The influence of sodium ions on GABA uptake into neurons cultured from cerebral cortex was investigated at sodium concentrations ranging from 16 to 151 mM. Sodium did not affect the Km for GABA uptake but the uptake rates as a function of the sodium concentration was sigmoid at all GABA concentrations studied (1-200 microM). Hill plots of these curves exhibited straight lines with slopes of 1.7-2.1, suggesting that the coupling ratio between sodium and GABA is at least 2. (RS)-Nipecotic acid, a GABA analogue, was transported with high affinity (Km 8.0 +/- 2.1 microM) like GABA, but the Vmax for nipecotic acid was lower than found for GABA (0.664 +/- 0.035 versus 0.955 +/- 0.059 nmol X min-1 X mg-1), suggesting a microheterogeneity of the GABA transport sites. Neurons loaded with the respective tritiated compounds exhibited a pronounced K+-stimulated, calcium-dependent release of both GABA and nipecotic acid indicating that these cultured cells have developed functionally active GABA-ergic synapses.