THE EFFECT OF CHRONIC TREATMENT WITH THE GABA TRANSAMINASE INHIBITORSGAMMA-VINYL-GABA AND ETHANOLAMINE-O-SULFATE ON THE IN-VIVO RELEASE OFGABA FROM RAT HIPPOCAMPUS

The effects of chronic treatment with the specific, mechanism-based, i rreversible inhibitors of 4-aminobutyrate aminotransferase (EC 2.6.1.1 9; GABA transaminase), ethanolamine O-sulphate (EOS), and 4-aminohexen oate [vigabatrin; gamma-vinyl-GABA (GVG)] on the extracellular concent rations of GABA in the hippocampus have been studied using in vivo mic rodialysis in conscious animals. Oral dosing [3 mg/ml of drinking wate r, giving doses of GVG of 194 +/- 38 mg/kg/day and of EOS of 303 +/- 4 2 mg/kg/day (mean +/- SD)] was followed by microdialysis at 2, 8, and 21 days. The basal outflow of GABA (in the range of similar to 1 -2 pm ol/30 mu l/30-min sample) after 2 and 8 days of treatment was not sign ificantly different from that in control animals, but the 21-day treat ment gave significant rises in the extracellular GABA concentration (u p to similar to 6-8 pmol/30 mu l/30-min sample). Both inhibitors gave similar results. Depolarisation with 100 mM K+ gave large increases in GABA release in control (similar to 20-60 pmol/30 mu l/30-min sample) and treated animals. The 8- and 21-day-treated animals showed signifi cant increases in the stimulated release compared with control animals (similar to 80-100 pmol/30 mu l/30-min sample). Excluding Ca2+ had no significant effect on either basal or stimulated release. The signifi cant increases in K+-evoked release of GABA show that the increased in tracellular pool of GABA is available for release, and this may be rel ated to the anticonvulsant action of these compounds.