Effect of progesterone on the expression of GABA_A receptor subunits in the prefrontal cortex of rats: implications of sex differences and brain hemisphere

Abstract

Progesterone is a neuroactive hormone with non-genomic effects on GABA(A) receptors (GABA(A)R). Changes in the expression of GABA(A)R subunits are related to depressive-like behaviors in rats. Moreover, sex differences and depressive behaviors have been associated with prefrontal brain asymmetry in rodents and humans. Thus, our objective was to investigate the effect of progesterone on the GABA(A)R α1 and γ2 subunits mRNA expression in the right and left prefrontal cortex of diestrus female and male rats exposed to the forced swimming test (FST). Male and female rats (n = 8/group) were randomly selected to receive a daily dose of progesterone (0·4 mg·kg⁻¹) or vehicle, during two complete female estrous cycles (8-10 days). On the experiment day, male rats or diestrus female rats were euthanized 30 min after the FST. Our results showed that progesterone significantly increased the α1 subunit mRNA in both hemispheres of male and female rats. Moreover, there was an inverse correlation between depressive-like behaviors and GABA(A)R α1 subunit mRNA expression in the right hemisphere in female rats. Progesterone decreased the GABA(A)R γ2 mRNA expression only in the left hemisphere of male rats. Therefore, we conclude that the GABA(A) system displays an asymmetric distribution according to sex and that progesterone, at lower doses, presents an antidepressant effect after increasing the GABA(A) R α1 subunit expression in the right prefrontal cortex of female rats.

Asymmetric effects of low doses of progesterone on GABA(A) receptor α4 subunit protein expression in the olfactory bulb of female rats

“…However, these authors did not find changes in mRNA expression of the ␣4 subunit in the hippocampus of treated male rats (Nin et al 2008). Another study by our group showed that low doses of progesterone presented an antidepressant-like effect in diestrus female rats, which was associated with increased mRNA expression of the ␣1 subunit in the right prefrontal cortex of female rats (Andrade et al 2012), evidencing a functional asymmetry of the GABA system related to sex and mood disorders. We believe that our data are relevant because most of the currently available studies have not investigated brain asymmetries related to the effect of neurosteroids and their implications in the control of behaviour.…”

“…The protein levels were measured following the method of Bradford (1976). Since there is functional asymmetry, and the expression of several genes and proteins are hemispheric-specific in the brain (Andrade et al 2012), we analysed the right and left OBs separately. After protein measurement, sodium dodecyl sulphate -polyacrylamide gel electrophoresis (SDS-PAGE) on 10% (w/v) acrylamide gels was carried out using a mini-protean system (Bio-Rad, Hercules, California, USA) with broad range molecular weight standards (FullRange Rainbow Molecular Weight Markers; GE Healthcare).…”

“…The GABA(A) receptor is formed by the combination of multiple subunits (␣1-6, ␤1-3, ␥1-3, ␦, , , ) determining agonist affinity, chance of opening and conductance of the receptor, and factors such as different cell types, distinct brain regions, and hormonal fluctuations, as well as environmental changes or disease affect the expression of these subunits (Follesa et al 2005;Andrade et al 2012). Specifically, receptors containing the ␣4 subunit are insensitive to benzodiazepines and display faster deactivation kinetics, which could underlie hyperexcitability states, and are supposed to be involved in different humoral disorders (Smith et al 2007).…”

Effect of injectable medroxyprogesterone acetate and etonogestrel implants on GABA-A and serotonin receptors in white and gray matter of the brain: experimental study in rats

“…Progesterone can cross the blood-brain barrier, due to its lipophilic structure and acts on receptors located in the central nervous system [4]. Estrogen and progesterone have their respective hormone receptors, whereas allopregnanolone acts via the GABA-A receptor [5].…”

“…Progesterone acts as a potent positive modulator of the GABA-A receptor because of its conversion into its metabolite, allopregnanolone. In vitro and in vivo studies have shown that progesterone and allopregnanolone levels are related to GABA-A receptor changes in different regions of the brain [3,4]. However, less is known with regard to the effects of progesterone on the serotonergic system.…”