The Importance of L-Arginine:NO:cGMP Pathway in Tolerance to Flunitrazepam in Mice.

The goal of the study was to investigate the effects of drugs modifying L-arginine:NO:cGMP pathway on the development of tolerance to flunitrazepam (FNZ)-induced motor impairment in mice. FNZ-induced motor incoordination was assessed on the 1st and 8th days of experiment, using the rotarod and chimney tests. It was found that (a) both a non-selective nitric oxide synthase (NOS) inhibitor: N ^G -nitro-L-arginine methyl ester (L-NAME) and an unselective neuronal NOS inhibitor: 7-nitroindazole (7-NI) inhibited the development of tolerance to the motor-impairing effects of FNZ in the rotarod and the chimney tests and (b) both a NO precursor: L-arginine and a selective inhibitor of phosphodiesterase 5 (PDE5): sildenafil did not affect the development of tolerance to FNZ-induced motor impairment in mice. Those findings provided behavioural evidence that NO could contribute an important role in the development of tolerance to FNZ in mice.
Competing Interests: Compliance with Ethical Standards All experiments were conducted according to the National Institute of Health Guidelines for the Care and Use of Laboratory Animals (8th edition) and to the European Community Council Directive for the Care and Use of Laboratory Animals of 22 September 2010 (2010/63/EU) and were approved by the local ethics committee.