Estrogen-regulated progestin receptors are found in the midbrain raphe but not hippocampus of estrogen receptor alpha (ER alpha) gene-disrupted mice.

Estrogen and progesterone may modulate serotonergic function through intracellular receptors, alpha (ER alpha) and/or beta (ER beta), and the progestin receptor (PR). Studies in macaque and rat suggest species differences in steroid action. Presently, we examined the mouse. To identify whether ER alpha is involved in estrogen induction of PR in midbrain raphe, we studied the 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-label immunocytochemistry was performed for PR or ER alpha and the serotonin-synthesizing enzyme, tryptophan hydroxylase (TPH). Cells exhibiting PR immunoreactivity (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 alpha ERKO brains. In raphe, PR-ir or ER alpha-ir often colocalized with TPH-ir. Thus, estrogen and progesterone may directly modulate gene expression in select serotonergic neurons via ER alpha and PR in female and male mice. Estrogen significantly increased the number of PR-ir cells, and the percentage of PR-ir cells colocalizing TPH-ir in both raphe nuclei, regardless of sex and genotype. Although less among alpha ERKO mice, the significant estrogen induction of PRs implicates the involvement of another ER, perhaps ER beta. In hippocampus, distinct estrogen-induced PR-ir cells were observed only in wildtype animals, demonstrating an ER alpha-mediated event in this forebrain region. Collectively, these findings suggest that estrogen can regulate the expression of one gene (the PR) via multiple mechanisms, based upon brain region. Copyright 2000 Wiley-Liss, Inc.