The Role of Cyclic AMP in Alcohol Withdrawal and Mental Disease

环磷酸腺苷在酒精戒断和精神疾病中的作用

• 批准号: 7890636
• 负责人: JULIA ANN CHESTER
• 金额: $ 18.48万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890636
• 关键词: Acoustics; Address; Adenylate Cyclase; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Alzheimer' s Disease; Animal Model; Anxiety; Anxiety Disorders; Behavior; Behavioral; Behavioral Model; Binding Proteins; Biological; Biological Markers; Brain Diseases; Brain Injuries; Brain region; Cells; Chronic; Clinical; Clinical Research; Cognition; Cognitive; Comorbidity; Convulsions; Cyclic AMP; Dependence; Development; Disease; Drug usage; Emotional; Epilepsy; Forskolin; Fright; Goals; Human; Impaired cognition; Impairment; In Vitro; Individual; Measures; Mental Depression; Mental disorders; Modeling; Mus; Natural Remedy; Obesity; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Physiologic pulse; Plants; Psyche structure; Response Elements; Risk; Role; Rolipram; Schizophrenia; Second Messenger Systems; Signal Pathway; Signs and Symptoms; Symptoms; Testing; Therapeutic; Therapeutic Effect; Withdrawal; alcohol abuse therapy; cognitive function; dietary supplements; improved; in vivo Model; indexing; novel; novel therapeutics; pre-clinical; preclinical study; public health relevance; response; second messenger; tool

DESCRIPTION (provided by applicant): Alcohol dependence, schizophrenia and anxiety disorders are comorbid disorders that occur at a remarkably high rate but there are presently very few treatments available for people with these comorbid mental diseases. Alcohol withdrawal may be one common factor in the pathogenesis of alcohol dependence and comorbid mental disorders. Alcohol withdrawal can damage the brain and produce cognitive and emotional impairments in alcohol-dependent individuals that are similar to that seen in people with schizophrenia and anxiety disorders. Evidence suggests that activating the 3',5'-cyclic adenosine monophosphate (cAMP) second messenger signaling pathway may reduce the behavioral effects of alcohol withdrawal. The broad, long-term objective of this exploratory R21 project is to explore the therapeutic potential of two promising drugs that raise intracellular cAMP levels, forskolin and rolipram, to reduce physical, cognitive, and emotional signs of alcohol withdrawal in mice. The goal of Specific Aim 1 is to explore the effects of forskolin and rolipram on the physical signs of alcohol withdrawal using handling-induced convulsions to assess withdrawal following chronic alcohol treatment. The goal of Specific Aim 2 is to explore the effects of forskolin and rolipram on cognitive signs of alcohol withdrawal using pre-pulse inhibition of the acoustic startle response to assess withdrawal following chronic alcohol treatment. The goal of Specific Aim 3 is to explore the effects of forskolin and rolipram on emotional signs of alcohol withdrawal (anxiety) using the fear-potentiated startle response to assess withdrawal following chronic alcohol treatment. We will also measure phosphorylated cAMP response element binding protein in three brain regions to provide a biological marker for cAMP activity under the proposed test conditions. The results of this exploratory R21 project may reveal that activation of the adenylate cyclase-cAMP signaling pathway reduces alcohol withdrawal effects and could improve cognitive and emotional function in people with alcohol dependence and comorbid mental diseases. PUBLIC HEALTH RELEVANCE: Alcohol dependence, schizophrenia and anxiety disorders are common comorbid disorders in that they are frequently found to occur together in the same individual. The goal of this project is to develop new models to assess alcohol dependence and comorbid conditions and identify two promising, novel therapeutic drugs to treat these conditions.

描述（由申请人提供）：酒精依赖、精神分裂症和焦虑症是以非常高的比率发生的共病障碍，但是目前很少有治疗方法可用于患有这些共病精神疾病的人。酒精戒断可能是酒依赖与精神障碍共病的共同发病因素。酒精戒断会损害大脑，并在酒精依赖者中产生认知和情感障碍，这与精神分裂症和焦虑症患者相似。有证据表明，激活3 '，5'-环磷酸腺苷（cAMP）第二信使信号通路可能会减少酒精戒断的行为影响。这个探索性R21项目的广泛，长期目标是探索两种有前途的药物的治疗潜力，提高细胞内cAMP水平，毛喉素和咯利普兰，以减少小鼠酒精戒断的身体，认知和情绪迹象。具体目标1的目的是探索毛喉素和咯利普兰对酒精戒断体征的影响，使用处理诱导的惊厥来评估长期酒精治疗后的戒断。具体目标2的目的是探索福司可林和咯利普兰对酒精戒断认知体征的影响，使用声惊吓反应的前脉冲抑制来评估长期酒精治疗后的戒断。具体目标3的目标是探索福司可林和咯利普兰对酒精戒断（焦虑）的情绪体征的影响，使用恐惧增强的惊吓反应来评估长期酒精治疗后的戒断。我们还将测量三个脑区的磷酸化cAMP反应元件结合蛋白，以提供在拟定试验条件下cAMP活性的生物标记物。这项探索性的R21项目的结果可能揭示，腺苷酸环化酶-cAMP信号通路的激活可以减少酒精戒断效应，并可以改善酒精依赖和共病精神疾病患者的认知和情感功能。 公共卫生关系：酒精依赖、精神分裂症和焦虑症是常见的共病障碍，因为它们经常被发现在同一个体中一起发生。该项目的目标是开发新的模型来评估酒精依赖和合并症，并确定两种有前途的新型治疗药物来治疗这些疾病。