Putative anxiety-linked effects of the nitric oxide synthase inhibitor l-NAME in three murine exploratory behavior models

Abstract

The aim of the current study was to extend investigation into possible linkage between nitric oxide (NO) and anxiety-linked behavior using a battery of tests. Effects of the NO synthase (NOS) inhibitor N G-nitro- l-arginine methyl ester ( l-NAME) were investigated in three murine models of anxiety—the light–dark, hole-board and elevated plus-maze—in between-groups designs. Treatment groups included l-NAME (0 [vehicle, or Veh], 10, 25, and 50 mg/kg) and 50 mg/kg of the inactive isomer N G-nitro- d-arginine methyl ester ( d-NAME) injected subcutaneously. Mice exhibited a robust anxiogenic-like response profile reflected by dose-related decreases in both light–dark (transitions and time in lighted area) and hole-board (head dips and time spent head dipping) test measures, reaching statistical significance at 25 and 50 mg/kg l-NAME when compared to Veh controls ( P<.05 or .01; Dunnett's t test), while distance traveled and rearing showed no significant differential pattern in either model. In both models, there was a strong dissociation between nonspecific locomotion and putative exploratory behaviors. d-NAME was not significantly different from Veh condition in either model, indicating a stereospecific action and supporting NO involvement. A dose-related decrease was also observed for several traditional and ethological measures in the plus-maze; however, the effect was limited and relatively weak or absent; with the exception of open-arm and percent open-arm entries, putative anxiety-sensitive measures reached statistical significance only at the highest dose. Reductions in motor activity compromised ability to dissociate an anxiety linkage from a nonspecific motor effect in most measures. It is concluded that the hole-board and light–dark tests provide indication of anxiogenic-like action of NOS inhibition, suggesting that NO has an anxiolytic action. Data from the plus-maze are unclear, owing to a confounding motor influence in most measures.