Treatment with estrogen was shown to exert differential effects on two subpopulations of putative substantia nigra dopamine-containing neurons as demonstrated by single cell electrophysiological techniques. The acute administration of 17 beta-estradiol to anesthetized, ovariectomized female rats increased the spontaneous activity of Type A, but decreased that of Type B neurons in a dose-dependent manner. Moreover, pretreatment with 17 beta-estradiol benzoate, 48 hr before recording, increased the response of Type A neurons to both small doses of the dopamine receptor agonist, apomorphine, and to microiontophoretically applied dopamine. In contrast, the responsiveness of Type B neurons to these same manipulations was significantly diminished by this pretreatment. Taken together, these data suggest that prior exposure to estrogen enhances the sensitivity of dopamine autoreceptors located on Type A neurons while attenuating the sensitivity of the autoreceptors located on Type B cells. The demonstration that estrogen has complex, bidirectional, rather than simple, unidirectional influences on the activity of dopamine cells of the nigra might aid in the understanding of current controversies in both the experimental animal and human clinical literature bearing on behaviorally relevant interactions between estrogen and brain dopamine systems.