INFUSION OF ANTISENSE OLIGODEOXYNUCLEOTIDES TO THE OXYTOCIN RECEPTOR IN THE VENTROMEDIAL HYPOTHALAMUS REDUCES ESTROGEN-INDUCED SEXUAL RECEPTIVITY AND OXYTOCIN RECEPTOR-BINDING IN THE FEMALE RAT

Exogenous administration of the neuropeptide oxytocin reliably facilit ates sexual behavior in the female rat and exposure to estrogen increa ses 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 oligodeoxynucleotides (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 mR NAs. OTR antisense oligo infusion significantly reduced lordosis frequ ency and intensity in females primed with estrogen. There was also a s ignificantly greater number of rejection behaviors exhibited by antise nse-oligo-infused estrogen-treated females versus controls and no evid ence of decreased locomotion by either treatment. In contrast to the e ffects in estrogen-primed-females, when females were primed to be sexu ally receptive with estrogen plus progesterone, OTR antisense-oligo in fusion had no effect on sexual behavior. The lack of effectiveness of OTR antisense oligo in females primed with progesterone may be the res ult of the action of this steroid on other neurotransmitter systems th at also facilitate lordosis and thereby override a deficit in oxytocin binding. Alternatively, via previously described mechanisms, progeste rone may enhance the effectiveness of oxytocin binding at its receptor . In vitro receptor autoradiography in estrogen-primed females indicat ed a 31% reduction in VMN OTR binding in the vicinity of the cannula t ip in antisense-oligo-infused females compared to controls. There was no significant difference in the level of OTR binding in the central n ucleus of the amygdala. In addition, OTR antisense-oligo-infused femal es exhibited a significant reduction in food intake as demonstrated by weight loss and a reduced appetite for sweetened milk compared to scr ambled-oligo-infused controls. Since VMN damage results in increased f ood intake, these results indicate a lack of damage to the VMN as a re sult of the OTR antisense infusions.