Understanding Your Inhibitions: Modulation of Brain Cortical Metabolism by GABAB Receptors

Abstract

Although the impact of neuronal excitation on the functional activity of brain is well understood, the nature of functional responses to inhibitory modulation is far from clear. In this work, we investigated the effects of modulation of the metabotropic GABAB receptor on brain metabolism using a targeted neuropharmacological, 1H/13C nuclear magnetic resonance spectroscopy, and metabolomic approach. While agonists at GABAB receptors (Baclofen and SKF 97541) generally decreased metabolic activity, mild agonist action could also stimulate metabolism. Less potent antagonists (CGP 35348, Phaclofen) significantly decreased metabolic activity, while more potent antagonists (CGP 52432 and SCH 50911) had opposite, stimulatory, effects. Examination of the data by principal components analysis showed clear divisions of the effects into excitatory and inhibitory components. GABAergic modulation can, therefore, have stimulatory, inhibitory, or even neutral net effects on metabolic activity in brain tissue. This is consistent with GABAergic activity being context dependent, and this conclusion should be taken into account when evaluating functional imaging data involving modulation of neuronal inhibition.