Estrogen modulation of the cyclic AMP response element-binding protein pathway - Effects of long-term and acute treatments

Actions of estrogen include mechanisms leading to alterations in gene trans cription that may be independent of nuclear estrogen receptors, as well as those involving direct action of the estrogen receptor on the genome. Also, the influence of estrogen in the brain appears to extend well beyond areas associated with reproduction and may include forebrain areas linked to aff ective and cognitive behaviors. We investigated the effects of acute and lo ng-term estradiol benzoate (E2) treatment on total and phosphorylated cycli c AMP responsive element-binding (CREB) protein levels and on cyclic AMP re sponse element (CRE)-DNA binding in forebrain areas of ovariectomized (OVX) rats. Long-term E2 treatment increased CRE-DNA binding in the amygdala but not in hippocampus, frontal cortex, or cerebellum. The increase in CRE-DNA binding in the amygdala was associated with increased levels of total and phosphorylated CREB (pCREB) protein during protracted E2 exposure. To local ize the estrogenic effect in the amygdala and determine if an effect in one hippocampal region was masked by a lack of effect in another subregion, we performed immunolabeling of pCREB in brain structures of chronically treat ed OVX animals with or without E2. This treatment resulted in a significant increase in relative total immunolabeled nuclei in the anteroventral subdi vision of the medial amygdala. In the hippocampus, a significant increase i n relative total immunolabeled nuclei was seen in the CA1 and CA3 regions, but not in the dentate gyrus or hilus of the dentate gyrus. Acute E2 treatm ent resulted in increased CRE-DNA binding in the frontal cortex but not in amygdala, hippocampus, or cerebellum. However, no changes in levels of tota l CREB or pCREB protein were observed in the frontal cortex under E2 treatm ent. No changes were observed either in basal or cAMP-stimulated protein ki nase A (PKA) activity or in PKA-alpha catalytic subunit immunoreactivity in the amygdala or the frontal cortex. Our study indicates that both long-ter m and acute treatments with estrogens influence the function of CREB in spe cific brain structures. Copyright (C) 2001 S. Karger AG, Basel.