We have previously shown that estrogen increases the expression of brain-derived neurotrophic factor (BDNF) mRNA in the olfactory bulb and cingulate cortex. Here we report that estrogen regulation of BDNF protein and the structurally related peptides nerve growth factor (NGF) and neurotrophin (NT)-4 is region- and peptide-specific. The olfactory bulb and cingulate cortex are both estrogen-sensitive targets and each receives a separate projection from neurons in the horizontal limb of the diagonal band of Broca (hlDBB). Furthermore, neurotrophins are retrogradely transported from the bulbar and cortical targets to the hlDBB. Four weeks of estrogen replacement to ovariectomized animals increased BDNF expression in the olfactory bulb, but decreased BDNF in the cingulate cortex. On the other hand, estrogen increased NT-4 expression in the cingulate cortex, but not in the olfactory bulb. NGF expression was not affected by estrogen in either region studied. In the hlDBB, estrogen increased BDNF but decreased NT-4, suggesting that estrogen differentially affects retrograde accumulation of these peptides. While both estrogen receptor alpha and beta have been identified in the olfactory bulb and cingulate cortex, our results indicate that estrogen receptor alpha expression is relatively higher in the olfactory bulb as compared to the cortex. Since the two estrogen receptors have been shown to stimulate different signaling pathways, we hypothesize that estrogen acting through specific receptors may differentially influence the extent and direction of neurotrophin expression.