The neurosteroids are steroids synthesized "de novo" in the brain from cholesterol or from precursors coming from peripheral sources. The progesterone reduced metabolites, allopregnanolone (AP) and allotetrahydrodeoxycorticosterone (THDOC), have the ability to modulate the type A receptor of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain which is involved in the regulation of different integrated brain functions. The observation that these compounds are selective modulators of GABAergic transmission suggests that endogenous variations in plasma and brain concentrations of these compounds induced by physiological, pharmacological or pathological conditions might affect the activity of GABAA receptors. Oral contraceptives prevent ovulation by suppressing pulsatile secretion of the gonadotropins and this results in a decreased synthesis of endogenous steroids (estrogen and progesterone). In this study we evaluated the effect of a daily subcutaneous injection of intact female rats with oral contraceptives on both the cerebral and plasma concentrations of AP, THDOC, pregnenolone and progesterone and GABAA receptor gene expression. Combination of ethinyl estradiol (EE, 0.030 mg/day/animal) and levonorgestrel (NG, 0.125 mg/day/animal) administered for 6 weeks results in a marked decrease in the cerebral and plasma concentrations of both AP (-84% and -40%, respectively) and THDOC (-54% and -33%, respectively). As expected, also progesterone and pregnenolone were markedly decreased by this treatment (-79%, p<0.001; -41%, p<0.001, respectively). Similar results were obtained by measuring the concentrations of allopregnanolone and THDOC in plasma of women using oral contraceptives. 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%, p<0.01 and +32%, p<0.01, respectively). The same treatment failed to change the mRNA encoding for different isoforms of the alpha and beta subunits. We have demonstrated that chronic administration of oral contraceptives induces in the rat brain a plastic adaptation of GABAA receptors gene expression. This effect is functionally related to the dramatic fall in the brain concentration of neuroactive steroids. Given the crucial role of GABAA receptors-mediated neurotransmission in the modulation of brain function and the role played by the gamma subunit in the action of anxiolytic-hypnotic drugs, the change in the gene expression encoding for this subunit might be a relevant molecular event associated to altered sensitivity to environmental and psychopharmacological stimuli sometimes shown by women addicted to these drugs.
Oral contraceptives decrease cerebral and plasma concentrations of neurosteroids and modify GABAA receptors gene expression
Porcu P;
2000
Abstract
The neurosteroids are steroids synthesized "de novo" in the brain from cholesterol or from precursors coming from peripheral sources. The progesterone reduced metabolites, allopregnanolone (AP) and allotetrahydrodeoxycorticosterone (THDOC), have the ability to modulate the type A receptor of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain which is involved in the regulation of different integrated brain functions. The observation that these compounds are selective modulators of GABAergic transmission suggests that endogenous variations in plasma and brain concentrations of these compounds induced by physiological, pharmacological or pathological conditions might affect the activity of GABAA receptors. Oral contraceptives prevent ovulation by suppressing pulsatile secretion of the gonadotropins and this results in a decreased synthesis of endogenous steroids (estrogen and progesterone). In this study we evaluated the effect of a daily subcutaneous injection of intact female rats with oral contraceptives on both the cerebral and plasma concentrations of AP, THDOC, pregnenolone and progesterone and GABAA receptor gene expression. Combination of ethinyl estradiol (EE, 0.030 mg/day/animal) and levonorgestrel (NG, 0.125 mg/day/animal) administered for 6 weeks results in a marked decrease in the cerebral and plasma concentrations of both AP (-84% and -40%, respectively) and THDOC (-54% and -33%, respectively). As expected, also progesterone and pregnenolone were markedly decreased by this treatment (-79%, p<0.001; -41%, p<0.001, respectively). Similar results were obtained by measuring the concentrations of allopregnanolone and THDOC in plasma of women using oral contraceptives. 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%, p<0.01 and +32%, p<0.01, respectively). The same treatment failed to change the mRNA encoding for different isoforms of the alpha and beta subunits. We have demonstrated that chronic administration of oral contraceptives induces in the rat brain a plastic adaptation of GABAA receptors gene expression. This effect is functionally related to the dramatic fall in the brain concentration of neuroactive steroids. Given the crucial role of GABAA receptors-mediated neurotransmission in the modulation of brain function and the role played by the gamma subunit in the action of anxiolytic-hypnotic drugs, the change in the gene expression encoding for this subunit might be a relevant molecular event associated to altered sensitivity to environmental and psychopharmacological stimuli sometimes shown by women addicted to these drugs.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
