Prefrontal cortex neurons recorded in vivo exhibit bistable activity states, consisting of a depolarized phase (-55mV) and a hyperpolarized phase (-85mV). These "up" and "down" states have durations ranging from 800ms to 1s and a periodicity of approximately 1Hz. This study examines the state-dependency of prefrontal cortical neuron responses to dopamine, in which the bistable-state was approximated in vitro by intracellular current injection. At resting membrane potential (n=10), dopamine caused a significant depolarization of the membrane potential without altering any of the other electrophysiological characteristics tested. In contrast, both dopamine (30 microM, 5min) and the D1 receptor agonist SKF 38393 (5 and 10 microM) increased cell excitability when the cell was in the depolarized state (i.e., -55mV) but not the hyperpolarized state (i.e., -85 mV; n=10). This increase in excitability was accompanied by a decrease in the rheobase current. The SKF 38393-enhanced excitability was dose-dependent and could be blocked by bath administration of the D1 receptor antagonist SCH 23390 (5 and 10 microM). Administration of the GABA antagonist bicuculline (7 microM) plus the N-methyl-D-aspartate channel blocker CPP (10 microM) produced an additional increase in the excitability of prefrontal cortex neurons that was not dependent on the membrane potential. From these data we suggest that dopamine exerts state-dependent modulatory effects on the excitability of neurons in deep layers of the prefrontal cortex.