CREB-related genes in Alcohol Drinking Behaviors

饮酒行为中 CREB ​​相关基因

• 批准号: 7031240
• 负责人: SUBHASH C. PANDEY
• 金额: $ 18.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031240
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; amygdala; behavioral /social science research tag; behavioral genetics; brain derived neurotrophic factor; brain morphology; cAMP response element binding protein; gene deletion mutation; genetic susceptibility; genetically modified animals; inhibitor /antagonist; injection /infusion; intermolecular interaction; laboratory mouse; neurochemistry; neuropeptide Y; neuropeptide receptor; nucleus accumbens; substance abuse related behavior

DESCRIPTION (provided by applicant): Excessive alcohol consumption is a worldwide problem. There is increasing evidence in recent years to suggest that genetic factors play an important role in the development of alcohol drinking behaviors. The cAMP-responsive element binding (CREB) protein is the common denominator of signaling cascades for a number of neurotransmitter receptors, and is regulated via phosphorylation by several protein kinases. Phosphorylated CREB regulates the downstream expression of cAMP-inducible genes such as neuropeptide Y (NPY) and its receptor NPY-Y1 as well as brain-derived neurotrophic factor (BDNF). Several lines of evidence support the notion that these CREB related genes may be associated with alcohol-drinking behaviors. However, the interactive role of NPY and BDNF genes, mediated via CREB gene transcription factor, in alcohol preference is unknown. The goals of the proposed studies are to examine the role of CREB related target genes in alcohol-drinking behaviors using CREB-knock out mice. Our proposal is based on the hypothesis that decreased function of NPY and BDNF due to deletion of CREB gene transcription factor in the brain is responsible for the genetic predisposition to alcohol-drinking behaviors. The following Specific Aims will test this hypothesis: 1) To evaluate a) whether intracerebroventricular (ICV) infusions of NPY attenuate alcohol preference in CREB knock out (-/- and +/-) mice; and b) if the effects of NPY on alcohol preference are blocked by co-infusion with NPY-Y1 receptor antagonist. 2) To evaluate a) whether ICV infusions of BDNF attenuate alcohol preference in CREB knock out (-/- and +/) mice, and b) if the effects of BDNF on alcohol preference are blocked by co-infusion with NPY-Y1 receptor antagonist. This exploratory grant will establish that CREB knock out mice are a useful model to study the interactions of CREB related genes and their roles in alcohol drinking behaviors. The results from these studies will provide direct evidence that CREB-related target genes might be potential molecular loci for developing future drugs to treat or prevent alcohol-drinking behaviors.

描述（由申请人提供）：过量饮酒是一个世界性问题。近年来，越来越多的证据表明遗传因素在饮酒行为的发展中发挥着重要作用。 cAMP 反应元件结合 (CREB) 蛋白是许多神经递质受体信号级联的共同点，并通过多种蛋白激酶的磷酸化进行调节。磷酸化 CREB ​​调节 cAMP 诱导基因的下游表达，例如神经肽 Y (NPY) 及其受体 NPY-Y1 以及脑源性神经营养因子 (BDNF)。多项证据支持这些 CREB ​​相关基因可能与饮酒行为有关的观点。然而，通过 CREB ​​基因转录因子介导的 NPY 和 BDNF 基因在酒精偏好中的相互作用尚不清楚。拟议研究的目的是使用 CREB ​​敲除小鼠来检查 CREB ​​相关靶基因在饮酒行为中的作用。我们的提议基于这样的假设：由于大脑中 CREB ​​基因转录因子的缺失，NPY 和 BDNF 功能下降是导致饮酒行为的遗传倾向的原因。以下具体目标将检验这一假设： 1) 评估 a) 脑室内 (ICV) 输注 NPY 是否会减弱 CREB ​​敲除（-/- 和 +/-）小鼠的酒精偏好； b) NPY 对酒精偏好的影响是否通过与 NPY-Y1 受体拮抗剂共同输注而被阻断。 2) 评估 a) BDNF 的 ICV 输注是否会减弱 CREB ​​敲除 (-/- 和 +/) 小鼠的酒精偏好，以及 b) BDNF 对酒精偏好的影响是否通过与 NPY-Y1 受体共输注而被阻断对手。这项探索性资助将确定 CREB ​​敲除小鼠是研究 CREB ​​相关基因的相互作用及其在饮酒行为中的作用的有用模型。这些研究的结果将提供直接证据，证明 CREB ​​相关靶基因可能是未来开发治疗或预防饮酒行为药物的潜在分子位点。