NMDA Receptors and NO:cGMP Signaling Pathway Mediate the Diazepam-Induced Sensitization to Withdrawal Signs in Mice

Abstract

The goal of the present study was to examine the effects of N-methyl—aspartate (NMDA) receptor antagonists—memantine and ketamine and the drugs modifying the NO:cGMP pathway—NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), the endogenous precursor of NO-L-arginine, and the guanylyl cyclase inhibitor—methylene blue (MB) on the development of sensitization to withdrawal signs precipitated after chronic, interrupted treatment with diazepam, a benzodiazepine receptor agonist, in mice. To develop the sensitization, the mice were divided into groups: continuously and sporadically (with two diazepam-free periods) treated with diazepam (15 mg/kg, sc). To precipitate the withdrawal syndrome (clonic and tonic seizures, and death), pentylenetetrazole (55 mg/kg, sc) with the benzodiazepine receptor antagonist, flumazenil (5.0 mg/kg, ip), were administered after the last injection of diazepam or saline. Memantine (2.5, 5.0 mg/kg), and ketamine (2.5, 5.0 mg/kg), L-NAME (100, 200 mg/kg) and 7-NI (20 and 40 mg/kg), L-arginine (250, 500 mg/kg) and MB (5 and 10 mg/kg) were administered ip in sporadically diazepam-treated mice during the diazepam-free periods. Our results indicated that both NMDA receptor antagonists and drugs that inhibit the NO:cGMP pathway, except L-arginine (the endogenous donor of NO), attenuated the diazepam-induced sensitization to withdrawal signs in mice. Thus, NMDA receptors and the NO:cGMP pathway are involved in the mechanisms of sensitization to benzodiazepine withdrawal.

NMDA receptors and L-arginine/nitric oxide/cyclic guanosine monophosphate pathway contribute to the antidepressant-like effect of Yueju pill in mice

“…Clinical widely used medicines such as fluoxetine, imipramine [44], and venlafaxine [35] were also reported to enhance the antidepressant-like effect with 7-NI. Our results demonstrated that ineffective YJ could decrease the immobility time in mice with 7-nitroindazole and MB treatment, which was consistent with other researches [52–54].…”

Influence of Diazepino[1,2-a]benzimidazole derivative (DAB-19) on behavioral aspects of animals

“…Among the most effective classic tranquilizers -derivatives of benzodiazepine used in the treatment of anxiety pathologies, diazepam stands out. However, it has side effects on the behavioral component -fatigue and lack of emotions or, on the contrary, acute agitation, anxiety, hallucinations and fits of rage (Talarek et al 2018). The group of "daytime" sedatives has milder unwanted actions, but even their use can result in increased irritability, psychomotor agitation, confusion (tofisopam), sedation, drowsiness, fatigue and a slow-down in reactivity (medazepam).…”

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

“…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.…”

“…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.…”