The Role of Cyclic AMP in Alcohol Withdrawal and Mental Disease

描述(申请人提供)：酒精依赖、精神分裂症和焦虑症是共病，发病率非常高，但目前对患有这些共病的精神疾病的人来说，治疗方法很少。酒精戒断可能是酒依赖和精神障碍共病的共同致病因素之一。戒酒会损害大脑，导致酒精依赖者的认知和情绪障碍，这与精神分裂症和焦虑症患者的情况相似。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效应。这个探索性的R21项目的广泛、长期的目标是探索两种有希望的药物福斯科林和罗利普兰提高细胞内cAMP水平的治疗潜力，以减少小鼠酒精戒断的身体、认知和情感迹象。具体目标1的目的是通过使用处理诱发的惊厥来评估慢性酒精治疗后的戒酒情况，探讨Forskolin和Rolipram对酒精戒断体征的影响。具体目标2的目的是通过对声学惊厥反应的预脉冲抑制来评估慢性酒精治疗后的戒酒情况，以探讨Forskolin和Rolipram对酒精戒断认知体征的影响。具体目标3的目标是探索Forskolin和Rolipram对酒精戒断(焦虑)情绪迹象的影响，使用恐惧增强的惊吓反应来评估慢性酒精治疗后的戒酒。我们还将在三个脑区测量磷酸化的cAMP反应元件结合蛋白，以提供在拟议的测试条件下cAMP活性的生物标记。这一探索性的R21项目的结果可能揭示，激活腺苷环化酶-cAMP信号通路可以减少酒精戒断效应，并可以改善酒精依赖和合并精神疾病的人的认知和情绪功能。 公共卫生相关性：酒精依赖、精神分裂症和焦虑症是常见的共病，因为它们经常被发现同时发生在同一个人身上。该项目的目标是开发新的模型来评估酒精依赖和共病情况，并确定两种有前途的新型治疗药物来治疗这些情况。

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.