We previously reported that high-affinity sigma type 1 (sigma 1) ligands attenuate the learning impairment induced in mice by dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist. Neurosteroids, such as pregnenolone sulfate, progesterone and dehydroepiandrosterone sulfate (DHEAS), modulate NMDA-evoked responses in the central nervous system. Furthermore, some of them were reported to interact with sigma-receptors. This study was carried out to investigate whether DHEAS, a neurosteroid with memory-enhancing effects, attenuates the dizocilpine-induced learning impairment in mice, and, if so, by a mechanism involving sigma 1-receptors. Learning was evaluated using spontaneous alternation in the Y-maze for spatial working memory and step-down type of passive avoidance for long-term memory. At doses about 10-20 mg/kg s.c., DHEAS significantly attenuated dizocilpine (0.15 mg/kg i.p.)-induced impairment of learning on both tests. The enhancing effect of DHEAS (20 mg/kg s.c.) was antagonized by co-administration of the sigma-antagonist BMY-14802 (5 mg/kg i.p.) and suppressed by a subchronic treatment with haloperidol (4 mg/kg/day s.c. for 7 days). These results indicate that DHEAS attenuates dizocilpine-induced learning impairment via an interaction with sigma 1-receptors.