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.

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