Chronic oral contraceptives (OC) change GABAA receptors gene expression and animal behavior in rats

The effect of a daily injection of female rats with OC on the cerebral and plasma concentrations of allopregnanolone (AP), pregnenolone (PR) and progesterone (P), on GABAA receptor gene expression and on animal behavior. Combination of ethynylestradiol (EE, 30 ug) and levonorgestrel (LNG, 125 ug) administered for 6 weeks dramatically decreased in the rat cerebrocortical concentrations of AP(-79%), P(-74%) and PR(-41%). The same treatment decreased by a lower extent the plasma concentrations of these steroids (AP-40%, P-43% and PR-35%). These changes were associated to an increase in the expression of the mRNA encoding for g2S (+22%) and g2L (+32%) subunits GABAA receptors, while failed to change the mRNA encoding for the isoforms of the a and b subunits. The same treatment in ovariectomized (OVX) rats further decreased the concentrations of these steroids and increased the gene expression for the g2S and g2L subunits GABAA receptors, while had no significant effects on the concentrations of these steroids in plasma. These data suggest that OCs might affect directly brain synthesis of these steroid hormones. Chronic treatment with OC produced an anxiogenic behavior in the elevated plus-maze test shown by a decrease in both the percent of total time spent on the open arms and the percent of total entries (-50% and -45%, respectively). These data demonstrate that chronic administration of OCs induces in the rat brain a plastic adaptation of GABAA receptors gene expression and an anxiogenic behavior. These effects seem to be functionally related to the dramatic fall in the brain concentration of neurosteroids.