Effects of Long-Term Treatment with Estradiol and Estrogen Receptor Subtype Agonists on Serotonergic Function in Ovariectomized Rats

Abstract

Acute estradiol treatment was reported to slow the clearance of serotonin via activation of estrogen receptors (ER)β and/or GPR30 and to block the ability of a selective serotonin reuptake inhibitor (SSRI) to slow serotonin clearance via activation of ERα. In this study, the behavioral consequences of longer-term treatments with estradiol or ER subtype-selective agonists and/or an SSRI were examined in the forced swim test (FST). Ovariectomized rats were administered the following for 2 weeks: estradiol, ERβ agonist (diarylpropionitrile, DPN), GPR30 agonist (G1), ERα agonist (PPT), and/or the SSRI sertraline. Similar to sertraline, longer-term treatment with estradiol, DPN or G1 induced an antidepressant-like effect. By contrast, PPT did not, even though it blocked the antidepressant-like effect of sertraline. Uterus weights, used as a peripheral measure of estrogenic activity, were increased by estradiol and PPT but not DPN or G1 treatment. A second part of this study investigated, using Western blot analyses in homogenates from hippocampus, whether these behavioral effects are accompanied by changes in the activation of specific signaling pathways and/or TrkB. Estradiol and G1 increased phosphorylation of Akt, ERK and TrkB. These effects were similar to those obtained after treatment with sertraline. Treatment with DPN increased phosphorylation of ERK and TrkB, but it did not alter that of Akt. Treatment with PPT increased phosphorylation of Akt and ERK without altering that of TrkB. In conclusion, activation of at least TrkB and possibly ERK may be involved in the antidepressant-like effect of estradiol, ERβ and GPR30 agonists whereas Akt activation may not be necessary.

Comparison of the Antidepressant-Like Effects of Estradiol and That of Selective Serotonin Reuptake Inhibitors in Middle-Aged Ovariectomized Rats

“…In 4-month OVX rats, it was shown previously that long-term E 2 (5 μg) induced an AD-like effect in the FST (Benmansour et al, 2016). In 10-month OVX rats, E 2 (5 μg) did not change immobility or swimming behavior in the FST as compared to that measured in control rats (data not shown).…”

“…We have selected a dose of sertraline that has been shown not only to downregulate the SERT but also to produce AD-like effects in the FST when given chronically to male rats (Benmansour et al, 1999; Bilge et al, 2008; Furmaga et al, 2011) as well as to female OVX rats (Benmansour et al, 2016). …”

“…On day 15 of chronic treatment (while estradiol or sertraline were still administered), a swim test session of 5 min was carried out with no pretest session. This approach is used in order to avoid the extended delay (2 weeks) between the first (pretest) and the second exposure (test) or the impact of drugs being present during the pretest session if pretest and test are separated by the usual 24 h. In addition, it has been shown that positive results with the drugs could be obtained even if no training session was carried out (Cryan et al, 2005; Benmansour et al, 2016). Rats were placed individually into a Plexiglas cylinder (21 × 46 cm) filled with 25°C water to a depth of 40-cm.…”

Involvement of the serotonergic system and neuroplasticity in the antidepressant effect of curcumin in ovariectomized rats: Comparison with oestradiol and fluoxetine

“…ERK1/2 has been implicated in several biological functions. ERK1/2 are highly expressed in different brain regions, including the hippocampus, amygdala, and the prefrontal area, supporting the putative effect of ERK1/2 on maintaining neuroplasticity (Benmansour, Adeniji, Privratsky, & Frazer, ; Dwivedi, Rizavi, Roberts, Conley, & Pandey, ; Zhang et al, ).…”

“…Several investigators have reported that decreased BDNF or ERK in a chronic‐stress model of depression could lead to impaired neurogenesis and depressive symptoms (Benmansour et al, ; Dwivedi et al, ; Liu et al, ; Pochwat et al, ; Zhang et al, ). Based on these studies, the effect of CUR on aromatase enzyme and the factors responsible for neuroplasticity, BDNF and ERK1/2 were evaluated in the limbic system relative to E 2 as a hormonal replacement therapy.…”