Progesterone exerts multiple actions on the nervous system, including a neuroprotective action against cerebral infarct caused by experimental occlusion of the middle cerebral artery in rats, the promotion of myelination in the central and peripheral nervous systems, and the possession of anticonvulsant properties through potentiation of the GABA-evoked Cl^? currents.

From its striking behavioral actions, the anxiolytic properties of progesterone have long been recognized in humans. Similarly, the exogenous administration of progesterone in estradiol-primed rats reduces anxiety8. J.F. Rodríguez-Sierra, J.L. Howard, G.T. Pollard and S.E. Hendriks, Effect of ovarian hormones on conflict behavior. Psychoneuroendocrinology 9 (1984), p. 293. Abstract | View Record in Scopus | Cited By in Scopus (42). Low levels of anxiety are concurrent with high levels of circulating progesterone occurring spontaneously throughout the estrous cycle and pregnancy. In addition, progesterone produces some anxiolytic actions in both estrogen- and non-estrogen-primed rats. However, while some antidepressant drugs produce anxiolytic effects, some anxiolytics also produce antidepressant actions. Progesterone consistently restores immobility to control values in the tail suspension test in ovariectomized mice; however, the action of progesterone in other tests that measure the antidepressant activity of drugs more specifically remains to be explored.

In the present study, we describe the changes that exogenous administration of progesterone elicited in the immobility measured in rats forced to swim. The validity of this experimental model in monitoring the potency of antidepressant drugs has been extensively discussed, the conclusion being that antidepressants reduce immobility, with few or no effects on locomotor activity. This is a different action from that exerted by anxiolytics, because these compounds commonly reduce locomotor activity and increase immobility in the forced swim test. We, therefore, tested the effect of ovariectomy and the administration of progesterone in rats forced to swim.

Wistar rats (aged 3 months, weighing 250–300 g) were used for this study following strict principles of animal care (NIH publication No. 86-23, revised 1985). The rats were assigned to one of two groups, vehicle or progesterone, and housed 4 to 5 rats per cage at a constant room temperature (25 ± 1°C) under a 12-h light-dark cycle (lights on at 7:00 h) with water and food freely available. All animals were anesthetized with ethylic ether and ovariectomized (OVX) from a ventral approach. After surgery, the animals were placed in their home cages for recovery and checked once daily to avoid any additional discomfort.

In both groups of rats, a 15-min pretest habituation session for locomotor activity and forced swim preceded the experimental sessions by 24 h. The first control test (C1) was applied 1 week before ovariectomy, with the majority of the rats in diestrus (80%); the second test was done 2 weeks after surgery (OVX), and from the third through the seventh tests, the animals received saline (NaCl 0.9%) and water-soluble progesterone (Sigma Chemical Co., St. Louis, MO, USA). Finally, the eighth test was done 1 week after the last injection of progesterone or saline (C2). In the experimental group (n = 9), each rat underwent once-weekly i.p. injections of water-soluble progesterone in a volume of 0.10 mL (NaCl 0.9%). Progesterone (0.20, 0.40, 0.80, 1.50 and 3.0 mg/kg) was injected 24 and 2 h before behavioral testing (between 10:00 and 12:00 h). To discard the cumulative effects of progesterone and a possible effect from the swimming test repetition, all animals received one of several progesterone doses in a different sequence, following a completely randomized experimental intrasubject design. The control group (n = underwent 8 once-weekly swim test sessions. In order to discard a possible influence of progesterone on locomotor activity impinging on the forced swim test, the open field test preceded the measurement of immobility in the forced swim test. The apparatus consisted of an opaque-Plexiglas box (40 × 30 × 20 cm). A black grid divided the floor into 12 equal squares (10 × 10 cm). The animals were placed in a corner of the apparatus and the number of times an animal entered a square on four paws during a 5-min videotaped session was counted by two independent observers (any discrepancy implied a re-analysis of the videotape).

Immediately thereafter, the forced swim test was practiced individually in a glass cage (50 × 30 × 60 cm) containing water (25 ± 1°C) at a depth of 19–21 cm, depending on the head-tail length of each rat. After the swimming session, the animals were allowed to recover in a warm, dry chamber. The 5-min videotaped test sessions took place the next day until eight weekly experimental sessions were completed. A rat was judged immobile when it remained floating in the water while making only the necessary movements to keep its head above water. Two observers unaware of the treatment evaluated the total time of immobility.

Because the data failed to follow a normal distribution, the results were analyzed from dosage and treatments by the Friedman test. The Student-Newman-Keuls test was used when at least p <0.05 was attained. The results are expressed as mean ± standard error of the mean.

In the open-field test, ovariectomy lowered by 50% the crossing amount observed in the session practiced before the surgery (p <0.05), but progesterone failed to produce changes in crossing after ovariectomy even at the highest dose tested (3.0 mg/kg).

Ovariectomy (OVX) did not produce any significant change in immobility in the forced swim test. Similarly, the weekly repetition of the test produced non-significant changes consisting of some trends to decrease or increase immobility in the saline-treated group throughout the 8 weeks of study, but in any case these oscillations reached the criterion of significance.

In the forced swim test, the total mean duration of immobility throughout the study (eight sessions) significantly decreased (p <0.05) in the progesterone group (16.4 ± 1.85 sec) with respect to the saline group (25.3 ± 5.55 sec), but in the analysis of the weekly sessions, a trend toward decreased immobility at a dose of 0.40 mg/kg of progesterone was found. A dose of 0.80 mg/kg significantly decreased immobility (p <0.001) to less than 30% of that obtained in the control test practiced after ovariectomy. In the post-treatment test practiced 1 week after the last injection of progesterone, the immobility values (C2, 25.3 ± 9.44) returned to the values observed in the control test (C1 23.1 ± 3.88; OVX 27.0 ± 6.23) recorded prior to surgery.

Total time in immobility. Progesterone reduced immobility from a dose of 0.80 mg/kg and immobility returned to control values (C2) 1 week after the last injection of progesterone. Open symbols correspond to saline group and filled symbols to progesterone group. ^• p <0.05 vs. C1, OVX and control group.

In this study, we explored some of the antidepressant-like action of progesterone by using the forced swim test. Progesterone shortened the total time spent during immobility in the forced swim test, but failed to show any significant action on locomotor activity, thus behaving as an antidepressant at the dose tested.