Actions of progesterone on depression-like behavior in a model of surgical menopause are mediated by GABAA receptors

Abstract

Introduction. In rats, long-term ovariectomy results in low concentrations of steroid hormones and reproduces anxiety- and depression-like behavior after surgical menopause in women. Progesterone produces antidepressant-like effects two weeks post-ovariectomy (i.e., early post-ovariectomy) through actions on γ-aminobutyric acid-A (GABAA) receptors, but its antidepressant-like effects and mechanism of action in rats eight weeks post-ovariectomy (i.e., late post-ovariectomy, considered a model of surgical menopause) remain unknown. Objective. To explore the antidepressant-like effects of progesterone and the participation of GABAA receptors in rats eight weeks post-ovariectomy. Method. Long-term ovariectomized female Wistar rats were treated sub-acutely with vehicle or progesterone (.5, 1, and 2 mg/kg) and subjected to the open field and forced swim tests, and behavior was compared with cycling or fluoxetine-treated rats. The rats were then pretreated with picrotoxin (1 mg/kg) followed by progesterone (1 mg/kg) to explore the role of GABAA receptors in long-term-induced depression-like behavior. Results. Long-term ovariectomized rats exhibited depression-like behavior in the forced swim test compared with intact rats, an effect that was not observed in progesterone- and fluoxetine-treated long-term ovariectomized rats. These effects were not attributable to psychomotor alterations. In the open field test, the time spent rearing and grooming was lower in ovariectomized rats compared with intact rats, which was not observed in progesterone- and fluoxetine-treated rats. Picrotoxin blocked the effects of progesterone in both behavioral tests. Discussion and conclusion. These results indicated that sub-acute progesterone treatment reduced depression-like behavior through actions on GABAA receptors in a rat model of surgical menopause.

Diverse modulatory effects of sex steroids on depressive-like behavior in socially stressed female rats.

“…Similarly, a dose-response effect was observed in another protocol examining the chronic use of PROG on the immobility rate in the FST. The study found that subacute treatment with PROG at a dose of 1 mg/kg reduced depressionlike behavior in a rat model of surgical menopause (Rodríguez-Landa et al, 2020). Previous research has shown that ovariectomized rats consume less sucrose (Curtis et al, 2005) and that estrogen therapy increases resilience on the learned helplessness test (Bredemann & McMahon, 2014).…”

Behavioral Despair Is Blocked by the Flavonoid Chrysin (5,7-Dihydroxyflavone) in a Rat Model of Surgical Menopause

“…In Xenopus laevis oocytes, chrysin binds on α1, β1, and γ2 subunits of the GABA A receptor, which could be associated with its anxiolytic-like actions [ 84 ]. In this way, it is probable that flavonoid chrysin acted through GABA A receptor increasing chloride ions influx in neurons, which relates to improvements in stress coping, anxiolytic-like effects, and even antidepressant-like effects in the forced swim test [ 35 ], as it occurs with GABAergic compounds, including neurosteroids as progesterone and allopregnanolone exerting protective effects against stress and behavior despair [ 38 , 83 , 85 , 86 ]. In support, it has been previously reported that pretreatment with picrotoxin, bicuculline and flumazenil, antagonists of the GABA A receptor, block the anxiolytic- and antidepressant-like effects of chrysin [ 30 , 32 , 35 ].…”

“…In addition, chrysin (1, 5, and 10 mg/kg for 28 days) produces antidepressant-like effects in the swimming test in male Wistar rats [ 34 ], and these effects are similar to those produced by steroid hormones progesterone and allopregnanolone, in post-menopausal rats [ 35 ]. However, it is unknown if the pre-treatment during seven days with chrysin can block the establishment of behavioral despair triggered by 15 min-swimming of post-ovariectomized rats as it occurs with progesterone and allopregnanolone [ 35 , 36 , 37 , 38 ]. Therefore, the present study explored the potential protective effect of the flavonoid chrysin against the acute stress induced by the swimming test in rats with chronic absence of ovarian hormones and it was compared with the effects produced by allopregnanolone and diazepam, two substances with proven anxiolytic and anti-stress effects at both preclinical and clinical research.…”

GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan

“…These studies have shown that supplementation of both estradiol and progesterone following OVX reduces hippocampal GAD expression in rats ( Weiland, 1992 ) and attenuates GABAergic gene expression within the hippocampus and amygdala of rhesus macaques ( Noriega et al, 2010 ). It has also been shown that exogenous hormone administration following OVX in aged female rats ameliorates depressive-like behaviors through a GABAergic mechanism ( Rodríguez-Landa et al, 2020 ), suggesting that HRT may modulate the GABA system to positively affect behavior in reproductively senescent rodents. However, not all studies find beneficial effects of HRT on brain function.…”