Effects of γ-acetylenic GABA and γ-vinyl GABA on synaptosomal release and uptake of GABA

Abstract

The effects of the irreversible inhibitors of GABA-transaminase (E.C.2.6.1.19), γ-acetylenic GABA (4-amino-hex-5-ynoic acid, RMI 71645) and γ-vinyl GABA (4-amino-hex-5-enoic acid, RMI 71754) on the release and uptake of endogenous and exogenous GABA by rat cerebral cortical synaptosomes were studied. γ-Acetylenic GABA increased the release of preloaded [U 14C]-GABA by 12 to 46% over the concentration range 0.5 to 5 mM. With γ-vinyl GABA, the concentration range 0.25–5 mM caused an increase of 22–95% above controls. All concentrations of γ-vinyl GABA were more effective than equivalent levels of γ-acetylenic GABA. The two agents had similar effects on the release of endogenous GABA, no change was observed in any other amino acid. The effect of both drugs on [U 14C]-GABA release was inhibited significantly by tetrodotoxin and blocked by Verapamil. When animals were pretreated with γ-acetylenic GABA (100 mg/kg) for 8 hr or γ-vinyl GABA (1000 mg/kg) for 14 hr, the control release of GABA from synaptosomes prepared subsequently was increased, but other amino acids showed no change. The GABA content of the tissue was also greatly increased. The veratrine-stimulated release of GABA, glutamate and aspartate were increased by this pretreatment, but no change occurred in the rates of release of other amino acids. All veratrine-stimulated changes in the release of endogenous GABA, glutamate and aspartate were prevented by tetrodotoxin.