Despite constant production and release from the neurons, brain interstitial fluid concentration of GABA is normally kept low and within narrow limits (Hoop et al. 1999). However, during both acute and chronic hypertensions, the protective function of the blood-brain barrier (BBB) is altered and the BBB is disrupted in spontaneously hypertensive rats (SHR) (Al-Sarraf & Philip, 2003; Ueno et al. 2004). In this study, brain uptake and brain-to-blood efflux transport of ¹⁴C-GABA were studied in SHR compared to normotensive Wistar Kyoto (WKY) rats. Rats were anesthetized intraperitoneally with urethane (1.25-1.5g/kg). To study brain uptake and efflux of ¹⁴C-GABA, in situ brain perfusion technique was used. The uptake of ¹⁴C-GABA into CSF and brain regions was found to be significantly greater in SHR when compared to the corresponding regions in WKY rats (p<0.05). Although the study of BBB integrity using ³H-mannitol revealed increased paracellular permeability at the brain capillaries of SHR when compared to WKY rats, this was found to be only partially responsible for the increased ¹⁴C-GABA uptake. The study of brain-to-blood efflux transport of ¹⁴C-GABA (after loading of brain with ¹⁴C-GABA by vascular perfusion) revealed that the half-time of elimination was significantly faster in SHR (5.35 ± 0.66 min) than in WKY rats (14.83 ± 1.94 min), (p0.05). The faster efflux in SHR might be, at least partially, responsible to compensate for increased uptake of this neurotransmitter and to preserve the protective function of BBB towards GABA. The protective function of the blood-CSF barrier towards GABA appears to be also preserved, since systemic infusion of GABA within a wide range of administered doses (0.004-5.00 mg/kg) produced an increase in GABA CSF concentration from around 0.5 microM to only 11 ¼M, and the obtained pattern of CSF GABA concentrations under these conditions did not differ between SHR and WKY rats, as revealed by HPLC.