Efflux of a suppressive neurotransmitter, GABA, across the blood-brain barrier

In this study, GABA efflux transport from brain to blood was estimated by u sing the brain eff lux index (BE[) method. [H-3]GABA microinjected into par tietal cortex area 2 (Par2) of the rat brain was eliminated from the brain with an apparent elimination half-life of 16.9 min. The blood-brain barrier (BBB) efflux clearance of [H-3]GABA was at least 0.153 mL/min/g brain, whi ch was calculated from the elimination rate constant (7.14 x 10(-2) min(-1) ) and the distribution volume in the brain (2.14 mL/g brain). Direct compar ison of the apparent BBB influx clearance [H-3]GABA (9.29 muL/min/g brain) and the apparent efflux clearance (153 muL/min/g brain) indicated that the efflux clearance was at least 16-fold greater than the influx clearance. In order to reduce the effect of metabolism in the neuronal cells following i ntracerebral microinjection, we determined the apparent eff lux of [H-3]GAB A in the presence of nipecotic acid, a GABA transport inhibitor in parenchy mal cells, using the BEI method. Under such conditions, the elimination of [H-3]GABA across the BBB showed saturation and inhibition by probenecid in the presence of nipecotic acid. Furthermore, the uptake of [H-3]GABA by MBE C4 cells was inhibited by GABA, taurine, beta -alanine and nipecotic acid i n a concentration-dependent manner. It is likely that GABA inhibits the fir st step in the abluminal membrane uptake by brain endothelial cells, and th at probenecid selectively inhibits the luminal membrane efflux transport pr ocess from the brain capillary endothelial cells based on the in vivo and i n vitro evidence. The BBB acts as the efflux pump for GABA to reduce the br ain interstitial fluid concentration.