We examined the effects on central nervous system excitability of deoxycorticosterone (DOC) and its ring A reduced derivatives, 5α-dihydro-DOC (DHDOC) and 3α-OH 5α-tetrahydro-DOC (THDOC). In adrenalectomized rats, under urethane anesthesia, i.p. injections of DOC, DHDOC, or THDOC 750 μg in 0.5 ml 4:1 saline, cremophor-EL solution, produced a significant decrease in the amplitude of sciatic evoked potentials in regions of the pontine brain stem. During simultaneous recording of brain stem evoked potentials and afferent volleys from L6 and L7 dorsal roots, i.v. injection of 750 μg DOC produced a decrease in the amplitude of brain stem responses without noticeable effects on the dorsal root afferent volleys. At the neuronal level, the effects of the steroid hormones were evaluated by the changes they induced in the mean firing frequency ( P < 0.01) measured during 5-min intervals as determined by a one-way analysis of variance and analysis with a test of multiple comparisons. Only cells which fired in a stationary mode for 15 min before the steroid injection were studied. The effects of i.v. DOC were tested on 23 neurons. Twelve responded by a decrease in their firing rate; in the other neurons firing patterns remained unchanged. In all responsive neurons the distribution of the interval histogram showed a decrease in the peak of the shorter intervals (15 to 30 ms) and/or broader distribution extending toward longer intervals. The effects of THDOC were tested in 10 neurons. In eight of them THDOC produced a rapid (12 to 96 s, x = 35.0 ), significant decrease in the mean firing frequency which began to recover to control values within 6 to 20 min ( x = 13.6 ) of steroid administration. This was associated with both a decrease in the interspike interval histogram and a shift to longer interspike intervals. The onset of the depressant effect observed with THDOC was significantly faster ( P < 0.01) than that of its parent compound DOC. These results support the contention that ring A reduced metabolites of adrenal corticosteroids may fulfill an important biologic role in modulating activity of certain central nervous system regions.