Molecular Mechanisms of Ethanol Reinforcement

乙醇增强的分子机制

• 批准号: 8039574
• 负责人: Clyde W Hodge
• 金额: $ 29.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039574
• 关键词: Abstinence; Acute; Adaptive Behaviors; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Behavior; Behavioral; Biochemical; Brain; Brain region; Calcium/calmodulin-dependent protein kinase; Cell Nucleus; Chronic; Clinic; Clinical; Complex; Coupled; Cues; Data; Development; Disease; Drug abuse; Drug usage; Ethanol; Genetic Transcription; Goals; Human; Immunohistochemistry; Lateral; Lead; Learning; Link; Maintenance; Mediating; Memory; Microinjections; Modeling; Molecular; Mus; Nature; Neuronal Plasticity; Organism; Pathology; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Process; Property; Psychological reinforcement; Regulation; Relapse; Role; Self Administration; Signal Transduction; Signaling Molecule; Site; Specificity; Stimulus; Sucrose; System; Testing; Time; addiction; alcohol abstinence; alcohol effect; alcohol reinforcement; alcohol relapse; alcohol seeking behavior; behavior test; behavioral pharmacology; calmodulin-dependent protein kinase II; chronic alcohol ingestion; classical conditioning; conditioning; craving; drinking; drug of abuse; drug seeking behavior; experience; immunoreactivity; inhibitor/antagonist; mouse model; neural circuit; neuroadaptation; neurobehavioral; neuromechanism; neuropsychiatry; novel; paired stimuli; preclinical study; problem drinker; protein expression; reinforcer; relating to nervous system; research study; response

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.

描述（由申请人提供）：酒精中毒是一种复杂的神经精神障碍，其特征是长期饮酒、戒酒和复发。新出现的证据表明，滥用乙醇和其他药物可能会在细胞信号传导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。这些适应被认为可以调节酒精中毒中发生的行为病理，对临床治疗酒精中毒具有重要意义。该应用的临床前研究主要集中在钙/钙调素依赖性蛋白激酶II （CaMKII）作为酒精相关行为病理的新分子机制。我们发现，自愿饮酒增加了小鼠杏仁核中CaMKII1蛋白的表达，而寻求酒精行为的恢复与侧杏仁核中CaMKII激活的增加有关，杏仁核是杏仁核的一个亚核，已知CaMKII调节联想学习。这些发现提出了这一应用的主要假设：自愿饮酒和戒酒导致CaMKII信号的适应，CaMKII信号在功能上调节与酒精中毒相关的行为病理，如复发。本应用程序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。这些研究将为自愿饮酒对贯穿大脑的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位特异性CaMKII抑制剂的显微注射来完成。这些研究将建立CaMKII活性与酒精维持长期饮酒的强化作用之间的直接联系。第三，我们提出了一些实验来描述CaMKII对复发样行为的调节，这些行为是通过小鼠模型来恢复寻酒行为的。因此，这些研究检查了CaMKII对酒精中毒发展和进展的基本行为过程的调节。更好地了解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。