Estrogen and tamoxifen differentially regulate beta-endorphin and cFos expression and neuronal colocalization in the arcuate nucleus of the rat

Estrogen regulates hypothalamic gene expression, synthesis and release of t he endogenous opioid peptide beta -endorphin (beta END), although a consens us estrogen response element sequence has not been identified in the rat pr oopiomelanocortin (POMC) gene. POMC gene expression is also regulated by th e activation of AP-1 promoter elements, which are known to be estrogen sens itive. The present studies examine whether estrogen modulates the hypothala mic POMC system through a non-classical mechanism involving AP-1 binding pr oteins such as cFos. Immunohistochemical double-labeling for beta END and c Fos was used and immunoreactive (-ir) populations were quantified in the ar cuate nucleus and periarcuate area across time using unbiased stereological methods. Ovariectomized rats were injected with 50 mug estradiol (E-2), 50 0 mug tamoxifen citrate (TAM) or both (E-2+TAM) and were perfused 1, 2, 4 o r 48 h later. Ep rapidly increased numbers of cFos-ir, beta END-ir and doub ly-labeled cells after 4 h, and the number of beta END-ir cells remained hi gh 48 h later, suggesting that the stimulatory effects of cFos on POMC in t he hypothalamus persist after the cFos signal decays. Treatment with TAM al one did not affect the numbers of immunoreactive cells, although E-2+TAM bl ocked the E-2-mediated induction in all immunoreactive populations. Similar effects were seen at the transcriptional level. E-2 increased hypothalamic POMC mRNA after 4 h, while TAM treatment or coadministration of E-2+TAM di d not significantly change the levels of POMC mRNA. Cellular colocalization of beta END-ir and cFos-ir supports a possible intracellular coregulation of these peptides by an estrogen-dependent mechanism within a subset of hyp othalamic neurons. It does not, however, appear that E-2 acts directly thro ugh an AP-1 site within the POMC gene. Copyright (C) 2000 S. Karger AG, Bas el.