Estradiol Stimulates Gene Expression of Norepinephrine Biosynthetic Enzymes in Rat Locus coeruleus

Abstract

Gender-specific differences in susceptibility to a number of disorders related to catecholaminergic systems, including depression and hypertension, have been postulated to be mediated, at least in part, by estrogens. In this study, we examined if estrogens may regulate gene expression of norepinephrine biosynthetic enzymes. Administration of five injections of 15 or 40 µg/kg estradiol benzoate to ovariectomized (OVX) female rats elicited a dose-dependent elevation in mRNA levels of tyrosine hydroxylase (TH) in locus coeruleus, to as great as 3-fold over control. Dopamine β-hydroxylase (DBH) mRNA levels were also similarly increased. To examine the mechanism, PC12 cells were cotransfected with luciferase reporter constructs under control of DBH or TH promoters [pDBH/Luc(–2,236/+21) or pTH/Luc(–272/+27 or –773/+27)] with an expression vector for estradiol receptor α. The cells were treated with 17β-estradiol (E₂) for 12–36 h. E₂ triggered a several fold increase in luciferase activity under control of the DBH promoter in a dose-dependent fashion. Omission of estrogen receptor α or addition of the estrogen receptor antagonist ICI 182,780 prevented the DBH promoter-driven increase in luciferase. When E₂ was given with 0.2 mM CPT-cAMP, reporter activity with pDBH/Luc(–2,236/+21) was increased greater than with either treatment alone. In contrast, addition of E₂ to cells transfected with pTH/Luc(–272/+27) elicited no change in basal luciferase activity nor in the response to 0.2 mM CPT-cAMP. These findings are the first to reveal that estrogen can stimulate DBH gene expression. Differing mechanisms may underlie the regulation of TH and DBH gene expression by estrogens.

Sex differences in cocaine-dependent individuals' response to disulfiram treatment

“…In a recent study of repeated administration of cocaine, alcohol, or combination, women reported significantly greater ratings for the visual analog "feel good" when cocaine alone was administered, a finding that approached significance for alcohol alone as well (McCanceKatz, Kosten, & Jatlow, 1998b). Moreover, recent evidence suggests that estradiol administration increases DBH in rodents (Serova, Rivkin, Nakashima, & Sabban, 2002). If estrogen stimulates DBH activity in humans, and disulfiram inhibits DBH, the disulfiram effect could possibly be attenuated in women.…”

Changes in α-estradiol receptor and progesterone receptor expression in the locus coeruleus and preoptic area throughout the rat estrous cycle

“…In LC neurons, estradiol stimulates gene expression of TH and dopamine beta hydroxylase (Serova et al 2002), probably by acting through ER. Besides, it is well established that estradiol induces PRs synthesis in CNS, and that their activation is critical for the LH surge occurrence, since it is blocked by RU-486 administration (Tebar et al 1998).…”

“…Since LC neurons concentrate estradiol (Heritage et al 1980), express mRNA for ER (Shughrue et al 1997) and PR (Curran-Rauhut & Petersen 2002), and are responsive to estradiol treatment, increasing the expression of noradrenaline synthetic enzymes (Serova et al 2002), it is likely that LC neurons are a target for estradiol action, as described for noradrenergic neurons A1 and A2 (Haywood et al 1999). If so, LC neurons should express ER and, consequently, PR.…”

Participation of the Monoaminergic System in the Antidepressant-Like Actions of Estrogens: A Review in Preclinical Studies

“…For example, in vitro studies have shown that E2, EE2, DES and some catechol-estrogens such as 2-hydroxy-EE2 (2-OH-EE2) and 2-hydroxy-E1 (2-OHE) inhibit NA reuptake sites in synaptosomes from the cerebral cortex and hypothalamus of rats that resulted in increased levels of NA in the synaptic cleft (Ghraf et al, 1983). In line with these findings, acute E2 administration to ovariectomized rats decreased NA reuptake rate in the hypothalamus (Hiemke et al, 1985) and increases mRNA levels of tyrosine hydroxylase in the locus coeruleus (Serova et al, 2002). Finally, it has been reported that estrogens increased NA concentration by inhibiting MAO-A activity (Holschneider et al, 1998).…”