Superfused frontal slices of cerebral cortex were preloaded with [3H]-norepinephrine ([3H]NE). Basal [3H]NE efflux and K+-induced [3H]NE release were studied during the estrous cycle and in the presence of neurosteroids. Basal [3H]NE efflux showed estrous cycle-related variations, with lowest values found during estrus and diestrus II. Allopregnanolone (10(-9) M) potentiated basal [3H]NE efflux from the 1st minute of its application; the effect of the steroid was still present after 20 min. This effect was also dependent upon the estrous cycle, since basal [3H]NE efflux was mainly increased during estrus diestrus I, and to a lesser degree only during proestrus. During diestrus II and after ovariectomy, basal [3H]NE efflux was no longer affected by the neurosteroid. In the presence of yohimbine (10(-6) M), the effect of allopregnanolone on basal efflux was potentiated only during the first 3 min but vanished thereafter. Allopregnanolone (10(-9) M) potentiated the K+-induced [3H]NE release during estrus, but pregnenolone (10(-9) M) was ineffective, suggesting specificity of the neurosteroid. Yohimbine (10(-6) M) also potentiated K+-induced [3H]NE release. When applied simultaneously with allopregnanolone (10(-9) M), a potentiating effect on [3H]NE release was observed. The present results suggest that allopregnanolone is a neurosteroid able to modulate norepinephrine release in the cerebral cortex in an estrous cycle-dependent manner, and that the effect could involve noradrenergic alpha-2 receptors.