Estradiol attenuates the forskolin-induced increase in hypothalamic tyrosine hydroxylase activity

The purpose of this study was to evaluate interactions between estradiol an d the 3',5' cyclic adenosine monophosphate (cAMP) signaling pathway to regu late tyrosine hydroxylase (TH) activity in hypothalamic dopaminergic neuron s. The first experiment examined the ability of forskolin to activate TH in the tuberoinfundibular dopaminergic neurons of adult ovariectomized rats w ith or without estradiol treatment. Estradiol treatment reduced both basal and forskolin-stimulated TH activity in the median eminence. The second gro up of experiments examined the effect of estradiol on the forskolin-induced activation of TH in fetal hypothalamic cells cultures. Estradiol decreased basal TH activity in the hypothalamic cell cultures to 80% of control leve ls. Forskolin treatment for Ih increased TH activity in a concentration-dep endent manner in control and estradiol-treated cells, but estradiol attenua ted the stimulatory response to 0.01-10 mu M forskolin. The suppressive eff ect of estradiol on cAMP-dependent activation of TH was evident with 1-12 h of forskolin treatment. The responses to other activators of the cAMP-prot ein kinase A pathway, including dibutyryl cAMP and 8-bromo-cAMP, and to a d epolarizing stimulus were blunted in estradiol-treated cultures. forskolin treatment for Ih increased radiolabeled phosphate incorporation into TH pro tein in control but not estradiol-treated cells, suggesting that estradiol interferes with the ability of the cAMP pathway to phosphorylate TH. Forsko lin caused a time-dependent increase in TH mRNA signal levels in control cu ltures. The magnitude of the forskolin-induced increase in TH mRNA levels w as less in the estradiol-treated cells after 6 h of forskolin treatment, in dicating that estradiol hinders cAMP-regulated TH gene expression. These da ta indicate that estradiol attenuates the ability of hypothalamic dopaminer gic neurons to respond to cAMP-dependent stimulation by interfering with ph osphorylation mechanisms in the short term and control of TH mRNA levels in the long term. Copyright (C) 2000 S. Karger AG, Basel.