High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

The glutamate uptake inhibitor L‐ trans ‐2,4‐pyrrolidine‐dicarboxylate (PDC) induces glutamate accumulation and neuronal damage in cultured cells. We have used dissociated cortical cells in culture to study whether the toxicity induced by inhibiting glutamate uptake with PDC could be blocked by the simultaneous inhibition of γ‐aminobutyric acid (GABA) uptake, because both types of transporters are affected during an ischemic event. After 6 hr of exposure to 100 μM GABA or to four different GABA uptake inhibitors, the concentration of extracellular GABA was augmented from the basal 2 μM value to about 25 μM and 5 μM, respectively. These increases, however, did not result in protection against the neuronal damage induced by the accumulation of extracellular glutamate because of the simultaneous exposure to PDC. In contrast, when 100 μM GABA and an inhibitor of GABA uptake were added, after 6 hr the concentrations of GABA reached 50 μM, and neurons were protected from PDC‐induced toxicity. The addition of the GABA A and GABA B receptor agonists muscimol and baclofen also partially protected against PDC‐induced damage. The results suggest that the excitotoxic damage resulting from chronic gradual elevation of extracellular glutamate may be prevented by high concentrations of extracellular GABA, an effect mediated by activation of GABA A and GABA B receptors. © 2002 Wiley‐Liss, Inc.