GABA transaminase inhibition induces spontaneous and enhances depolarization-evoked GABA efflux via reversal of the GABA transporter

The GABA transporter can reverse with depolarization, causing nonvesicular GABA release. However, this is thought to occur only under pathological con ditions. Patch-clamp recordings were made from rat hippocampal neurons in p rimary cell cultures. inhibition of GABA transaminase with the anticonvulsa nt gamma -vinyl GABA (vigabatrin; 0.05-100 muM) resulted in a large leak cu rrent that was:blocked by bicuculline (50 muM). This leak current occurred in the absence of extracellular calcium and was blocked by the GABA transpo rter antagonist SKF-89976a (5 muM). These results indicate that vigabatrin induces spontaneous GABA efflux from neighboring cells via reversal of GABA transporters, subsequently leading to the stimulation of GABA(A) receptors on the recorded neuron. The leak current increased slowly over 4 d of trea tment with 100 muM vigabatrin, at which time it reached an equivalent condu ctance of 9.0 +/- 4.9 nS. Blockade of glutamic acid decarboxylase with semi carbazide (2 mM) decreased the leak current that was induced by vigabatrin by 47%. In untreated cells, carrier-mediated GABA efflux did not occur spon taneously but was induced by an increase in [K+](o) from 3 to as little as 6 mM. Vigabatrin enhanced this depolarization-evoked nonvesicular GABA rele ase and also enhanced the heteroexchange release of GABA induced by nipecot ate. Thus, the GABA transporter normally operates near its equilibrium and can be easily induced to reverse by an increase in cytosolic [GABA] or mild depolarization. We propose that this transporter-mediated nonvesicular GAB A release plays an important role in neuronal inhibition under both physiol ogical and pathophysiological conditions and is the target of some anticonv ulsants.