CREB Mediated GABA-B Receptor Regulation in the Nucleus Accumbens

CREB 介导的伏核 GABA-B 受体调节

基本信息

批准号：
7680007
负责人：
Sophie Desbiens
金额：
$ 1.18万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7680007
关键词：
ATF2 gene Address Adult Affect Agonist Alternative Splicing Animal Model Attenuated Autologous Baclofen Binding Biological Assay Brain CREB1 gene Ca(2+)-Calmodulin Dependent Protein Kinase Calcium/calmodulin-dependent protein kinase Chronic Cocaine Cocaine Abuse Cocaine Dependence Cocaine Users Consumption Corpus striatum structure Cyclic AMP-Responsive DNA-Binding Protein Dorsal Embryo Exposure to Family member Foundations Future GABA-B Receptor Genetic Transcription Human Injection of therapeutic agent Intake Laboratories Lead Light Luciferases Mediating Messenger RNA Methods Modeling Molecular Neurons Nucleus Accumbens Occupations Phosphorylation Play Preparation Process Protein Family Protein Isoforms Protein Kinase Inhibitors Protein Subunits Proteins RNA RRM1 gene Rattus Regulation Relapse Relative (related person)Reporting Reverse Transcription Role Self Administration Signal Pathway Site Testing Time Transcriptional Regulation Western Blotting addiction behavioral sensitization chromatin immunoprecipitation cocaine exposure in vivo promoter protein kinase inhibitor receptor receptor function research study transcription factor transcription factor USF

项目摘要

DESCRIPTION (provided by applicant): Cocaine abuse is an important problem: in the US alone it is estimated that there over 5 million cocaine users in 2000. Studies have shown that GABA-B receptor (GABABR) agonists and modulators are effective in reducing cocaine consumption in humans and/or animal models of addiction. The GABABR mediates slow metabotropic. inhibition, and expression of two subunits GABABR1 (R1) and GABABR2 (R2) is believed required for receptor function. Expression of the R1 isoforms (R1a and R1b) is under the control of alternative promoters in the R1 gene. The promoters are differentially regulated by CREB family members and by the upstream stimulatory factor (USF) that recognizes a composite CRE/Ebox site in R1b. Interestingly, chronic cocaine exposure leads to an increase in phosphorylated CREB. In this proposal, we will test the role that CREB, ATF4, and USF play in controlling endogenous expression of R1a and R1b in the nucleus accumbens (NAc) (Aim 1). Then, we will the address whether R1a and R1b regulation in the NAc is affected by chronic baclofen treatment (Aim 2) and in a rat model of cocaine self-administration (Aim 3).

描述（由申请人提供）：可卡因滥用是一个重要问题：据估计，2000 年仅美国就有超过 500 万可卡因使用者。研究表明，GABA-B 受体 (GABABR) 激动剂和调节剂可有效减少可卡因人类和/或成瘾动物模型中的消费。 GABABR 介导缓慢的代谢性。据信，两个亚基 GABABR1 (R1) 和 GABABR2 (R2) 的抑制和表达是受体功能所必需的。 R1 亚型（R1a 和 R1b）的表达受 R1 基因中替代启动子的控制。启动子受到 CREB 家族成员和识别 R1b 中复合 CRE/Ebox 位点的上游刺激因子 (USF) 的差异调节。有趣的是，长期接触可卡因会导致磷酸化 CREB 增加。在本提案中，我们将测试 CREB、ATF4 和 USF 在控制伏隔核 (NAc) 中 R1a 和 R1b 内源表达中所发挥的作用（目标 1）。然后，我们将探讨 NAc 中 R1a 和 R1b 的调节是否受到长期巴氯芬治疗（目标 2）和可卡因自我给药大鼠模型（目标 3）的影响。