Novel Receptor GIR in Amphetamine Sensitization

描述：(申请人提供) 重复应激或刺激物可启动行为敏感化 药品管理局。我们实验室最近克隆并测序了一个 大鼠前额叶皮质糖皮质激素诱导受体(GIR)基因的表达 习得性无助的压力模型。全长GIR基因编码一个 属于G蛋白偶联受体超家族的蛋白质，其配体 是未知的。该蛋白质的氨基酸同源性为31%-34% 粘着斑激肽受体NK-1、NK-2、NK-3。作为神经基因的调控 基因表达被认为是安非他明导致 长期的行为敏感化，我们建议探讨 GIR与敏化的启动或维持有关。我们的初步研究 证明长期服用苯丙胺会导致 GIR在大鼠前额叶皮质的长期表达(7天) 在停药后。这些发现使我们假设 GIR表达的调节可能参与了生理调节 以及上瘾过程中的神经适应。这项提案将决定 致敏大鼠GIR的时间依赖性和区域特异性表达 苯丙胺，通过原位研究GIR的细胞定位 杂交和免疫细胞化学，并产生转基因小鼠模型 过表达大鼠GIR。

DESCRIPTION: (provided by applicant) Behavioral sensitization can be initiated by repetitive stress or stimulant drug administration. Our laboratory has recently cloned and sequenced a glucocorticoid-induced receptor (GIR) cDNA from rat prefrontal cortex in a stress model of learned helplessness. The full-length GIR cDNA encodes a protein belonging to the G protein-coupled receptor superfamily, whose ligand is unknown. This protein shares 31 percent-34 percent amino acid identity to the tackykinin receptors NK-1, NK-2, NK-3. As regulation of neuronal gene expression is hypothesized to be one mechanism by which amphetamine leads to long-term behavioral sensitization, we propose to explore the relationship of GIR to the initiation or maintenance of sensitization. Our preliminary studies demonstrate that chronic amphetamine administration results in elevated expression of GIR in rat prefrontal cortex, which persists long-term (7 days) following drug discontinuing. These findings lead us to hypothesize that modulation of GIR expression may be involved in the physiological regulation and neuroadaptation in the addictive process. This proposal will determine the time-dependent and region-specific expression of GIR in rats sensitized to amphetamine, explore the cellular localization of GIR through in situ hybridization and immunocytochemistry, and generate a transgenic mouse model overexpressing rat GIR.