Activity-dependent γ-aminobutyric acid release controls brain cortical tissue slice metabolism

Vigabatrin (γ-vinyl-GABA) is an irreversible inhibitor of the enzyme γ-aminobutyric acid (GABA) transaminase. It has been shown to increase levels of GABA in brain and result in increased release of GABA from nonsynaptic sources following activation. Here, we use a guinea pig cortical tissue slice model to identify the metabolic sequelae of vigabatrin when incubated with tissue slices alone or when the tissue slices were activated by ligands with targeted activating mechanisms. We show that incubation of slices with AMPA, the group II metabotropic glutamate antagonist EGLU [(2S)-α-ethylglutamic acid], or the GABA(B) R antagonist CGP 52432 in the presence of vigabatrin produces very similar metabolic profiles, consistent with the large-scale turning off of metabolic activity. This effect is blocked by the GABA(Arho) antagonist TPMPA [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid]. Taken together, these results suggest that GABA, released following activation, acts on extrasynaptic receptors consistent with GABA(Arho) and that these receptors act as a kind of "master switch" that is capable of turning off a range of differently induced activities.