Gamma-vinyl GABA reduces paired pulse inhibition in the rat dentate gyrus in vivo and in vitro.
Sayin U., Rutecki PA., Mellanby J., Sutula TP.
Gamma vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, has anticonvulsant effects. GVG increases GABA levels in the brain by blocking its degradation, and is presumed to enhance GABAergic inhibition, however, in some cases it exacerbates seizures. We investigated the effects of GVG in vivo and in vitro on paired pulse inhibition (PPI) recorded in the rat dentate gyrus (DG) evoked by perforant path stimulation. At 2.5 h and 24 h after administration of GVG (1 g/kg, i.p.), there was a loss of PPI at both 15- and 25-ms interpulse intervals (IPI). Activation of presynaptic GABA(B) autoreceptors could explain this in vivo effect. We therefore further investigated the effects of co-application of GVG with the GABA(B) antagonists 2-OH saclofen (saclofen) or CGP 35348 (CGP) on PPI in hippocampal slices by in vitro study. Bath application of GVG (400 and 500 microM) not only resulted in a loss of perforant path evoked PPI at a 15-ms IPI, but produced facilitation of the second population spike relative to the first. Co-application of saclofen (250 microM) with GVG (500 microM) prevented facilitation of the second response of a paired-pulse. The facilitation of the second stimulation response produced by GVG (400 microM) was converted to inhibition by bath application of CGP 35348 (400 microM). These results suggest that activation of presynaptic GABA(B) receptors by increased extracellular GABA may be one of the contributing factors to the apparent paradoxical effect of GVG on PPI in the DG.