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

Abstract

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.

The L‐arginine‐NO‐cGMP pathway mediates the locomotor activity alterations during the expression of sensitization to mephedrone in mice

“…We can assume that in the paradigm applied in our experiment the L‐arginine‐NO‐cGMP‐dependent pathway plays an important role in the expression of sensitization to mephedrone‐induced responses. In our previous studies, we demonstrated that the tested substances affecting the L‐arginine‐NO‐cGMP‐dependent pathway do not influence the spontaneous locomotor activity of male albino Swiss mice when given alone at the doses used in the current experiment 59–62 . Therefore, the observed effects could not have been noted because of disturbed locomotor activity of mice exerted by the tested agents.…”

“…In our previous studies, we demonstrated that the tested substances affecting the L-arginine-NO-cGMP-dependent pathway do not influence the spontaneous locomotor activity of male albino Swiss mice when given alone at the doses used in the current experiment. [59][60][61][62] Therefore, the observed effects could not have been noted because of disturbed locomotor activity of mice exerted by the tested agents. Similarly to the outcomes of our study, 7-nitroindazole blocked the expression of psychomotor sensitization produced by methamphetamine, 36 3,4-methylenedioxymethamphetamine, 33 methylphenidate 37 and cocaine, 38 whereas L-NAME inhibited the expression of sensitization produced by amphetamine 35 and morphine.…”

“…Mice from the control group received only saline. All doses and pretreatment schedules were selected on the basis of outcomes of previous experiments performed in our lab 24,59,61,62 …”

“…To check whether the L-arginine-NO-cGMP-dependent pathway previous experiments performed in our lab. 24,59,61,62 Locomotor activity of animals was measured in actimeter cages (Multiserv). On the 1st, 5th and 20th day of the experiment, just after the mephedrone or saline injection, a given mouse was placed individually into the cage and its locomotion was measured for 10, 30 and 60 min.…”

The role of the L-arginine-NO-cGMP pathway in the development of tolerance to mephedrone-induced hyperlocomotion in mice

“…NO is an important messenger molecule in the brain since it takes part in the regulation of neuronal excitability, synaptic plasticity, learning, emotions, seizure activity, drug tolerance, and many other brain processes [30,31]. Previously, our research team demonstrated that this NO-dependent signalling is implicated in the development of tolerance to diazepam [32] and flunitrazepam [33], whereas Mansouri et al [34] and Ozdemir et al [35], confirmed its role in morphine tolerance. NO is synthesized from L-arginine by NO synthase (NOS).…”