The uptake of estradiol into the cerebrospinal fluid (CSF) after intranasal and intravenous administration in rats was investigated to study whether direct nose-CSF transport of estradiol exits or not. Animals received 0.48 mg kg(-1) estradiol randomly methylated beta-cyclodextrin (RAMEB) inclusion complex intranasally and intravenously. Following nasal delivery, estradiol reached a C(max) value (mean+/-S.D.) in plasma (26.70+/-11.37 ng ml(-1)) and CSF (54.76+/-32.84 ng ml(-1)) after 20 min in each case, while after intravenous infusion, estradiol reached a C(max) value in plasma (170.08+/-64.67 ng ml(-1)) and CSF (26.48+/-11.34 ng ml(-1)) at 5 min and 60 min, respectively. The AUC(CSF)/AUC(plasma) ratio (1.60+/-0.67) after intranasal delivery differed significantly from the ratio (0.61+/-0.16) observed after intravenous infusion (P<0.05). All these results indicate that estradiol is transported into CSF via olfactory neurons, and, hence, there is a direct transport route from the nasal cavity into the CSF for estradiol.