Estrogen, Predominantly via Estrogen Receptor α, Attenuates Postpartum-Induced Anxiety- and Depression-Like Behaviors in Female Rats

Abstract

Contributions from estrogen receptor (ER) subtypes (ERα and ERβ) to postpartum anxiogenic and depressive responses remain unresolved in rats. Using the elevated-plus maze (EPM) and forced swim (FS) tests, we confirmed that primiparous rats exhibited anxiogenic and depressive responses 3 weeks postpartum, improved 5 weeks postpartum (EPM), and recovered at 5 (FS) or 10 weeks postpartum (EPM) compared with diestrus nulliparous females. Immunohistochemistry suggested that these behavioral changes were temporally associated with decreased ERα but not ERβ expression in the medial amygdala (MEA). Additionally, ERα expression in the medial preoptic area (MPOA) significantly increased 10 weeks postpartum. Brain-derived neurotrophic factor (BDNF) expression was significantly elevated in the MEA 3 weeks postpartum. BDNF receptor tropomyosin-related kinase expression was significantly elevated in the MEA at 3 and 10 weeks but not at 5 weeks postpartum. The phosphorylation of ERK (pERK)-2 in the MEA, MPOA, and hippocampal CA1 region was significantly elevated 3 and 5 weeks postpartum. The effects of single daily sc injections of the ERα-selective agonist, propyl pyrazoletriol (PPT); ERβ-selective agonist, diarylpropionitrile; 17β-estradiol (E₂); and vehicle for 6 days in primiparous rats were assessed. PPT and E₂ significantly produced anxiolytic and antidepressant actions in the EPM and FS tests but PPT to a lesser degree than E₂ in the EPM test. Diarylpropionitrile affected the EPM test but was not significantly different from vehicle. BDNF expression was significantly increased 3 weeks postpartum by all treatments in the MPOA but not the CA1 and MEA. E₂ and PPT treatment significantly increased tropomyosin-related kinase and pERK1/2 expression in the MEA and MPOA and increased pERK1/2 expression in the CA1. The onset of anxiety- and depression-like behaviors in postpartum rats may be partly caused by a complex estrogen-mediated mechanism; nevertheless, changes in the ERα-related system, likely in the MEA, are predominantly involved.

The Role of Brain-Derived Neurotrophic Factor in Comorbid Depression: Possible Linkage with Steroid Hormones, Cytokines, and Nutrition

“…We have observed depressive-like behaviors in primiparous female rats at 3 weeks postpartum compared with nulliparous rats (53). Furthermore, decreased expression of ERα (not ERβ), and increased expression of BDNF and its receptor TrkB in the medial amygdala were observed at 3 weeks postpartum (53).…”

Activation of GPR30 attenuates chronic pain-related anxiety in ovariectomized mice

“…However, ER subtypes mediated by anxiolytic actions are not fully accepted. For example, estrogen reduces postpartum-induced anxiety-and depression-like behavior predominantly via ER␣ (Furuta et al, 2013). The behavioral changes are temporally associated with decreased ER␣ but not with ER␤ expression in the medial amygdala (Furuta et al, 2013).…”

“…For example, estrogen reduces postpartum-induced anxiety-and depression-like behavior predominantly via ER␣ (Furuta et al, 2013). The behavioral changes are temporally associated with decreased ER␣ but not with ER␤ expression in the medial amygdala (Furuta et al, 2013). Studies using a combination of pharmacological and genetic approaches have demonstrated that the anxiolytic actions of estradiol are mediated by ER␤ in female mice (Lund et al, 2005;Oyola et al, 2012).…”

Reproductive Steroid Regulation of Mood and Behavior

“…Of note, this regulation of hippocampal spine density is dependent on glutamate receptor (NMDA) signaling (358), which has also been implicated in the etiopathogenesis of depression (162,183). In the amygdala, estradiol also increases BDNF, TrkB, and proline-rich receptor-like protein kinase 2 (pERK2), which is associated with decreased depressive-like behavior (101).…”