The effects of isoflurane on uptake of 5-hydroxytryptamine(serotonin; 5-HT) by rat brain synaptosomes and binding of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ketanserin to 5-HT1A and 5-HT2 receptors were examined. Isoflurane caused a concentration-dependent decrease in synaptosomal 5-HT uptake that was kinetically defined as non-competitive; exposure to isoflurane decreased Vmax but had no effect on the apparent Km. Removal of the drug from the reaction mixture resulted in the return of 5-HT accumulation rates to control levels. Isoflurane inhibited 8-OH-DPAT binding to hippocampal membranes by up to 27 +/- 6% at 4.5 mM, but did not significantly affect ketanserin binding to 5-HT2 receptors. These findings suggest that presynaptic actions are more important than postsynaptic actions in the modulation of serotonergic neutrotransmission by isoflurane.