Cerebral side effects of therapy with glucocorticoids include mental alterations and behavioral disturbances such as nervousness, insomnia, changes in mood or psychological state and psychopathies of manic-depressive or schizophrenic type. We have investigated the effects of glucocorticoids, anabolic/androgenic steroids and the 5-alpha-reductase inhibitor N, N-bis (1-methyl)-3-oxo-4-aza-5-alpha-androstane-17-beta-carboxamide (1-MAC) on the synthesis of the GABAergic steroids 5-alpha-pregnane-3.20-dione (5-alpha-dihy-droprogesterone) and 5-alpha-pregnane-3-alpha-ol-20-one (5-alpha-tetrahy-droprogesterone) in rat cortex in vitro. We found potent inhibition of proges-terone-3-alpha-hydroxysteroid dehydrogenase (3-alpha-HSDH) by prednisone, prednisolone, dexamethasone and fluocortolone. Inhibition of progesterone 5-alpha-reductase by glucocorticoids was not found. In addition, inhibition of 3-alpha-HSDH and 5-alpha-reductase by androgenic/anabolic steroids and inhibition of 5-alpha-reductase by 1-MAC could be demonstrated. The inhibition of progesterone metabolism in the cerebral cortex by exogenous steroids might lead to altered neuronal activity. We conclude that this mechanism could induce the cerebral side effects, such as mental modifications and behavioral disturbances, of the drugs investigated.