Estrogen-regulated progestin receptors are found in the midbrain raphe butnot hippocampus of estrogen receptor alpha (ER alpha) gene-disrupted mice

Estrogen and progesterone may modulate serotonergic function through intrac ellular receptors, alpha (ER alpha) and/or beta (ER beta), and the progesti n receptor (PR). Studies in macaque and rat suggest species differences in steroid action. Presently, we examined the mouse. To identify whether ER al pha is involved in estrogen induction of PR in midbrain raphe, we studied t he ER alpha gene-disrupted (alpha ERKO) mouse. The hippocampus was examined as another estrogen/progestin-sensitive brain area reported to express ER alpha, ER beta, and PR. Female and male homozygous alpha ERKO and wildtype mice were gonadectomized and given estradiol benzoate or vehicle. Dual-labe l immunocytochemistry was performed for PR or ER alpha and the serotonin-sy nthesizing enzyme, tryptophan hydroxylase (TPH). Cells exhibiting PR immuno reactivity (PR-ir) or ER alpha -ir were observed in dorsal and median raphe and hippocampus in both sexes. No ER alpha -ir cells were observed in alph a ERKO brains. In raphe, PR-ir or ER alpha -ir often colocalized with TPH-i r. Thus, estrogen and progesterone may directly modulate gene expression in select serotonergic neurons via ER alpha and PR in female and male mice. E strogen significantly increased the number of PR-ir cells, and the percenta ge of PR-ir cells colocalizing TPH-ir in both raphe nuclei, regardless of s ex and genotype. Although less among alpha ERKO mice, the significant estro gen induction of PRs implicates the involvement of another ER, perhaps ERP. In hippocampus, distinct estrogen-induced PR-ir cells were observed only i n wildtype animals, demonstrating an ER alpha -mediated event in this foreb rain region. Collectively, these findings suggest that estrogen can regulat e the expression of one gene (the PR) via multiple mechanisms, based upon b rain region. (C) 2000 Wiley-Liss, Inc.