Effects of valproate, vigabatrin and aminooxyacetic acid on release of endogenous and exogenous GABA from cultured neurons.
Valproate (VPA) and vigabatrin (gamma-vinyl GABA, GVG) are two novel antiepileptic drugs with a presumed GABAergic mechanism of action. However, for VPA, this aspect has been extensively debated. The aim of the present study was to investigate whether treatment of cultured neurons with clinically relevant concentrations of VPA and GVG might enhance release of endogenous GABA. In order to address the question of the fate of released GABA, studies involving exogenous, radiolabeled GABA were also undertaken. Exposure of neurons to GVG in a concentration range of 10-300 microM led to a significant increase in the cellular GABA content, whereas concentrations of VPA of 30-300 microM had no such effect. Treatment of the neurons with concentrations of GVG as low as 25 microM resulted in a pronounced increase in evoked release of endogenous GABA, compared to controls. Only high concentrations of VPA (300 microM) caused an increase in the synaptic GABA release, which reached statistical significance. Preincubating the neurons with exogenously labeled GABA in the presence of GVG or aminooxyacetic acid, both of which block GABA metabolism, caused a decrease in the specific radioactivity in the cellular GABA pool. This, together with the observation that the specific radioactivity of the releasable GABA pool always exceeded that of the cellular pool, indicates that exogenously supplied GABA preferentially labels the transmitter pool of GABA.
D000085:Acetates / Q000494:pharmacology*; D000614:Aminocaproates / Q000494:pharmacology*; D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D014635:Valproic Acid / Q000494:pharmacology*; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000085:Acetates; D000614:Aminocaproates; D000625:Aminooxyacetic Acid; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D020888:Vigabatrin