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合并症的疾病，以非常高的速度出现，但目前对患有这些合并症的人的治疗方法很少。戒酒可能是酒精依赖和合并精神障碍的发病机理的一个常见因素。饮酒会损害大脑，并在酒精依赖性个体中产生认知和情绪障碍，这些人与精神分裂症和焦虑症患者相似。有证据表明，激活3'，5'-循环腺苷单磷酸盐（CAMP）第二信号信号通路可能会减少戒断酒精的行为影响。该探索性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，这些药物提高了细胞内营地水平，即福斯科林和rolipram，以减少小鼠中戒酒的身体，认知和情绪迹象。特定目的1的目的是探索福斯科蛋白和rolipram对使用操纵引起的抽搐的物理戒烟迹象的影响，以评估慢性酒精治疗后的戒断。特定目的2的目的是探索福斯科蛋白和rolipram对使用脉冲前抑制声学惊吓后反应以评估慢性酒精治疗后的戒断的影响。特定目的3的目的是探索福斯科林和rolipram对戒酒（焦虑）情绪迹象（焦虑）的影响，使用恐惧感应的惊吓反应来评估慢性酒精治疗后的戒断。我们还将在三个大脑区域中测量磷酸化的CAMP反应元件结合蛋白，以在拟议的测试条件下为cAMP活动提供生物学标记。该探索性R21项目的结果可能表明，腺苷酸环化酶 - 训练营信号通路的激活减少了酒精戒断的效果，并且可以改善酒精依赖和合并精神疾病的人的认知和情感功能。 公共卫生相关性：酒精依赖，精神分裂症和焦虑症是常见的合并症，因为它们经常被发现同一个人发生。该项目的目的是开发新的模型来评估酒精依赖性和合并状况，并确定两种有希望的新型治疗药物来治疗这些疾病。