Understanding your inhibitions: effects of GABA and GABAA receptor modulation on brain cortical metabolism.

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.