Exogenous administration of the neuropeptide oxytocin reliably facilitates sexual behavior in the female rat and exposure to estrogen increases oxytocin receptor (OTR) binding in the ventromedial nucleus (VMN) of the hypothalamus. We have used a novel approach to investigate the role of hypothalamic OTR in controlling behavior by infusing antisense oligodeoxy- nucleotides (oligo) to the 5'-region of the human OTR mRNA into the VMN of hormonally primed rats. Control infusions consisted of a scrambled-sequence oligo that had little or no homology to known mRNAs. OTR antisense oligo infusion significantly reduced lordosis frequency and intensity in females primed with estrogen. There was also a significantly greater number of rejection behaviors exhibited by antisense-oligo-infused estrogen-treated females versus controls and no evidence of decreased locomotion by either treatment. In contrast to the effects in estrogen-primed-females, when females were primed to be sexually receptive with estrogen plus progesterone. OTR antisense-oligo infusion had no effect on sexual behavior. The lack of effectiveness of OTR antisense oligo in females primed with progesterone may be the result of the action of this steroid on other neurotransmitter systems that also facilitate lordosis and thereby override a deficit in oxytocin binding. Alternatively, via previously described mechanisms, progesterone may enhance the effectiveness of oxytocin binding at its receptor. In vitro receptor autoradiography in estrogen-primed females indicated a 31% reduction in VMN OTR binding in the vicinity of the cannula tip in anti- sense-oligo-infused females compared to controls. There was no significant difference in the level of OTR binding in the central nucleus of the amygdala. In addition, OTR antisense- oligo-infused females exhibited a significant reduction in food intake as demonstrated by weight loss and a reduced appetite for sweetened milk compared to scrambled-oligo-infused controls. Since VMN damage results in increased food intake, these results indicate a lack of damage to the VMN as a result of the OTR antisense infusions.