METABOTROPIC GLUTAMATE REGULATION OF AMPHETAMINE ACTION

描述：(申请人摘要) 一次注射精神刺激剂苯丙胺，就会上浮 大鼠即刻早期基因(IEG)和阿片肽基因的表达 纹状体。这些基因组反应可能对神经元的可塑性很重要。 与行为的长期变化有关。在探索细胞内 表面受体刺激转导核内的信号通路 基因表达，我们最近发现代谢性谷氨酸受体 (MGluR)通过G连接到多个第二信使系统 蛋白质和在纹状体中高表达，调节急性 苯丙胺刺激的大鼠IEG和阿片基因表达 纹状体。基于这一令人鼓舞的发现，我们在这个项目中建议 进一步表征苯丙胺刺激的纹状体基因的调控 通过mGluRs和mGluR连接的细胞内信号通路表达。这个 假设纹状体mGluR活性有助于 急性苯丙胺刺激大鼠IEG和阿片基因表达 纹状体和磷脂酰肌醇的水解量增加，这是最著名的 最彻底地研究了细胞对mGluR激活的反应， 作为表面mGluR刺激与核之间的信号通路 基因表达。这一假设将在两个目标上进行检验，这两个目标是 (1)检测纹状体mGluR增强和降低的效果 通过注射mGluR选择性激动剂和拮抗剂的活性， 分别对急性苯丙胺刺激的纹状体IEG和阿片类基因的影响 在具有良好特征的大鼠体内模型中表达，以及(2)评估 MGluR磷脂酰肌醇连接的信号通路的贡献，即， 对mGluR敏感的细胞内钙离子动员和蛋白激酶C 新生大鼠纹状体原代培养神经元基因表达的研究 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 纹状体基因在体内和体外的表达。该项目应提供 信号转导与刺激-转录偶联的新视角 对苯丙胺的反应，提高对安非他明的认识 精神刺激剂诱导的长期变化背后的分子可塑性 行为。

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.