The rate of turnover of cortical GABA from [1-C-13]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA)

Brain GABA levels rise and plateau following prolonged administration of the irreversible GABA-transaminase inhibitor vigabatrin (gamma-vinylGABA). Recently it has been shown that increased GABA levels reduces GAD(67) protein, one of two major isoforms of glutamic acid decarboxylase (GAD). The effects of GABA elevation on GABA synthesis were assessed in vivo using H-1 and C-13-edited NMR spectroscopy. Rates of turnover of cortical glutamate and GABA from intravenously administered [1-C-13]glucose were measured in alpha-chloralose anesthetized rats 24 hours after receiving vigabatrin (500 mg/kg, i.p.) and in non-treated controls. GABA concentration was increased 2-fold at 24 hours (from 1.3 +/- 0.4 to 2.7 +/- 0.9 mu mol/g) and GABA-T activity was inhibited by 60%. Tricarboxylic acid cycle flux was not affected by vigabatrin treatment compared to non-treated rats (0.47 +/- 0.19 versus 0.52 +/- 0.18 mu mol/g, respectively). GABA-C2 fractional enrichment (FE) measured in acid extracts rose more slowly in vigabatrin-treated compared to nontreated rats, reaching >90% of the glutamate FE after 3 hours. In contrast, GABA FE greater than or equal to glutamate FE in non-treated rats. A metabolic model consisting of a single glutamate pool failed to account for the rapid labeling of GABA from glutamate. Metabolic modelling analysis based on two (noncommunicating) glutamate pools revealed a similar to 70% decrease in the rate of GABA synthesis following vigabatrin-treatment, from 0.14 (non-treated) to 0.04 mu mol/g/min (vigabatrin-treated). These findings, in conjunction with the previously reported differential effects of elevated GABA on the GAD isoforms, suggests that GAD(67) may account for a major fraction of cortical GABA synthesis in the alpha-chloralose anesthetized rat brain in vivo.