INVOLVEMENT OF GLUTAMATERGIC AND GABAERGIC TRANSMISSION IN MK-801-INCREASED GAMMA BAND OSCILLATION POWER IN RAT CORTICAL ELECTROENCEPHALOGRAMS
INVOLVEMENT OF GLUTAMATERGIC AND GABAERGIC TRANSMISSION IN MK-801-INCREASED GAMMA BAND OSCILLATION POWER IN RAT CORTICAL ELECTROENCEPHALOGRAMS
复制标题
DOI：
10.1016/j.neuroscience.2014.08.047
复制
发表时间：
2014-11-07
期刊：
影响因子：
3.3
通讯作者：
Chaki, S.
中科院分区：
文献类型：
--
作者：
Hiyoshi, T.;Kambe, D.;Chaki, S.
N-甲基-D-天冬氨酸受体(NMDAR)功能低下被认为在精神分裂症的病理生理学中起重要作用。在啮齿动物脑电(EEG)研究中，非竞争性NMDAR拮抗剂被报道会产生异常的基础伽马频段振荡(GBO)，如在精神分裂症中观察到的那样。作为一种新型抗精神病药物的翻译生物标志物，GBO能力的异常已经引起了人们的注意。然而，NMDAR拮抗剂诱导的GBO功率异常的神经机制及其药理学意义尚未得到充分的研究。在本研究中，我们研究了MK-801(0.1 mg/kg)增加大鼠大脑皮层脑电基础GBO功率的药理学特性。谷氨酸释放抑制剂利鲁唑(3-10 mg/kg)可降低MK-801增加的基础GBO功率。相反，α2/3/5亚基选择性GABA(A)受体阳性变构调节剂L-838,417(1-3 mg/kg)可增强GbO的升高。氟哌啶醇(0.05-0.3 mg/kg)和氯氮平(1-10 mg/kg)等抗精神病药物可剂量依赖性地减弱MK-801增加的GBO能力。同样，代谢型谷氨酸2/3受体(mGlu2/3受体)激动剂LY379268(0.3-3 mg/kg)以剂量依赖的方式抑制GBO增加，该作用可被mGlu2/3受体拮抗剂LY341495所拮抗。这些结果表明，NMDAR功能低下引起的皮层GBO功率的增加可能与局部环路兴奋性锥体神经元和抑制性中间神经元的异常活动有关。在精神分裂症患者中观察到的反映皮质网络功能障碍的异常的皮质GBO能力可能是发现新型抗精神病药物的有用的生物标志物。(C)2014年IBRO。爱思唯尔有限公司出版。保留所有权利。
Hypofunction of the N-methyl-D-aspartic acid receptor (NMDAr) has been considered to play a crucial role in the pathophysiology of schizophrenia. In rodent electroencephalogram (EEG) studies, non-competitive NMDAr antagonists have been reported to produce aberrant basal gamma band oscillation (GBO), as observed in schizophrenia. Aberrations in GBO power have attracted attention as a translational biomarker for the development of novel antipsychotic drugs. However, the neuronal mechanisms as well as the pharmacological significance of NMDAr antagonist-induced aberrant GBO power have not been fully investigated. In the present study, to address the above questions, we examined the pharmacological properties of MK-801 (0.1 mg/kg)-increased basal GBO power in rat cortical EEG. Riluzole (3-10 mg/kg), a glutamate release inhibitor, reduced the MK-801-increased basal GBO power. In contrast, L-838,417 (1-3 mg/kg), an alpha 2/3/5 subunit-selective GABA(A) receptor-positive allosteric modulator, enhanced the GBO increase. Antipsychotics such as haloperidol (0.05-0.3 mg/kg) and clozapine (1-10 mg/kg) dose-dependently attenuated the MK-801-increased GBO power. Likewise, LY379268 (0.3-3 mg/kg), an metabotropic glutamate 2/3 receptor (mGlu2/3 receptor) agonist, reduced the GBO increase in a dose-dependent manner, which was antagonized by an mGlu2/3 receptor antagonist LY341495. These results suggest that an increase in cortical GBO power induced by NMDAr hypofunction can be attributed to the aberrant activities of both excitatory pyramidal neurons and inhibitory interneurons in local circuits. The aberrant cortical GBO power reflecting cortical network dysfunction observed in schizophrenia might be a useful biomarker for the discovery of novel antipsychotic drugs. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.