METABOTROPIC GLUTAMATE REGULATION OF AMPHETAMINE ACTION

安非他明作用的代谢谷氨酸调节

• 批准号: 6024052
• 负责人: QIANG WANG
• 金额: $ 8.65万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-16 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6024052
• 关键词: amphetamines; biological signal transduction; calcium flux; endogenous opioid; gene expression; glutamate receptor; in situ hybridization; laboratory rat; newborn animals; phosphatidylinositols; protein kinase C; psychopharmacology; regulatory gene; tissue /cell culture

DESCRIPTION: (Applicant's Abstract) A single injection of the psychostimulant, amphetamine, upregulates immediate early gene (IEG) and opioid peptide gene expression in the rat striatum. These genomic responses may be important in neuronal plasticity related to long-term changes in behavior. In exploring intracellular signaling pathways trans-mitting surface receptor stimulation to nuclear gene expression, we recently found that metabotropic glutamate receptors (mGluR) which are coupled to multiple second messenger systems through G proteins and are highly expressed in the striatum, regulate acute amphetamine-stimulated IEG as well as opioid gene expression in the striatum. Based on this encouraging finding, we propose in this project to further characterize the regulation of amphetamine-stimulated striatal gene expression by mGluRs and mGluR-linked intracellular signaling pathways. The hypothesis is that striatal mGluR activity contributes to the ability of acute amphetamine to stimulate IEG and opioid gene expression in the rat striatum and that increases in phosphoinositide hydrolysis, the best known and most thoroughly investigated cellular response to mGluR activation, serve as the signaling pathway bridging surface mGluR stimulation to nuclear gene expression. This hypothesis will be tested in two aims which are to (1) examine the effects of enhancement and reduction of striatal mGluR activity by injections of mGluR selective agonists and antagonists, respectively, on acute amphetamine-stimulated striatal IEG and opioid gene expression in a well characterized rat in vivo model, and (2) evaluate the contribution of the mGluR phosphoinositide-linked signaling pathways, i.e., intracellular Ca2+ mobilization and protein kinase C, to mGluR-sensitive gene expression in primary striatal cultured neurons from neonatal rats with both pharmacological (activators/inhibitors) and molecular (antisense technique) approaches. We will rely on in situ hybridization to analyze striatal mRNA expression in vivo and in vitro. This project should provide new insight into the signal transduction coupling stimulus-transcription in response to amphetamine, and improve understanding of the molecular plasticity underlying psychostimulant-induced long-term changes in behavior.

描述：（申请人的摘要） 单一注射心理刺激剂，苯丙胺，上调 大鼠的直接早期基因（IEG）和阿片类肽基因表达 纹状体。 这些基因组反应在神经元可塑性中可能很重要 与行为的长期变化有关。 在探索细胞内 信号通路向核刺激表面受体刺激 基因表达，我们最近发现代谢型谷氨酸受体 （mglur）通过g耦合到多个第二个使者系统 蛋白质并在纹状体中高度表达，调节急性 苯丙胺刺激的IEG以及阿片类药物基因表达 纹状体。 基于这一令人鼓舞的发现，我们在这个项目中建议 进一步表征了苯丙胺刺激的纹状体基因的调节 通过mglurs和mglur连接的细胞内信号通路表达。 这 假设是纹状体mglur活性有助于 急性苯丙胺刺激大鼠的IEG和阿片类药物基因表达 纹状体和磷酸肌醇水解的增加，这是最著名的 最彻底地研究了细胞对mglur激活的反应， 用作信号通路桥接表面mglur刺激到核 基因表达。 该假设将以两个目的进行检验 （1）检查纹状体mglur增强和减少的影响 通过注射mglur选择性激动剂和拮抗剂的活动， 分别在急性苯丙胺刺激的纹状体IEG和阿片类药物基因上 在体内特征良好的大鼠中表达，（2）评估 mglur磷酸肌醇连锁信号通路的贡献，即 细胞内Ca2+动员和蛋白激酶C，向mglur敏感 来自新生大鼠的原代纹状体培养神经元中的基因表达 药理学（激活剂/抑制剂）和分子（反义） 技术）方法。 我们将依靠原位杂交来分析 体内和体外的纹状体mRNA表达。 这个项目应提供 对信号转导耦合刺激转录的新见解 对苯丙胺的反应，并提高对 精神刺激剂引起的长期变化的分子塑性 行为。