Clinical observations have suggested that ovarian steroid hormones modulate the symptomology of psychiatric disorders and this modulation is thought to be due to a protective effect of estrogen on dopaminergic activity. To test this hypothesis, mesolimbic dopamine (DA) activity was examined in relationship to endogenous hormone levels. Using in vivo electrochemical techniques, K+-stimulated DA release was measured in the nucleus accumbens of control, intact cycling female rats and experimental rats which had received bilateral 6-hydroxydopamine (6-OHDA) lesions to the medial prefrontal cortex (PFC) to produce subcortical hyperactivity. DA release and reuptake fluctuated with changes in circulating steroid levels in both control and lesion groups. In non-lesioned control rats, stimulated DA release peaked during diestrus I (DI) and was attenuated during diestrus II (DII) and estrus. DA transport, as measured by a change in T1/2 time, was significantly potentiated during proestrus. The expression of subcortical hyperactivity following lesions to the medial PFC appeared to be dependent on the steroid environment; during DII an increased responsiveness was observed while a significant decrease in K+-stimulated release was observed during DI. These cyclic changes in DA release were not associated with dramatic changes in DA transport except during proestrus when transport was significantly prolonged. These data suggest that cyclic fluctuation of ovarian steroids may modulate DA activity presynaptically through an alteration in both release and reuptake and that this modulation effectively dampens the expression of subcortical hyperactivity except under specific hormonal conditions.