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

The tetrahydro-reduced derivatives of progesterone and deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone are potent positive modulators of GABAA 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 C3,5 reduction of 11-deoxycortisol and cortisol generates steroids with GABAA 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.