Levonorgestrel-induced changes in brain concentrations of neurosteroids, GABAA receptor gene expression and behaviour

Recently, we have shown that long-term treatment with the combination of ethynylestradiol (EE) and levonorgestrel, two of the most frequent steroid components of oral contraceptives, administered daily for 6 weeks to female rats induced: i) a decrease in the cerebrocortical and plasma concentrations of allopregnanolone and progesterone; ii) an increase in the abundance of mRNAs encoding the gamma2S and gamma2L subunits and the relative protein of the gamma-aminobutyric acid type A (GABAA) receptor in the cerebral cortex; iii) an anxiety-like behavior in the elevated plus-maze test. In order to determine which component of the oral contraceptives is responsible for the effects described above, females rats were treated with either EE or LNG alone for six weeks. Long-term treatment with EE (30 ug/day, s.c.) markedly decreased the cerebrocortical and plasma concentrations of progesterone (-73% and -69%, respectively) and allopregnanolone (-77% and -40%, respectively), but failed to modify the amount of the gamma2 subunit polypeptide of GABAA receptors as well as the behavior of the animals in the elevated plus-maze test. Similarly, long-term treatment with LNG (125 ug/day, s.c.), induced a marked decrease in the cerebrocortical and plasma concentrations of progesterone (-67% and -57%, respectively) and allopregnanolone (-75% and -41%, respectively) but, at variance with EE, this treatment increased (+30%) the abundance of the gamma2 subunit polypeptide of GABAA receptors in the cerebral cortex and induced an anxiety-like behavior in the elevated plus-maze as demonstrated by the 50% decrease of the time spent and the 45% decrease of the number of entries in the open arms of the maze. All together, these results demonstrated that the plastic adaptation of GABAA receptors gene expression in the rat brain and the anxiogenic behavior of the animals induced by oral contraceptives seems to be due to the progestinic component, levonorgestrel. Given the importance of GABAA receptor-mediated neurotransmission in the modulation of brain function, the change sin GABAA receptor and behavior of animals induced by oral contraceptives might be relevant to the side effects sometimes exhibited by women taking these drugs.