3alpha,5beta-Reduced cortisol exhibits antagonist properties on cerebral cortical GABA(A) receptors.
The tetrahydro-reduced derivatives of progesterone and deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone are potent positive modulators of GABA(A) receptors that are elevated by hypothalamic-pituitary-adrenal axis activation in rodents. In humans, 11-deoxycortisol and cortisol are important hypothalamic-pituitary-adrenal axis steroids. We hypothesized that C(3,5) reduction of 11-deoxycortisol and cortisol generates steroids with GABA(A) receptor activity. 3alpha,5beta-Reduced cortisol dose-dependently inhibited muscimol-stimulated chloride flux and tetrahydrodeoxycorticosterone potentiation of muscimol responses. Cortisol, 11-deoxycortisol, 5alpha-dihydrocortisol, 3alpha,5alpha-reduced cortisol, 3alpha,5alpha-reduced 11-deoxycortisol, and 3alpha,5beta-reduced 11-deoxycortisol had no activity at 1 muM and weaker negative modulatory activity at 10 muM. We conclude that cortisol metabolism may produce antagonistic GABAergic activity.
Penland
Shannon N
SN
Department of Pharmacology, Bowles Center for Alcohol Studies, CB No. 7178, 3027 Thurston Bowles Building, UNC School of Medicine, Chapel Hill, NC 27599, USA.
Morrow
A Leslie
AL
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects*; D002712:Chlorides / Q000378:metabolism; D003350:Cortodoxone / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002712:Chlorides; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D003350:Cortodoxone; D006854:Hydrocortisone