Prolonged alcohol consumption leads to the development of tolerance to and dependence on ethanol, resulting in a decreased response to the sedative/hypnotic effects of ethanol, and by negative symptomatology following abrupt termination of use. One symptom associated with ethanol withdrawal in humans, as well as laboratory animals, is enhanced susceptibility to seizures. This study investigated the effects of the neurosteroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-5 alpha-THP), on alterations in seizure sensitivity associated with ethanol withdrawal. 3 alpha-5 alpha-THP is a potent anxiolytic and anticonvulsant agent that acts via selective interactions with GABAA receptors. Extensive evidence suggests that some aspects of ethanol dependence and withdrawal are mediated by alterations in GABAA receptor function. Withdrawal from chronic ethanol exposure elicited dramatic increases in seizure susceptibility in male and female rats. Administration of 3 alpha-5 alpha-THP just before seizure threshold determinations blocked the increased seizure susceptibility induced by ethanol withdrawal. Ethanol-withdrawn animals were protected by 3 alpha-5 alpha-THP at a dose that had no effect on control animal seizure thresholds. Moreover, male and female rats displayed differential responses to the seizure-threshold lowering effects of ethanol withdrawal, as well as the protection by 3 alpha-5 alpha-THP pretreatment. These findings suggest that there are gender differences associated both with ethanol withdrawal as well as the protection by 3 alpha-5 alpha-THP in ethanol-dependent rats.