Oral contraceptives are among the most widely prescribed drugs, especially in young healthy women. 10 to 40% of oral contraceptive users develop mild to moderate depressive symptoms, anxiety or other mood disorders. We have shown that long-term administration of ethynilestradiol and levonorgestrel, two of the most widely used steroids in the oral contraceptive pills, decreases neurosteroid concentrations in rat cerebral cortex and plasma. The decrease in neurosteroid levels was accompanied by altered gamma-aminobutyric acid type A (GABAA) receptor plasticity, with increased expression of the gamma2 subunit, and by anxiety-like behavior in the elevated plus-maze test. We hypothesize that these neurochemical changes may contribute to some of the mood disorders observed in oral contraceptive users. To better clarify the role of the estrogen and of the progestin component of the oral contraceptive pill on neurosteroid levels and GABAA receptor plasticity, we evaluated the effects of long-term treatment with ethynilestradiol alone or levonorgestrel alone on brain and plasma concentrations of (3alpha,5alpha)-3-hydroxypregnan-20-one (allopregnanolone) and its precursors progesterone and pregnenolone. We further evaluated their effects on GABAA receptor plasticity and anxiety-like behavior. Female rats were injected subcutaneously with ethynilestradiol (0.030 mg), levonorgestrel (0.125 mg) or a mixture of these two steroids once a day for six weeks. Administration of ethynilestradiol decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 76, 72 and 33%, respectively (p<0.005) and hippocampal levels by 52, 56 and 50%, respectively (p<0.0001). Likewise, administration of levonorgestrel decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 75, 68 and 33%, respectively (p<0.01) and hippocampal levels by 55, 65 and 60%, respectively (p<0.0005). As expected, administration of the ethynilestradiol-levonorgestrel combination decreased cerebral cortical and hippocampal levels of neurosteroids. Plasma concentrations of neurosteroids were similarly decreased following administration of each treatment condition. We next examined the effects of ethynilestradiol, levonorgestrel or their combination on GABAA receptor plasticity. As expected, administration of the steroid combination increased the gamma2 subunit peptide in the cerebral cortex, hippocampus and cerebellum by 30, 43 and 45%, respectively (p<0.01). Administration of levonorgestrel also increased the gamma2 subunit peptide in the cerebral cortex, hippocampus and cerebellum by 38, 59 and 48%, respectively (p<0.01). In contrast, administration of ethynilestradiol failed to alter the gamma2 subunit peptide in either region examined. Levels of alpha1 and alpha2 subunits of the GABAA receptor were differentially regulated by administration of ethynilestradiol, levonorgestrel or their mixture in the three brain regions examined. In contrast, levels of the alpha4 subunit were not altered by any of the treatment conditions in any of the regions examined. Finally, administration of levonorgestrel alone decreased the time spent in the open arms of the maze and the number of entries into the open arms by 56 and 43%, respectively (p<0.05), consistent with an increased anxiety-like behavior also observed following treatment with the oral contraceptive combination. In contrast, administration of ethynilestradiol alone did not alter the anxiety-like behavior in the elevated plus-maze. These results suggest that changes in GABAA receptor plasticity and anxiety-like behavior observed following administration of oral contraceptives are mediated by the progestinic component of the oral contraceptive pill. Because both ethynilestradiol and levonorgestrel decrease allopregnanolone levels in a similar manner, these results suggest that changes in allopregnanolone levels are not associated with GABAA receptor plasticity.
Chronic treatment with ethynil estradiol or levonorgestrel decreases brain neurosteroid levels and selectively alters GABAA receptor plasticity and anxiety-like behavior
Porcu P;
2011
Abstract
Oral contraceptives are among the most widely prescribed drugs, especially in young healthy women. 10 to 40% of oral contraceptive users develop mild to moderate depressive symptoms, anxiety or other mood disorders. We have shown that long-term administration of ethynilestradiol and levonorgestrel, two of the most widely used steroids in the oral contraceptive pills, decreases neurosteroid concentrations in rat cerebral cortex and plasma. The decrease in neurosteroid levels was accompanied by altered gamma-aminobutyric acid type A (GABAA) receptor plasticity, with increased expression of the gamma2 subunit, and by anxiety-like behavior in the elevated plus-maze test. We hypothesize that these neurochemical changes may contribute to some of the mood disorders observed in oral contraceptive users. To better clarify the role of the estrogen and of the progestin component of the oral contraceptive pill on neurosteroid levels and GABAA receptor plasticity, we evaluated the effects of long-term treatment with ethynilestradiol alone or levonorgestrel alone on brain and plasma concentrations of (3alpha,5alpha)-3-hydroxypregnan-20-one (allopregnanolone) and its precursors progesterone and pregnenolone. We further evaluated their effects on GABAA receptor plasticity and anxiety-like behavior. Female rats were injected subcutaneously with ethynilestradiol (0.030 mg), levonorgestrel (0.125 mg) or a mixture of these two steroids once a day for six weeks. Administration of ethynilestradiol decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 76, 72 and 33%, respectively (p<0.005) and hippocampal levels by 52, 56 and 50%, respectively (p<0.0001). Likewise, administration of levonorgestrel decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 75, 68 and 33%, respectively (p<0.01) and hippocampal levels by 55, 65 and 60%, respectively (p<0.0005). As expected, administration of the ethynilestradiol-levonorgestrel combination decreased cerebral cortical and hippocampal levels of neurosteroids. Plasma concentrations of neurosteroids were similarly decreased following administration of each treatment condition. We next examined the effects of ethynilestradiol, levonorgestrel or their combination on GABAA receptor plasticity. As expected, administration of the steroid combination increased the gamma2 subunit peptide in the cerebral cortex, hippocampus and cerebellum by 30, 43 and 45%, respectively (p<0.01). Administration of levonorgestrel also increased the gamma2 subunit peptide in the cerebral cortex, hippocampus and cerebellum by 38, 59 and 48%, respectively (p<0.01). In contrast, administration of ethynilestradiol failed to alter the gamma2 subunit peptide in either region examined. Levels of alpha1 and alpha2 subunits of the GABAA receptor were differentially regulated by administration of ethynilestradiol, levonorgestrel or their mixture in the three brain regions examined. In contrast, levels of the alpha4 subunit were not altered by any of the treatment conditions in any of the regions examined. Finally, administration of levonorgestrel alone decreased the time spent in the open arms of the maze and the number of entries into the open arms by 56 and 43%, respectively (p<0.05), consistent with an increased anxiety-like behavior also observed following treatment with the oral contraceptive combination. In contrast, administration of ethynilestradiol alone did not alter the anxiety-like behavior in the elevated plus-maze. These results suggest that changes in GABAA receptor plasticity and anxiety-like behavior observed following administration of oral contraceptives are mediated by the progestinic component of the oral contraceptive pill. Because both ethynilestradiol and levonorgestrel decrease allopregnanolone levels in a similar manner, these results suggest that changes in allopregnanolone levels are not associated with GABAA receptor plasticity.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
