Changes in GABAA receptor gamma 2 subunit gene expression induced by long-term administration of oral contraceptives in rats.
The effects of oral contraceptives (OCs) on neurosteroid concentrations were evaluated in female rats and women. In rats, ethynylestradiol and levonorgestrel (0.030 and 0.125 mg, respectively, subcutaneously) administered daily for 6 weeks reduced the concentrations of pregnenolone (-41%) progesterone (-74%) and allopregnanolone (-79%) in the cerebral cortex; the plasma concentrations of these steroids were also reduced but by smaller extents. OC administration for 3 months also reduced the serum concentrations of pregnenolone, progesterone and allopregnanolone in women. Chronic administration of OCs in rats increased the abundance of gamma-aminobutyric acid type A (GABA(A)) receptor gamma 2L and gamma 2S subunit mRNAs and the relative protein in the cerebral cortex, while the amounts of various alpha and beta subunit mRNAs were unaffected. Ovariectomy did not modify the effect of OCs administration on the concentrations of neurosteroids in the rat cerebral cortex (but not in the plasma) as well as on the GABA(A) receptor gene expression, suggesting a direct effect of OCs in brain. Finally, rats treated with OCs exhibited an anxiety-like behavior in the elevated plus-maze test. These results indicate that long-term treatment with OCs induced a persistent reduction in the concentrations of pregnenolone, progesterone and its GABA(A) receptor-active metabolite, allopregnanolone, both in rats and women. In rats this effect was associated with a plastic adaptation of GABA(A) receptor gene expression in the rat cerebral cortex.
Follesa
P
P
Department of Experimental Biology, University of Cagliari, 09100 Cagliari, Italy.
Porcu
P
P
Sogliano
C
C
Cinus
M
M
Biggio
F
F
Mancuso
L
L
Mostallino
M C
MC
Paoletti
A M
AM
Purdy
R H
RH
Biggio
G
G
Concas
A
A
D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003280:Contraceptives, Oral, Synthetic / Q000008:administration & dosage*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007279:Injections, Subcutaneous; D011280:Pregnanolone / Q000097:blood / Q000378:metabolism; D011284:Pregnenolone / Q000097:blood / Q000378:metabolism; D011374:Progesterone / Q000097:blood / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000235:genetics*
D003280:Contraceptives, Oral, Synthetic; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011374:Progesterone; D011284:Pregnenolone; D011280:Pregnanolone