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.