THIS study examined the effects of neurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and progesterone on the Porsolt forced swim test of depression in mice, and investigated the possible involvement o σ receptors. The immobility time in the mouse forced swimming test was significantly reduced by DHEAS (5 and 2 0 mg/kg, s.c.) and PS (5 mg/kg) without accompanying changes in the ambulatory or open-field activity. Pretreatment with DHEAS (&PHgr; mg/kg) or PS (10 and &PHgr; mg/kg), however, failed to modify the immobility. The relief of behavioral despair in the immobility test by DHEAS (5 and 20 mg/kg) was dose-dependently blocked by preadministration of NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl-ethylamine monohydrochloride; 0.5 and 1 mg/kg), a putativeσ1receptor antagonist, or progesterone (1 0 mg/kg), aσ receptor antagonistic neurosteroid. On the other hand, PS (5 mg/kg)-induced decrease in the immobility was significantly blocked by NE-100 (0. 5 mg/kg), but not by progesterone (1 0 mg/kg). Neither NE-100 nor progesterone influenced the immobility alone. These data suggest a role for centralσ receptor in the antidepressant-like effects of neurosteroids, and reinforced their potential therapeutic use in depression.