We explored the possibility that circulating glutamine affects -aminobutyric acid (GABA) levels in rat striatal tissue and GABA concentrations in striatal extracellular fluid (ECF). Striatal microdialysates, each collected over a 20 min interval, were obtained after no treatment, oral L-glutamine (0.5 g/kg), or glutamine followed by NMDA (administered via the microdialysis probe). GABA concentrations were measured by HPLC using a stable OPA/sulfite precolumn derivatization and an electrochemical detection method. L-Glutamine administration significantly increased ECF GABA concentrations by 30%, and enhanced the response evoked by NMDA alone (70%) to 120% over baseline (all P<0.05). Striatal GABA levels increased significantly 2.5 h after oral L-glutamine (e.g., from 1.76 ± 0.04 µmol/g in vehicle-treated rats to 2.00 ± 0.15 µmol/g in those receiving 2.0 g/kg of glutamine). Striatal glutamine levels also increased significantly, but not those of glutamate. These data suggest that GABA synthesis in, and release from, rat striatum may be regulated in part by circulating glutamine. Hence, glutamine administration may provide a useful adjunct for treating disorders (e.g., anxiety, seizures) when enhanced GABAergic transmission is desired. Moreover, the elevation in plasma and brain glutamine associated with hepatic failure may, by increasing brain GABA release, produce some of the manifestations of hepatic encephalopathy.--Wang, L., Maher, T. J., Wurtman, R. J. Oral L-glutamine increases GABA levels in striatal tissue and extracellular fluid.