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 of delta receptors. The immobility time in the mouse forced swimming test was significantly reduced by DHEAS (5 and 20 mg/kg, s.c.) and PS (5 mg/kg) without accompanying changes in the ambulatory or open-field activity. Pretreatment with DHEAS (10 mg/kg) or PS (10 and 20 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 putative delta1 receptor antagonist, or progesterone (10 mg/kg), a delta 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 (10 mg/kg). Neither NE-100 nor progesterone influenced the immobility alone. These data suggest a role for central delta receptor in the antidepressant-like effects of neurosteroids, and reinforced their potential therapeutic use in depression.