Nasrallah Fatima A, Griffin Julian L, Balcar Vladimir J, Rae Caroline
Prince of Wales Medical Research Institute, and Brain Sciences UNSW, Randwick, New South Wales, Australia.
J Neurochem. 2009 Jan;108(1):57-71. doi: 10.1111/j.1471-4159.2008.05742.x. Epub 2008 Nov 10.
A targeted neuropharmacological, (1)H/(13)C NMR spectroscopy and multivariate statistical approach was used to examine the effects of exogenous GABA and ligands at the GABA(A) receptor family on brain metabolism in the Guinea pig cortical tissue slice. All ligands at GABA(A) receptors generated metabolic patterns which were distinct from one another with the major variance in the data arising because of metabolic work (shown by net flux into Krebs cycle byproducts and increased metabolic pool sizes). Three major clusters of metabolic signatures were identified which corresponded to: (i) activity at phasic (synaptic) GABA(A) receptors, dominated by alpha1-containing receptors and responsive to GABA at 10 micromol/L; (ii) activity at perisynaptic receptors, dominated by response to high (40 micromol/L) GABA and the superagonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride, and C, activity at extrasynaptic receptors, dominated by response to low (0.1-1.0 micromol/L) GABA, zolpidem (400 nmol/L) and the non-specific allosteric modulator RO19-4603 (1 nmol/L). These results highlight the utility of a different but robust approach to study of the GABAergic system using metabolic systems analysis.
采用靶向神经药理学、（1）H/（13）C核磁共振波谱和多变量统计方法，研究外源性γ-氨基丁酸（GABA）和GABA（A）受体家族配体对豚鼠皮质组织切片脑代谢的影响。GABA（A）受体的所有配体产生的代谢模式彼此不同，数据中的主要差异源于代谢活动（表现为进入三羧酸循环副产物的净通量和代谢池大小增加）。确定了三个主要的代谢特征簇，分别对应于：（i）相位性（突触性）GABA（A）受体的活性，以含α1的受体为主，对10 μmol/L的GABA有反应；（ii）突触周围受体的活性，以对高浓度（40 μmol/L）GABA和超激动剂盐酸4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇的反应为主；以及（iii）突触外受体的活性，以对低浓度（0.1 - 1.0 μmol/L）GABA、唑吡坦（400 nmol/L）和非特异性变构调节剂RO19 - 4603（1 nmol/L）的反应为主。这些结果突出了使用代谢系统分析研究GABA能系统的一种不同但强大的方法的实用性。
