The effects of trifluoperazine (TFP), a phenothiazine antipsychotic, on hippocampal activity were studied in the CA1 subfield, both in situ and in slices. In the extracellular studies in situ and in vitro, both somatic population spikes and dendritic excitatory postsynaptic potentials (EPSP) fields were depressed reversibly by TFP, applied by microiontophoresis or in the bath (50-100 microM). Similar effects were also seen during iontophoretic applications of sphingosine in situ. Like TFP (at micromolar concentrations) sphingosine is a dual Ca2+/calmodulin-dependent kinase and protein kinase C (PKC) inhibitor. In intracellular recordings from slices, 50-100 microM TFP induced a slow depolarization and a decrease in input resistance (RN), probably through a gamma-aminobutyric acid (GABA)-mediated increase in Cl- conductance (GCl). TFP also reduced the slow afterhyperpolarization (AHP) as well as electrically evoked inhibitory postsynaptic potentials (IPSPs), but EPSPs were augmented in both amplitude and duration. When CA1 neurons were voltage clamped, TFP elicited a corresponding inward current (consistent with depolarization), increased the leak conductance, and enhanced excitatory synaptic currents; whereas inhibitory synaptic currents and high-threshold Ca2+ currents were reduced. In conclusion, these effects of TFP--which cannot be readily explained by its potent antidopamine action--are in keeping with other evidence that both Ca2+/calmodulin-dependent kinase and PKC can modulate GCl-conductance and high-threshold Ca(2+)-conductance, as well as inhibitory and excitatory postsynaptic currents.