Although the exact basis of their action remains unknown, volatile agents affect noradrenergic and serotoninergic systems. Imipramine and fluoxetine have documented effects on these neurotransmitter transmission systems. Given the common sites of action of these antidepressants and halothane, we examined their individual and combined effects on tonic excitatory post-synaptic potentials (EPSPs) and frequency dependent blockade in the rat dentate gyrus in vitro. Extracellular recordings of field EPSPs were maintained from the dentate gyrus, in the presence of picrotoxin (100 microM). Stimulation at 30 Hz (200 ms) allowed investigation of frequency dependent blockade. Once a stable equilibrium was established, halothane, imipramine and fluoxetine were administered via the perfusate and recordings were made. Halothane produced a dose dependent reduction in EPSP amplitude (EC50 0.28 mM; n = 12). Imipramine (1-10 microM) potentiated the EPSP amplitude (148.2 +/- 8.2%; imipramine 1 microM; n = 6). Fluoxetine (0.5-10 microM) reduced EPSP amplitude to 83.7 +/- 22.1% of control (n = 6). In the presence of halothane 0.2 mM, imipramine reduced the EPSP amplitude to 56.5 +/- 9.9% of control (imipramine 10 microM; n = 6; p < 0.05 compared with imipramine alone). Halothane (0.2 mM) demonstrated frequency dependent blockade. However, neither imipramine nor fluoxetine showed use dependent inhibition at the doses investigated. When combined with halothane 0.2 mM, fluoxetine 10 microM demonstrated frequency dependent blockade at the sixth pulse in the train compared with controls (13.8 +/- 4.7% vs 38.1 +/- 8.3%; n = 6; p < 0.05). The halothane-imipramine combination did not exhibit use dependent blockade greater than controls. The reversal of imipramine-induced EPSP potentiation by the preapplication of halothane has not been previously reported. It may be due to modulation of noradrenergic transmission by halothane. The frequency dependent blockade produced by the combination of fluoxetine 10 microM and halothane may be mediated by a nonspecific membrane effect on 5-HT uptake. These differing effects underline the broad action of volatile agents on synaptic mechanisms.