The ability of estrogen to modulate mesolimbic dopamine (DA) was examined using in vivo voltammetry. Estrogen priming (5 micrograms, 48 h) of ovariectomized (ovx) female rats resulted in a slight decrease in K(+)-stimulated DA release measured in the nucleus accumbens: this decrease was accompanied by a significant increase in both DA reuptake and DA clearance times. Following estrogen priming nomifensine, a potent inhibitor of the DA uptake carrier, was still able to potentiate K(+)-stimulated DA release and alter the time course of DA availability, but the response was attenuated compared with ovx controls. Direct infusion of 17 beta-estradiol hemisuccinate (17 beta-E, 20-50 pg) into the nucleus accumbens resulted in a biphasic potentiation of K(+)-stimulated release. An initial increase in release was observed 2 min after 17 beta-E infusion; this increase, although reduced by 15 min, was still significantly higher than control values. A subsequent potentiation was observed 60 min after the initial 17 beta-E infusion; this response remained for at least an additional 60 min. Nomifensine did not significantly alter K(+)-stimulated DA release following 17 beta-E infusion, but was still able to potentiate the total time DA was available extracellularly. These data suggest that the mesolimbic A10 DA neurons that terminate in the nucleus accumbens can be modulated in vivo by estrogen and that this modulation may be mediated by both genomic (long term) and nongenomic (short term) mechanisms.