PKA and NPY Signaling in Ethanol-Induced Sensitization

乙醇诱导致敏中的 PKA 和 NPY 信号转导

• 批准号: 7221401
• 负责人: Dayna M. Hayes
• 金额: $ 2.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221401
• 关键词: adeno associated virus group; alcoholic beverage consumption; amygdala; behavioral /social science research tag; behavioral habituation /sensitization; biological signal transduction; corpus striatum; ethanol; genetically modified animals; immunocytochemistry; intermolecular interaction; laboratory mouse; molecular psychobiology; neuropeptide Y; neuroregulation; nucleus accumbens; polymerase chain reaction; predoctoral investigator; protein kinase A; stereotaxic techniques; transfection /expression vector

DESCRIPTION (provided by applicant): Low neuropeptide Y (NPY) and cAMP-dependent protein kinase A (PKA) signaling are both associated with increased ethanol consumption and enhanced sensitivity to ethanol-induced locomotor stimulation. Recent evidence shows that PKA signaling drives NPY synthesis. Therefore, the guiding hypothesis of the present proposal is that the increased ethanol intake and sensitivity to ethanol-induced locomotor sensitization that are characteristic of mutant mice with low central PKA activity (i.e., Rll-beta deficient mice) are consequences of blunted NPY signaling. Specific Aim 1 will utilize immunohistochemistry and real-time PCR to determine if PKA mutant mice have low NPY signaling at baseline and in response to ethanol administration in candidate brain regions. Specific Aim 2 will utilize a recombinant adeno-associated viral vector (rAAV) to determine if site-directed overexpressioh of NPY in the striatum, nucleus accumbens, and/or amygdala will protect against increased sensitivity to ethanol-induced locomotor sensitization and elevated ethanol drinking in PKA mutant mice. These studies will provide important insight into the interactions between PKA and NPY signaling in modulating neurobiological responses to ethanol.

描述（由申请人提供）：较低的神经肽Y（NPY）和依赖CAMP的蛋白激酶A（PKA）信号传导都与乙醇消耗的增加以及对乙醇诱导的运动刺激的敏感性增强有关。最近的证据表明，PKA信号传导驱动NPY合成。因此，本提案的指导假设是，乙醇的摄入量增加和对乙醇诱导的运动敏化的敏感性，这是中央PKA活性低的突变小鼠的特征（即RLLL-BETA可获得的预后小鼠）是钝性的NPY信号传导的结果。具体目标1将利用免疫组织化学和实时PCR来确定PKA突变小鼠在基线时是否具有低NPY信号传导，并响应候选脑区域的乙醇给药。具体目标2将利用重组腺相关的病毒载体（RAAV）来确定在纹状体，八核和/或杏仁核中是否在纹状体中定向的NPY过表达，将防止对乙醇诱导的乙醇诱导的乙醇敏感性敏感性，并在pka杂种中含有乙醇诱导的乙醇。这些研究将在调节对乙醇的神经生物学反应中对PKA和NPY信号之间的相互作用的重要见解。