Release of endogenous GABA can occur through Ca-dependent and Ca-independent processes

Release of γ-aminobutyric acid (GABA) can be elicited by electrical field stimulation even in the absence of external Ca²⁺. Indeed, the release of GABA under such conditions is even higher than in the presence of Ca²⁺. To investigate the underlying mechanism of this phenomenon, the release of endogenous GABA from rat striatal slices was measured by high performance liquid chromatography with electro- chemical detection. Electrical stimulation at 2 Hz for 3 min elevated GABA efflux by 4.5-fold. Withdrawing external Ca²⁺ and adding 1 mM EGTA produced a small, transient increase in the basal efflux of GABA and increased electrically-evoked overflow 3-fold. Tetrodotoxin (5 μM) did not affect basal efflux in either normal or Ca²⁺-free conditions, but abolished electrically-evoked release. In the presence of normal Ca²⁺, nipecotic acid (1 mM) enhanced both spontaneous efflux and evoked overflow. Nipecotic acid also increased spontaneous release when external Ca²⁺ was removed. However, in the absence of Ca²⁺, nipecotic acid failed to increase electrically evoked GABA overflow. These results suggest that there exists a Ca²⁺-independent process for GABA release via the same carrier system that is utilized for high affinity GABA uptake.