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疾病，其特征是长期饮酒，禁欲和复发。新兴的证据表明，乙醇和其他滥用药物可能会导致细胞信号传导和基因转录途径的适应性变化，从而导致脑功能的持久变化。这些适应被认为可以调节酒精中毒中发生的行为病理，并且对于治疗诊所中的酒精饮料至关重要。该应用中的临床前研究集中在钙/钙调蛋白依赖性蛋白激酶II（CAMKII）上，作为酒精相关行为病理学的一种新型分子机制。我们已经发现，自愿饮酒会增加小鼠杏仁核中CAMKII1蛋白的表达，并且恢复寻求酒精的行为与杏仁核的CAMKII激活增加有关，杏仁核是杏仁核的一个亚核，其中CAMKII已知CAMKII已知可以调节联想学习。这些发现表明了此应用的主要假设：自愿性酒精自我给药和戒酒导致CAMKII信号的适应，该信号在功能上调节与酒精中毒相关的行为病理，例如复发。该应用中的研究具有三个独立但集成的特定目的。首先，实验将阐明与慢性自愿饮酒和戒酒有关的CAMKII中的分子和细胞神经适应。这些研究将提供有关自愿饮酒对整个大脑这一关键分子途径的影响的新信息。其次，研究将研究CaMKII调节酒精加固的功能性神经回路。这将使用一种行为药理学方法以及特定CAMKII抑制剂的大脑位点特异性显微注射来完成。这些研究将建立CAMKII活性与维持慢性饮酒的饮酒的增强作用之间的直接联系。第三，提出了实验来表征CaMKII对复发行为的调节，使用恢复酗酒行为的小鼠模型。因此，这些研究检查了CAMKII对酒精中毒发展和发展基础的行为过程的调节。对调节酒精中毒行为病理的分子和细胞机制的更好理解有可能导致新的药物治疗策略。 公共卫生相关性：戒酒期间的长期使用和复发是酒精中毒的标志行为病理和一个主要的临床问题。新兴的证据表明，细胞信号传导和基因转录途径中的神经适应能介导酒精和药物滥用中的复发和其他行为病理。因此，在这种更新应用中，临床前研究的总体目标是识别和验证酒精增强的分子和细胞机制和复发样行为。