Sex-dependent antidepressant effects of lower doses of progesterone in rats

Abstract

Major depression is more prevalent among women than men, and progesterone might be involved in the mechanisms that generate these differences. Progesterone is clinically used for women in several reproductive events, but its antidepressant effect is unclear. Animal studies showed the interference of progesterone on depressive behaviors of rodents, but they are inconclusive, and no study compared different treatment durations. This study investigated the antidepressant effect of low doses of progesterone in male and female rats under acute or chronic administration. Male and female Wistar rats in different phases of the estrous cycle were acutely administered different doses of progesterone (0.0, 0.4. 0.8 and 1.2mg/kg) and tested in the forced swimming test (FST). The lowest dose of progesterone (0.4 mg/kg) was chronically administered during two complete estrous cycles and diestrous II female and male rats were tested in the FST. Progesterone decreased depressive-like behaviors only in chronically treated diestrous II female rats and increased immobility in male rats. This low dose of progesterone did not interfere in the hormonal cycling in female rats. Results also showed that diestrous II female rats had greater immobility than male rats in the FST. The greater immobility of diestrous II female rats shows that rats in this estrous phase present more depressive-like behaviors that may be associated with their lower serum levels of progesterone. We showed that progesterone chronically administered at low doses reverses these depressive-like behaviors and has an antidepressant effect during the diestrous II phase of the estrous cycle.

Factors influencing behavior in the forced swim test

“…Acute progesterone administration between pre-test and test FST sessions did not alter behavior both in intact female or male rats, while chronic treatment with progesterone (8–10 days) decreased depressive-like behaviors in female rats but increased immobility in males [139]. …”

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

“…Female rats were randomly selected to receive a daily intraperitoneal injection of 0.4 mg/kg body mass of progesterone or the vehicle, during 2 complete female oestrous cycles. Previous studies by our laboratory showed that the administration of this dose did not change the oestrous cycle of these rats (Andrade et al 2010). To determine the oestrous cycle of the female rats, vaginal smears were performed throughout the treatment period.…”

“…Only female rats having 2 regular 4-5 day cycles and that were in the diestrus II phase on the last day of the experiment were included in this study (n = 4 animals per group for the vehicle treatment and 5 animals per group for the progesterone treatment). On the last day of the experiment, all of the animals were exposed to the FST, which was performed as previously described (Andrade et al 2010). Briefly, on the first day of the treatment, the rats were exposed to a pretest session of 15 min.…”

“…Because progesterone was chronically administered, the pretest session was performed on the first day of treatment. Behaviour was recorded, and the data have already been published (Andrade et al 2010). The rats were euthanised by decapitation 30 min after the end of the FST.…”

“…Progesterone, a female sex hormone secreted by the ovaries, is also synthesised and metabolised inside the central nervous system (CNS), in glial cells and neurons (Garcia-Segura and Melcangi 2006). A previous study by our group showed that low doses of progesterone have an antidepressant-like effect on female rats exposed to the forced swimming test (FST), which is a preclinical test with good predictive validity for detecting the antidepressant effects of drugs (Andrade et al 2010). However, the pathways involved in this effect are not fully understood.…”