Molecular Mechanisms of Ethanol Reinforcement

描述(申请人提供)：酒精中毒是一种复杂的神经精神障碍，以长期饮酒、戒酒和复发为特征。新出现的证据表明，乙醇和其他滥用药物可能会在细胞信号和基因转录途径中产生适应性变化，从而导致大脑功能的持久变化。这些适应被认为是调节发生在酒精中毒中的行为病理，对于临床上治疗酗酒者是至关重要的。这一应用中的临床前研究主要集中在钙/钙调蛋白依赖的蛋白激酶II(CaMKII)，作为酒精相关行为病理的一种新的分子机制。我们已经发现，自愿饮酒增加了小鼠杏仁核CaMKII1蛋白的表达，并且酒精寻求行为的恢复与杏仁外侧核CaMKII激活的增加有关，杏仁外侧核是杏仁核的一个亚核，CaMKII在那里调节联想学习。这些发现提出了这一应用的主要假设：自愿酒精自我管理和戒酒导致CaMKII信号的适应，从功能上调节与酒精中毒相关的行为病理，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CaMKII中与长期自愿饮酒和戒酒有关的分子和细胞神经适应。这些研究将为自愿饮酒对整个大脑这一关键分子通路的影响提供新的信息。其次，研究将探讨CaMKII调节酒精强化的功能神经回路。这将通过行为药理学方法结合脑部特定部位微量注射特定的CaMKII抑制剂来实现。这些研究将建立CaMKII活性和酒精强化作用之间的直接联系，酒精可以维持长期饮酒。第三，提出了利用小鼠酒精寻求行为恢复的模型来表征CaMKII对复发类行为的调控的实验。因此，这些研究考察了CaMKII对行为过程的调控，这些过程是酒精中毒发生和发展的基础。更好地了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物治疗策略。 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，细胞信号和基因转录通路中的神经适应调节酒精和药物滥用中的复发和其他行为病理。因此，这种更新应用的临床前研究的总体目标是识别和验证酒精强化和复发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.