RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling.
RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling.
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DOI：
10.1007/s00213-011-2606-8
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发表时间：
2012-06
影响因子：
3.4
通讯作者：
McGinty JF
中科院分区：
文献类型：
--
作者：
Schwendt M;Sigmon SA;McGinty JF
g蛋白信号传导调节因子4 （RGS4）是脑富集的g蛋白偶联受体信号传导负调节因子。在精神分裂症和药物成瘾的动物模型中已经描述了额叶皮层和纹状体中RGS4的可用性降低。然而，大脑中rgs4依赖性受体信号失调的细胞和行为后果仍然知之甚少。探讨RGS4是否通过抑制mGluR5受体在背纹状体（dSTR）的功能，调节急性安非他明对细胞和行为的反应。将HSV-RGS4注入dSTR后，观察RGS4过表达以及重组RGS4与mGluR5的结合情况。记录RGS4过表达对纹状体内mGluR5激动剂、DHPG或安非他明诱导的行为活动的影响。在每次行为实验结束时，测量dSTR组织中细胞外信号调节激酶（ERK）和蛋白激酶B （Akt）的激活。RGS4在dSTR中过表达，与mGluR5受体共免疫沉淀，抑制DHPG诱导的行为活性和phospho-ERK水平。RGS4过表达或mGluR5拮抗剂MTEP可减弱安非他明诱导的phospho-ERK（但不减弱phospho-Akt）水平。RGS4在90分钟内抑制安非他明诱导的垂直活性，增强水平活性。同样，MTEP增强了安非他明诱导的水平活性，但不影响垂直活性。目前的数据表明，dSTR中的RGS4可能通过限制mGluR5的功能，减弱安非他明诱导的ERK信号，降低急性安非他明的行为疗效。
Regulator of G-protein signaling 4 (RGS4) is a brain-enriched negative modulator of G-protein-coupled receptor signaling. Decreased availability of RGS4 in the frontal cortex and striatum has been described in animal models of schizophrenia and drug addiction. However, cellular and behavioral consequences of dysregulated RGS4-dependent receptor signaling in the brain remain poorly understood. To investigate whether RGS4, through inhibiting function of mGluR5 receptors in the dorsal striatum (dSTR), regulates cellular and behavioral responses to acute amphetamine. After HSV-RGS4 was infused into dSTR, RGS4 overexpression as well as binding of recombinant RGS4 to mGluR5 were assessed. The effect of RGS4 overexpression on behavioral activity induced by the intra-striatal mGluR5 agonist, DHPG, or amphetamine was recorded. Activation of extracellular signal-regulated kinase (ERK) and Akt (protein kinase B) was measured in the dSTR tissue at the end of each behavioral experiment. RGS4 overexpressed in the dSTR co-immunoprecipitated with mGluR5 receptors and suppressed both behavioral activity, as well as phospho-ERK levels induced by DHPG. RGS4 over-expression or the mGluR5 antagonist, MTEP attenuated amphetamine-induced phospho-ERK (but not phospho-Akt) levels. RGS4 suppressed amphetamine–induced vertical activity and augmented horizontal activity over 90 min. Similarly, MTEP augmented amphetamine-induced horizontal activity but did not affect vertical activity. The present data demonstrate that RGS4 in the dSTR attenuates amphetamine-induced ERK signaling and decreases the behavioral efficacy of acute amphetamine likely by limiting mGluR5 function.