Decreased allopregnanolone induced by hormonal contraceptives is associated with a reduction in social behavior and sexual motivation in female rats

The progesterone metabolite allopregnanolone is a neurosteroid that exerts a rapid non genomic effect on neuronal excitability through a direct modulation of the gamma-aminobutyric acid type A receptor (GABA-A). It has been shown that allopregnanolone facilitates social and sexual behavior in rodents, which evoke further increases in brain allopregnanolone concentrations. Thus, systemic or local allopregnanolone administration in the hypothalamus or midbrain promotes sexual behavior while block of progesterone metabolism through a 5alpha-reductase inhibitor (finasteride) reduces proceptivity and receptivity compared to control animals. We have previously demonstrated that chronic treatment with a combination of ethinylestradiol and levonorgestrel (EE/LNG), two of the compounds most frequently used in hormonal contraceptives, decreases brain concentrations of allopregnanolone and progesterone. Here we evaluate whether the reduction in the brain concentrations of allopregnanolone induced by EE/LNG treatment alters social and sexual behavior in female rats. Female rats were orally treated with a combination of EE (0.030 mg) and LNG (0.125 mg) once a day for four weeks and were sacrificed or subjected to the behavioral tests 24 hours after the last treatment. Social behavior was assessed using the resident-intruder test, while sexual receptivity and motivation were assessed using paced and non-paced mating tests. Progesterone (4 mg/kg) was administered subcutaneously 4 hours before the paced mating test; finasteride (50 mg/kg) was administered subcutaneously 2 hours before progesterone administration. In the resident-intruder test, EE/LNG treatment specifically affected social and agonistic behavior by decreasing the frequency of the dominance score (-114%, p<0.01), the duration and the frequency of agonistic behaviors delivered (-78% and -60%, respectively, p<0.01) and the duration and the frequency of social investigation (-37%, p<0.05 and -37%, p<0.01, respectively); in contrast, the duration of social inactivity was increased (+238%, p<0.05). In the paced mating test, EE/LNG-treated rats showed no proceptive behaviors (ear wiggling, hops and darts), while the receptivity, measured as lordosis quotient (LQ, number of lordosis/male mount + intromissions × 100), was not affected. Progesterone administration before the paced mating test significantly increased proceptivity (+230%, p<0.001) as well as brain allopregnanolone concentration (+124%, p<0.0005) in EE/LNG-treated animals. Administration of the 5alpha-reductase inhibitor finasteride, 2 hours before progesterone, decreased allopregnanolone concentrations (-73%, p<0.0005) and almost completely abolished (-75%, p<0.05) the increase in proceptivity induced by progesterone administration. In conclusion, chronic treatment with EE/LNG specifically affects social behavior and sexual motivation in female rats. Given that chronic treatment with EE/LNG decreases brain and plasma concentrations of allopregnanolone, the decrease in dominant behaviors and in sexual motivation induced by EE/LNG treatment may be related to the drastic reduction in the brain concentrations of this neurosteroid. Accordingly, the recovery of allopregnanolone concentrations induced by progesterone administration results in a significant increase in sexual motivation, while the subsequent blocking of its synthesis by finasteride decreases proceptives behaviors. These results might be relevant to the side effects sometimes exhibited by women taking hormonal contraceptives.