Modulation of responses to stress by estradiol benzoate and selective estrogen receptor agonists

Abstract

Previously, pretreatment with estradiol benzoate (EB) was found to modulate the response of hypothalamic-pituitary-adrenal (HPA) axis and gene expression in several catecholaminergic neuronal locations in ovariectomized (OVX) rats exposed to single immobilization stress (IMO). Here, we investigated the role of estrogen receptor (ER) subtypes, using selective agonists for ERalpha (propyl pyrazole triol, PPT) or ERbeta (WAY-200070) in two major central noradrenergic systems and the HPA axis after exposure to single and repeated IMO. OVX female rats received 21 daily injections of either EB (25 mug/kg), PPT (10 mg/kg), WAY-200070 (10 mg/kg), or vehicle. Injections of EB and PPT, but not WAY-200070, elicited reduced body weight and increased uterine weight, showing their selectivity. Both EB and PPT increased corticosterone levels about two- to threefold, but prevented any further rise with either single or repeated IMO, indicating an ERalpha (ESR1)-, but not ERbeta (ESR2)-, mediated mechanism. In the locus coeruleus (LC), the rise in dopamine-beta-hydroxylase (Dbh) mRNA with both stress paradigms was abrogated in EB- or PPT-injected animals. However, WAY-200070 blocked the response of DBH mRNA to single IMO but not to repeated IMO. In the nucleus of the solitary tract (NTS), the rise in tyrosine hydroxylase and DBH mRNAs with both IMOs was absent, or greatly attenuated, in EB- or PPT-treated rats. In most cases, WAY-200070 inhibited the response to single IMO but not to repeated IMO. The results demonstrate that pretreatment with estradiol, or ER-selective agonists, modulates the stress-triggered induction of gene expression of norepinephrine biosynthetic enzymes in LC and NTS, with ER selectivity depending on duration of the stress.