Rat estrous cycle influences the sexual diergism of HPA axis stimulation by nicotine.

We previously reported that female rats had significantly greater hypothalamic-pituitary-adrenal (HPA) axis responses to cholinergic stimulation by nicotine (NIC) than did male rats. Females in defined estrous cycle stages, however, were not studied because of sample size limitations. We further explored this finding by determining HPA axis responses to two doses of NIC in female rats (N = 101) during different estrous cycle stages, and in males (N = 69). NIC doses were: 0.3 mg/kg, which provided the greatest female-male difference in the earlier study, and 0.5 mg/kg, which stimulated the HPA axis similarly in the two sexes. Plasma AVP, ACTH, and corticosterone were measured. Proestrous and estrous females had higher ACTH responses to NIC (0.3 mg/kg) compared to metestrous and diestrous females, and compared to males. ACTH responses to NIC (0.5 mg/kg) were similar, regardless of estrous cycle stage or sex. Males had higher AVP responses to both NIC doses compared to females in all estrous cycle stages. Corticosterone responses followed the ACTH responses, except that females in all estrous stages started from a higher corticosterone baseline compared to males. These results are similar to our earlier findings across the estrous cycle with non-specific cholinergic stimulation by physostigmine and suggest that the nicotinic system contributes to the differential HPA axis responses to cholinergic challenge across the estrous cycle.