3α,5β-Reduced cortisol exhibits antagonist properties on cerebral cortical GABA A receptors

Abstract

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. 3α,5β-Reduced cortisol dose-dependently inhibited muscimol-stimulated chloride flux and tetrahydrodeoxycorticosterone potentiation of muscimol responses. Cortisol, 11-deoxycortisol, 5α-dihydrocortisol, 3α,5α-reduced cortisol, 3α,5α-reduced 11-deoxycortisol, and 3α,5β-reduced 11-deoxycortisol had no activity at 1 μM and weaker negative modulatory activity at 10 μM. We conclude that cortisol metabolism may produce antagonistic GABAergic activity.