Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is presently unknown. Probably the most consistent and widespread deficit seen in this syndrome is that of the basal forebrain cholinergic system. We have previously demonstrated that estradiol (E2) modulates the function of these neurons and plays a role in their maintenance by preventing the ovariectomy-induced decrease in choline acetyltransferase activity. It has been postulated that the lack of neurotrophic support may contribute at least in part to degeneration of cholinergic neurons in AD. As such, it is hypothesized that E2 may affect cholinergic function by modulating the levels of certain neurotrophic factors. We have shown that 3 months after ovariectomy (OVX) there was a significant reduction in NGF messenger RNA (mRNA) levels. In the present study, we extended the hypothesis that E2 may serve a neurotrophomodulatory role by assessing the effect of OVX and E2 replacement on brain-derived nerve factor (BDNF) mRNA levels using in situ hybridization. BDNF mRNA levels were quantified in three groups of animals: Ovary-intact animals, 28-week ovariectomized (OVX) animals, and E2-replaced OVX animals. Twenty-eight weeks after OVX, there were significant reductions in two of the three cerebral cortical regions analyzed [frontal (35%) and temporal (39%) cortexes], but E2 replacement was without effect. Twenty-eight weeks after OVX, there were also reductions in BDNF mRNA in all subregions of the hippocampus except CA1 (CA2 by 38%, CA3 by 44%, CA4 by 39%, and dentate gyrus by 37%), whereas E2 replacement was effective in elevating BDNF mRNA levels in the CA3, CA4, and dentate gyrus subregions. Collectively, the data demonstrate that E2 deprivation leads to a reduction in BDNF mRNA. Further, at the time point studied, E2 replacement is more effective in maintaining BDNF mRNA in the hippocampus than in the cortex, suggesting a regional difference in the ovarian steroid requirement for expression of BDNF.