Anxiolytic effects induced by inhibition of the nitric oxide-cGMP pathway in the rat dorsal hippocampus

Psychopharmacology (Berl). 2007 Dec;195(2):183-92. doi: 10.1007/s00213-007-0890-0. Epub 2007 Jul 28.


Rationale: Conflicting results have been reported regarding the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the hippocampus on anxiety modulation.

Objectives: To investigate the effects of intrahippocampal injections of drugs that modify the NO-cGMP pathway in rats submitted to two animal models that are sensitive to anxiolytic drugs, the elevated plus-maze and the Vogel punished licking test.

Materials and methods: Male Wistar rats with cannulae aimed at the dentate gyrus of the dorsal hippocampus received microinjections of the NO synthase (NOS) inhibitors N (G)-nitro-L: -arginine methyl ester (LNAME, 15-300 nmol/0.2 microl), N (G)-nitro-L: -arginine (LNOARG, 50-300 nmol/0.2 microl), 7-nitroindazole (7NI, 10-100 nmol/0.2 microl), or the soluble guanylate cyclase inhibitor 1H-oxadiazolo-quinoxalin-1 one (ODQ, 10-100 nmol/0.2 microl), and were submitted to the elevated plus-maze. In a second group, the animals received 7NI, LNAME, or ODQ and were submitted to the Vogel punished licking test. To control for drug-induced changes in locomotor behavior, the animals were submitted to an open arena or to the Rota-rod test.

Results: All drugs increased the exploration of the open arms of the elevated plus-maze. They also increased the number of punished licks in the Vogel test, indicating an anxiolytic effect. The anxiolytic effect of LNAME was prevented by previous treatment with L: -arginine (300 nmol/0.2 microl). Except for the lower dose of LNAME (15 nmol), administration of the NOS inhibitors or ODQ did not change exploratory activity in the open field nor cause any gross locomotor impairment in the Rota-rod test.

Conclusion: The results suggest that NO plays an anxiogenic role in the dentate gyrus of the dorsal hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anxiety / physiopathology*
  • Anxiety / psychology
  • Cyclic GMP / antagonists & inhibitors*
  • Cyclic GMP / physiology
  • Dentate Gyrus
  • Dose-Response Relationship, Drug
  • Guanylate Cyclase / antagonists & inhibitors
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology*
  • Indazoles / pharmacology
  • Male
  • Maze Learning / drug effects
  • Microinjections
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / antagonists & inhibitors*
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitroarginine / pharmacology
  • Oxadiazoles / pharmacology
  • Punishment
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Soluble Guanylyl Cyclase


  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • Indazoles
  • Oxadiazoles
  • Quinoxalines
  • Receptors, Cytoplasmic and Nuclear
  • Nitroarginine
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • Cyclic GMP
  • 7-nitroindazole
  • NG-Nitroarginine Methyl Ester