Paradoxical reduction of synaptic inhibition by vigabatrin

GABAergic inhibition, a primary target for pharmacological modulation of ex citability in the CNS, can be altered by multiple mechanisms including alte ration of GABA metabolism. Gamma-vinyl GABA (vigabatrin, GVG) is an irrever sible inhibitor of the GABA catabolic enzyme GABA transaminase, thus its an ticonvulsant properties are thought to result from an elevation of brain GA BA levels. We examined the effects of GVG on GABAergic synaptic transmissio n in hippocampal slices. GVG unexpectedly reduced miniature and evoked inhi bitory postsynaptic currents (IPSCs) in dentate granule cells. The reductio n in synaptic events was accompanied by an increase in tonic GABA(A) recept or-mediated current. These effects developed slowly and persisted following wash out of GVG. The GVG pretreatment reduced sucrose-evoked GABA release as well as postsynaptic sensitivity to exogenous GABA, indicating that both pre- and postsynaptic mechanisms contributed to the reduction in synaptic currents. These results suggest that tonic rather than phasic increases in GABA underlie the anticonvulsant properties of GVG, and that mechanisms tha t elevate brain neurotransmitter levels do not necessarily correlate with e nhanced synaptic release.