We have recently demonstrated that chronic ethanol administration lowers blood pressure (BP) in female rats and this effect is significantly attenuated by ovariectomy. The present study investigated whether ethanol hypotension is estrogen dependent. Further, since estrogen regulates AP-1 activity, the study was extended to determine whether estrogen/c-jun interaction is involved in the estrogen-dependent hypotensive effect of ethanol. Changes in BP and heart rate (HR) were evaluated in radiotelemetered pair-fed sham-operated (SO), ovariectomized (OVX), and OVX estradiol (E2)-treated rats receiving liquid diet with or without ethanol (5%, w/v) for 12 weeks. The in situ hybridization technique was used to measure the c-jun mRNA expression in two brainstem areas, the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (RVLM). Ethanol feeding caused significant (P<0.05) decreases in BP in SO rats that started at week 1 and reached its maximum (approximately 10 mmHg) at week 6 and remained at that level till the end of week 12. In OVX rats, ethanol had no effect on BP during the first 5 weeks after which a decrease of 5 mmHg was demonstrated and remained thereafter. Estrogen replacement (17β-estradiol subcutaneous pellet, 14.2 μg/day) restored the hypotensive effect of ethanol to a level similar to that of SO rats both in terms of magnitude and duration. Densitometric analysis of the in situ hybridization autoradiograms revealed that OVX and E2 replacement had no effect on c-jun mRNA expression in the NTS or RVLM. Ethanol feeding produced a significant (twofold) increase in c-jun mRNA expression in the RVLM of SO rats versus no effect in the NTS. The increased expression of c-jun mRNA observed following ethanol treatment in the RVLM of SO rats was abolished in OVX rats and restored to SO levels after E2 replacement. These findings suggest a link between the estrogen-dependent hypotensive effect of chronically administered ethanol and the increased expression of c-jun mRNA in the brainstem of female rats.