Understanding your inhibitions: modulation of brain cortical metabolism by GABA(B) receptors.
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 GABA(B) receptor on brain metabolism using a targeted neuropharmacological, (1)H/(13)C nuclear magnetic resonance spectroscopy, and metabolomic approach. While agonists at GABA(B) 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.
Nasrallah
Fatima A
FA
Prince of Wales Medical Research Institute, Randwick, New South Wales, Australia.
Griffin
Julian L
JL
Balcar
Vladimir J
VJ
Rae
Caroline
C
D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism; D002247:Carbon Isotopes / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D018755:GABA Agonists / Q000737:chemistry / Q000378:metabolism; D018756:GABA Antagonists / Q000737:chemistry / Q000378:metabolism; D058786:GABA-B Receptor Agonists; D006168:Guinea Pigs; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D010721:Phosphinic Acids / Q000737:chemistry / Q000378:metabolism; D025341:Principal Component Analysis; D018080:Receptors, GABA-B / Q000378:metabolism*
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D001596:Benzylamines; D002247:Carbon Isotopes; D018755:GABA Agonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D009025:Morpholines; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D018080:Receptors, GABA-B; C052329:phaclofen; C068457:3-aminopropyl(methyl)phosphinic acid; C083008:CGP 52432; C066430:CGP 35348; D001418:Baclofen