SELECTIVE POTENTIATION OF THE METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 2 BLOCKS PHENCYCLIDINE-INDUCED ACTIVATION HYPERLOCOMOTION AND BRAIN
SELECTIVE POTENTIATION OF THE METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 2 BLOCKS PHENCYCLIDINE-INDUCED ACTIVATION HYPERLOCOMOTION AND BRAIN
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DOI：
10.1016/j.neuroscience.2010.02.057
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发表时间：
2010-06-16
期刊：
影响因子：
3.3
通讯作者：
Gore, J. C.
中科院分区：
文献类型：
--
作者：
Hackler, E. A.;Byun, N. E.;Gore, J. C.
先前的临床前和临床研究已经证明了II组代谢型谷氨酸受体（mGluR）激动剂作为潜在抗精神病药的功效。最近利用mGluR 2-、mGluR 3-和双敲除小鼠的研究支持这些化合物的抗精神病作用由mGluR 2介导。事实上，联苯茚酮-A（BINA），mGluR 2的变构增效剂，在精神病的实验模型中是有效的，阻断苯环利定（PCP）诱导的小鼠过度运动和前脉冲抑制缺陷。在这项研究中，我们给NMDA受体拮抗剂PCP（5.6 mg/kg i. p.）对大鼠，一个建立的动物模型预测精神分裂症。在此，我们显示BINA（32 mg/kg i. p.）减弱PCP诱导的大鼠自发活动。使用行为相关剂量的BINA和PCP，我们进行了药理学磁共振成像（phMRI），以评估特定的大脑区域，PCP的拟精神病效应的基础，并检查如何BINA调制PCP诱导的功能变化在体内。在麻醉大鼠中，PCP的急性给药在特定的皮质、边缘系统、丘脑和纹状体区域产生了稳健的、持续的血氧水平依赖性（BOLD）激活。用BINA预处理抑制了前额叶皮层、尾壳核、丘脑背核和丘脑背内侧核对PCP的BOLD反应幅度。我们的研究结果显示了精神分裂症临床前模型中PCP诱导行为的关键脑结构，重要的是，通过BINA增强mGluR 2来逆转PCP诱导行为，揭示了在功能上参与其药理作用的特定脑区域。最后，我们的研究结果支持了越来越多的证据表明mGluR 2是治疗精神分裂症的可行靶点。(C)2010年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Previous preclinical and clinical studies have demonstrated the efficacy of group II metabotropic glutamate receptor (mGluR) agonists as potential antipsychotics. Recent studies utilizing mGluR2-, mGluR3-, and double knockout mice support that the antipsychotic effects of those compounds are mediated by mGluR2. Indeed, biphenyl indanone-A (BINA), an allosteric potentiator of mGluR2, is effective in experimental models of psychosis, blocking phencyclidine (PCP)-induced hyperlocomotion and prepulse inhibition deficits in mice. In this study, we administered the NMDA receptor antagonist PCP (5.6 mg/kg i.p.) to rats, an established animal model predictive of schizophrenia. Here, we show that BINA (32 mg/kg i.p.) attenuated PCP-induced locomotor activity in rats. Using behaviorally relevant doses of BINA and PCP, we performed pharmacological magnetic resonance imaging (phMRI) to assess the specific brain regions that underlie the psychotomimetic effects of PCP, and examined how BINA modulated the PCP-induced functional changes in vivo. In anesthetized rats, acute administration of PCP produced robust, sustained blood oxygenation level-dependent (BOLD) activation in specific cortical, limbic, thalamic, and striatal regions. Pretreatment with BINA suppressed the amplitude of the BOLD response to PCP in the prefrontal cortex, caudaute-putamen, nucleus accumbens, and mediodorsal thalamus. Our results show key brain structures underlying PCP-induced behaviors in a preclinical model of schizophrenia, and, importantly, its reversal by potentiation of mGluR2 by BINA, revealing specific brain regions functionally involved in its pharmacological action. Finally, our findings bolster the growing body of evidence that mGluR2 is a viable target for the treatment of schizophrenia. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.