Possible role of nitric oxide in the nootropic and antiamnesic effects of neurosteroids on aging- and dizocilpine-induced learning impairment

Brain Res. 1998 Jul 20;799(2):215-29. doi: 10.1016/s0006-8993(98)00419-3.


The ability of the nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), to modulate the attenuating effects of neurosteroids on the aging- and NMDA receptor antagonist dizocilpine-induced learning impairment, was tested in mice using two different behavioral models of long-term memory. The performance of aged mice (16 months old) in step-down type of passive-avoidance and elevated plus-maze paradigms was significantly impaired compared to that of young mice (3 months old). Neurosteroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), at 1-20 mg/kg, s.c., significantly improved the passive-avoidance and plus-maze performances in aged mice. Neurosteroids PS and DHEAS, at doses 1-20 mg/kg, s.c., significantly attenuated dizocilpine (0.1 mg/kg, i.p.)-induced amnesia, without producing 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 that did not disrupt cognition alone in either young or aged mice, significantly blocked the beneficial and antiamnesic effects of neurosteroids 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-NAME were completely reversed by L-arginine (300 mg/kg, i.p.), a competitive substrate for NO synthase. Neither L-NAME nor L-arginine alone affected 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 of neurosteroids PS and DHEAS on the aging- and dizocilpine-induced impairment of learning and memory processes.

MeSH terms

  • Aging / psychology*
  • Amnesia / drug therapy*
  • Animals
  • Avoidance Learning / drug effects
  • Dehydroepiandrosterone Sulfate / pharmacology*
  • Dizocilpine Maleate* / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Learning Disabilities / chemically induced*
  • Male
  • Maze Learning / drug effects
  • Memory / drug effects
  • Mice
  • Mice, Inbred Strains
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nootropic Agents / pharmacology*
  • Pregnenolone / pharmacology*


  • Enzyme Inhibitors
  • Nootropic Agents
  • pregnenolone sulfate
  • Nitric Oxide
  • Dehydroepiandrosterone Sulfate
  • Dizocilpine Maleate
  • Pregnenolone
  • Nitric Oxide Synthase
  • NG-Nitroarginine Methyl Ester