Changes in brain neuroactive steroid concentrations, GABAA receptor plasticity and animal behaviour induced by oral contraceptives

Oral contraceptives (OC) prevent ovulation by suppressing secretion of the gonadotropins and this results in a decreased synthesis of estrogen and progesterone (P). Since P is the precursor of neuroactive steroids acting at the GABAA receptors, we evaluated the effect of a daily injection of female rats with OC on the cerebral and plasma concentrations of neuroactive steroids, on GABAA receptor gene expression and on animal behavior. Combination of ethinyl estradiol (EE, 30 ug/day/animal) and levonorgestrel (NG, 125 ug/day/animal) administered for 6 weeks results in a marked decrease in the cerebral and plasma concentrations of allopregnanolone (AP) (-84% and -40%, respectively, p<0.001, n=15) and P (-79%, p<0.001; -43%, p<0.001, respectively). In the rat cerebral cortex the decrease of neuroactive steroids induced by EE and NG was paralleled by an increase in the expression of the mRNA encoding for gamma2S and gamma2L subunits GABAA receptors (+22%, and +33%, p<0.01, respectively). The same treatment in ovariectomized rats still decreased the concentrations of the above neuroactive steroids and increased the gene expression for the gamma2S and gamma2L subunits GABAA receptors, while had no significant effects on the concentrations of these steroids in plasma, suggesting that OC might affect directly brain synthesis and accumulation of these steroid hormones. Finally chronic treatment with OC produced an anxiogenic behavior in the elevated plus-maze test with a decrease in both the percent of total time spent on the open arms and the percent of total entries (-50% and -45%, p<0.005 n=35, respectively). These results demonstrate that chronic administration of OC induces in the rat brain a plastic adaptation of GABAA receptors gene expression and an anxiogenic behavior. This effect seems to be functionally related to the dramatic fall in the brain concentration of neuroactive steroids.