POSSIBLE ROLE OF NITRIC-OXIDE IN THE NOOTROPIC AND ANTIAMNESIC EFFECTS OF NEUROSTEROIDS ON AGING-INDUCED AND DIZOCILPINE-INDUCED LEARNING IMPAIRMENT

The ability of the nitric oxide (NO) synthase inhibitor, N-G-nitro-L-a rginine methyl ester (L-NAME), to modulate the attenuating effects of neurosteroids on the aging- and NMDA receptor antagonist dizocilpine-i nduced learning impairment, was tested in mice using two different beh avioral models of long-term memory. The performance of aged mice (16 m onths old) in step-down type of passive-avoidance and elevated plus-ma ze paradigms was significantly impaired compared to that of young mice (3 months old). Neurosteroids pregnenolone sulfate (PS) and dehydroep iandrosterone sulfate (DHEAS), at 1-20 mg/kg, s.c., significantly impr oved the passive-avoidance and plus-maze performances in aged mice. Ne urosteroids PS and DHEAS, at doses 1-20 mg/kg, s.c., significantly att enuated dizocilpine (0.1 mg/kg, i.p.)-induced amnesia, without produci ng any promnestic effects alone in adult mice. In both cognitive tasks , the effects exhibited by the neurosteroids tested had a bell-shaped curve. Preadministration of L-NAME (10 and 20 mg/kg, i.p.), at doses t hat did not disrupt cognition alone in either young or aged mice, sign ificantly blocked the beneficial and antiamnesic effects of neurostero ids PS (5 mg/kg) and DHEAS (10 mg/kg). A selective action of L-NAME on the effects of neurosteroids was indicated, since the effects of L-NA ME were completely reversed by L-arginine (300 mg/kg, i.p.), a competi tive substrate for NO synthase. Neither L-NAME nor L-arginine alone af fected the antinociception, locomotor activity or rota-rod performance of young or aged mice. These observations suggest that a NO-dependent mechanism may be involved in the beneficial and antiamnesic effects o f neurosteroids PS and DHEAS on the aging- and dizocilpine-induced imp airment of learning and memory processes. (C) 1998 Elsevier Science B. V. All rights reserved.