Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility

Abstract

Withdrawal from high levels of progesterone in rodents has been proposed as a model for premenstrual syndrome or postpartum depression. Forced swim test (FST) immobility, used to model depression, was assessed in intact female DBA/2J mice following progesterone withdrawal (PWD) or treatment with the 5alpha-reductase inhibitor finasteride. Following 5 daily progesterone injections (5 mg/kg IP) FST immobility increased only in mice withdrawn for 3 days (p<.05). In another experiment, 3 days of PWD significantly decreased levels of progesterone compared to 0 days of withdrawal, but progesterone levels at 3 days of PWD did not differ from vehicle-treated controls. In a final study, mice received daily injections of progesterone (5 mg/kg IP) for 8 days, with 0 mg/kg, 50 mg/kg, or 100 mg/kg finasteride co-administered for the last three days. Mice that received 100 mg/kg finasteride, but not 50 mg/kg finasteride, displayed increased FST immobility. PWD and finasteride treatment, both of which reduce allopregnanolone levels, were associated with increased FST immobility in female DBA/2J mice. These findings suggest that decreased levels of the GABAergic neurosteroid allopregnanolone contribute to symptoms of PWD. Future studies of PWD may provide information about human conditions that are associated with hormone changes such as premenstrual syndrome or postpartum depression.

Figure 1

Mean (± SEM) seconds of immobility in the FST in female DBA/2J mice following different intervals of withdrawal (group labels) from repeated 5 mg/kg IP injections of progesterone, or following repeated vehicle injections. * p < .05 compared to 3 d PWD group by Tukey HSD.

Figure 2

Mean (± SEM) ng/mL of progesterone in plasma from female DBA/2J mice. (A) Blood was collected at various times (group labels) following a single 5 mg/kg IP injection of progesterone. *p < .05 compared to 0.5 hr group by Tukey HSD. (B) Blood was collected at various times of withdrawal (group labels) following repeated 5 mg/kg IP injections of progesterone, or after repeated vehicle injections. *p < .05 compared to 0 d PWD group by Tukey HSD.

Figure 3

Mean (± SEM) seconds of immobility in the FST in female DBA/2J mice following repeated 5 mg/kg IP injections of progesterone, co-administered with different doses of finasteride (group labels). *p < .05 compared to 100 mg/kg finasteride dose by Tukey HSD.