5-HT2 and 5-HT1A Receptors in PKC-gamma Null Mutant Mice

PKC-gamma 无效突变小鼠中的 5-HT2 和 5-HT1A 受体

• 批准号: 6684770
• 负责人: BARBARA J BOWERS
• 金额: $ 14.8万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684770
• 关键词: G protein coupled receptor kinase; alcoholism /alcohol abuse; autoradiography; behavior test; behavioral /social science research tag; buspirone; drug screening /evaluation; enzyme mechanism; ethanol; hydrolysis; impulsive behavior; isozymes; laboratory mouse; messenger RNA; neurochemistry; neuropharmacology; neuropsychology; neurotransmitter agonist; neurotransmitter antagonist; phosphatidylinositols; protein kinase C; receptor expression; serotonin; serotonin receptor; substance abuse related behavior; tissue /cell preparation

DESCRIPTION (provided by applicant): A genetic relationship between behavioral disinhibition and alcoholism has been reported in recent studies of the etiology of alcoholism, suggesting that a shared neurochemical pathway regulates these behaviors. Disregulation of the serotonergic neurotransmitter system has been implicated as one factor in several behaviors associated with alcoholism, including behavioral disinhibition, anxiety, and high levels of alcohol consumption. This may be the result of pleiotropic regulation by one or more genes that impact the diverse family of serotonergic receptors. The identification of gene(s) underlying this shared regulation is largely unknown. We have previously demonstrated that mice lacking the neural specific y isotype of PKC demonstrate both increased impulsivity and increased ethanol consumption as well as alterations in endogenous behavioral anxiety, indicating that PKCgamma is one mediator of these behaviors Preliminary data from behavioral pharmacological investigations of serotonergic activity in PKCgamma mutant and wild-type control mice provide evidence that 5-HT2Nc and 5-HT1A receptor systems are disrupted in mutant mice. Because PKC has been shown to regulate 5-HT2A/C and 5-HT1A receptor function, the goal of the proposed studies to determine if PKCgamma, plays a specific role in regulating these receptors by investigating serotonin-mediated behaviors and 5 # HT 2A/C and 5-HT1A receptor function in PKCgamma null mutant and wild-type littermate control mice. In specific aim # 1 5-HT2A/C agonists and antagonists will be administered to mutant and wild-type mice prior to impulsivity training or ethanol consumption to determine the association of PKCy and the 5-HT2 receptor system in regulating these behaviors. In specific aim # 2, 5-HT2A and 5-HT2c receptors will be compared in brain tissue from naive and drug-treated mutant and wild-type mice using receptor autoradioraphy and agonist-stimulated phosphoinositide hydrolysis. In specific aim #3 5-HT1A-mediated effects on anxiety and 5-HT1A receptor number and affinity, measured using receptor autoradiography, will be compared between mutant and wild-type mice. The results of these studies will help to elucidate the specific role of PKCgamma, in complex behaviors associated with alcohol dependence.

描述（由申请人提供）： 在最近的酒精中毒病因学研究中，已经报道了行为去抑制和酒精中毒之间的遗传关系，这表明共同的神经化学途径调节这些行为。酒精能神经递质系统的失调被认为是与酒精中毒相关的几种行为的一个因素，包括行为去抑制、焦虑和高水平饮酒。这可能是一个或多个基因的多效性调节的结果，影响不同家族的多巴胺能受体。这种共同调控的基因的鉴定在很大程度上是未知的。我们以前已经证明，缺乏神经特异性γ同种型PKC的小鼠表现出冲动性增加和乙醇消耗增加以及内源性行为焦虑的改变，表明PKC γ是这些行为的一种介质。来自PKC γ突变体和野生型对照小鼠中的β-羟色胺能活性的行为药理学研究的初步数据提供了5-HT 2Nc和5-HT 2Nc与5-HT 2Nc之间的相互作用的证据。HT 1A受体系统在突变小鼠中被破坏。由于PKC已被证明可调节5-HT 2A/C和5-HT 1A受体功能，因此本研究的目的是通过研究PKC γ无效突变小鼠和野生型同窝对照小鼠中的降钙素介导的行为和5-HT 2A/C和5-HT 1A受体功能来确定PKC γ是否在调节这些受体中起特定作用。在具体目标#1中，在冲动训练或乙醇消耗之前，将5-HT 2A/C激动剂和拮抗剂给予突变型和野生型小鼠，以确定PKC γ和5-HT 2受体系统在调节这些行为中的关联。在具体目标#2中，将使用受体放射自显影和激动剂刺激的磷酸肌醇水解在来自未处理和药物处理的突变型和野生型小鼠的脑组织中比较5-HT 2A和5-HT 2c受体。在具体目标#3中，将在突变型和野生型小鼠之间比较5-HT 1A介导的对焦虑和5-HT 1A受体数量和亲和力的影响，使用受体放射自显影法测量。这些研究的结果将有助于阐明PKC γ在与酒精依赖相关的复杂行为中的具体作用。