Biochemical and electrophysiological and electrophysiological studies suggest that GABA agonists increase the activity of dopaminergic neurons in the zona compacta (ZC) of the substantia nigra despite a known GABAergic input to ZC cells. Using single-unit recording techniques we have investigated this "paradoxical" effect. One population of neurons located in the zona reticulata (ZR) of the substantia nigra was found to be 20 times more sensitive to iontophoretically applied GABA than ZC neurons. GABA introduced by means of microiontophoresis into the ZR caused an increase in ZC cell activity while glutamic acid introduced in the same manner produced an inhibition of ZC cells. The latter effect was blocked by low doses of picrotoxin. Muscimol (i.v.) caused a decrease in ZR cell activity at the same dose that caused a parallel increase in ZC cell firing rate. These data suggest that ZC cells receive an inhibitory GABAergic input from ZR cells that are in turn inhibited by low doses of GABA agonists. Such an anatomical arrangement would account for the "paradoxical" excitatory effect of GABA agonists on ZC neuron activity.