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: 6916216
• 负责人: BARBARA J BOWERS
• 金额: $ 14.9万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916216
• 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）： 在最近关于酒精中毒的病因研究中，行为抑制与酒精中毒之间的遗传关系已经报道，这表明共同的神经化学途径调节了这些行为。忽视血清素能神经递质系统已被认为是与酒精中毒相关的几种行为的一个因素，包括行为抑制，焦虑和高水平的酒精消耗。这可能是由一个或多个影响多元化血清素能受体家族的基因进行多效性调节的结果。该共同调节的基因的鉴定在很大程度上是未知的。我们先前已经证明，缺乏神经特异性PKC的小鼠既表现出增加的冲动性，又增加了乙醇的消耗量以及内源性行为焦虑的变化，表明PKCGAMMA是这些行为的介体，是这些行为的一种介体，该行为是由PARCHIMATAL PARCHINAL PARDINAL PRACHICTAL PARCHINATINAL PATIT提供的证据和PKCGCGCGAMMA MUTICENC MUTICENC MUTICENC MUTICENC中的证据，以致是STICPENC MUTINC 2-htrc Muttrc Mutcem 2-htc。 5-HT1A受体系统在突变小鼠中被破坏。由于已显示PKC调节5-HT2A/C和5-HT1A受体功能，因此提出的研究的目的是确定PKCGAMMA是否通过研究5-＃HT 2A/C和5-HT1A受体在PKCGCGCGMAMMA NULL-MUTTATE CONTRUTEN中通过研究血清素介导的行为和5＃HT 2A/C和5-HT1A受体的功能来调节这些受体的特定作用。在特定的目标＃1 5-HT2A/C激动剂和拮抗剂中，将在冲动性训练或乙醇消耗之前对突变体和野生型小鼠进行施用，以确定PKCY和5-HT2受体系统的关联，以调节这些行为。在特定的目标＃2中，使用受体自缩影和激动剂刺激的磷酸肾上腺素水解的脑组织将比较脑组织中的5-HT2A和5-HT2C受体。在特定目标中，将比较使用受体放射自显影测量的焦虑和5-HT1A受体数量和亲和力的影响，将在突变体和野生型小鼠之间进行比较。这些研究的结果将有助于阐明与酒精依赖相关的复杂行为中PKCGAMMA的特定作用。