应性变化，导致大脑功能的持久变化。这些适应被认为可以调节酒精中毒中发生的行为病理，并且对于临床治疗酒精中毒具有根本的重要性。本申请中的临床前研究集中在钙/钙调蛋白依赖性蛋白激酶II（CaMKII）作为酒精相关行为病理学的新分子机制。我们已经发现，自愿饮酒增加小鼠杏仁核中的CaMKII 1蛋白表达，并且饮酒行为的恢复与外侧杏仁核中CaMKII激活的增加有关，外侧杏仁核是杏仁核的一个亚核，其中CaMKII已知调节联想学习。这些发现表明了本申请的主要假设：自愿酒精自我施用和戒酒导致CaMKII信号传导的适应，其功能性地调节与酒精中毒相关的行为病理，例如复发。本申请中的研究有三个独立但综合的具体目标。首先，实验将阐明与慢性自愿饮酒和戒酒相关的CaMKII的分子和细胞神经适应性。这些研究将提供有关自愿饮酒对整个大脑中这一关键分子通路影响的新信息。第二，研究将调查CaMKII调节酒精强化的功能神经回路。这将使用行为药理学方法结合特定CaMKII抑制剂的脑部位特异性显微注射来实现。这些研究将建立CaMKII活性与维持慢性饮酒的酒精强化作用之间的直接联系。第三，实验提出的特点CaMKII的复发样行为的调节，使用小鼠模型的恢复酒精寻求行为。因此，这些研究检查了CaMKII对行为过程的调节，这些行为过程对酒精中毒的发展和进展至关重要。更好地理解调节酒精中毒行为病理的分子和细胞机制有可能导致新的药理学策略。 公共卫生相关性：长期饮酒和戒酒后复发是酒精中毒的标志性行为病理，也是一个主要的临床问题。新出现的证据表明，细胞信号传导和基因转录途径中的神经适应介导酒精和药物滥用的复发和其他行为病理。因此，本更新申请中临床前研究的总体目标是识别和验证酒精强化和复发样行为的分子和细胞机制。

DESCRIPTION (provided by applicant): Alcoholism is a complex neuropsychiatric disorder that is characterized by periods of chronic drinking, abstinence and relapse. Emerging evidence suggests that ethanol and other drugs of abuse may produce adaptive changes in cell signaling and gene transcription pathways that lead to enduring changes in brain function. These adaptations are thought to regulate behavioral pathologies that occur in alcoholism and are of fundamental importance for treating the alcoholic in the clinic. The preclinical studies in this application are focused on calcium/calmodulin-dependent protein kinase II (CaMKII) as a novel molecular mechanism of alcohol-related behavioral pathologies. We have discovered that voluntary alcohol drinking increases CaMKII1 protein expression in mouse amygdala and that reinstatement of alcohol-seeking behavior is associated with increased CaMKII activation in the lateral amygdala, a sub-nucleus of the amygdala where CaMKII is known to regulate associative learning. These findings suggest the primary hypothesis of this application: voluntary alcohol self- administration and abstinence lead to adaptations in CaMKII signaling that functionally regulate behavioral pathologies associated with alcoholism, such as relapse. The studies in this application have three separate but integrated Specific Aims. First, experiments will elucidate molecular and cellular neuroadaptations in CaMKII that are associated with chronic voluntary alcohol drinking and abstinence. These studies will provide novel information on the effect of voluntary drinking on this key molecular pathway throughout the brain. Second, studies will investigate the functional neural circuitry of CaMKII regulation of alcohol reinforcement. This will be accomplished using a behavioral pharmacology approach coupled with brain site-specific microinjection of specific CaMKII inhibitors. These studies will establish a direct link between CaMKII activity and the reinforcing effects of alcohol that maintain chronic drinking. Third, experiments are proposed to characterize CaMKII regulation of relapse-like behavior using a mouse model of reinstatement of alcohol-seeking behavior. Thus, these studies examine CaMKII regulation of behavioral processes that are fundamental to the development and progression of alcoholism. A better understanding of the molecular and cellular mechanisms that regulate behavioral pathologies in alcoholism has the potential to lead to new pharmacotherapeutic strategies. PUBLIC HEALTH RELEVANCE: Chronic alcohol use and relapse after periods of abstinence are hallmark behavioral pathologies of alcoholism and a major clinical problem. Emerging evidence suggests that neuroadaptations in cell signaling and gene transcription pathways mediate relapse and other behavioral pathologies in alcohol and drug abuse. Thus, the overall goal of the preclinical studies in this renewal application is to identify and validate molecular and cellular mechanisms of alcohol reinforcement and relapse-like behavior.