The role of the L-arginine-NO-cGMP-dependent pathway in the development of sensitization to mephedrone effects on the locomotor activity in mice

Mephedrone, a popular psychostimulating substance widely used illegally in recreational purposes, exerts in rodents that regularly and intermittently were exposed to it a sensitized response to the drug. Behavioral sensitization is one of experimental models of drug dependency/abuse liability. In the present study we evaluated a potential involvement of the L-arginine-NO-cGMP pathway in the development of sensitization to the mephedrone-induced hyperlocomotion. Locomotor activity was measured automatically and experiments were performed on male Albino Swiss mice. We demonstrated that a 5-day administration of 7-nitroindazole (10 or 20 mg/kg/day) and L-NAME (50 mg/kg/day) suppressed the development of sensitization to the mephedrone-induced hyperlocomotion. As for L-arginine (125 or 250 mg/kg/day) and methylene blue (5 or 10 mg/kg/day) the obtained outcomes are inconclusive. Furthermore, the lower dose of L-NAME (25 mg/kg/day) surprisingly potentiated the development of sensitization to the mephedrone-induced effects on the spontaneous locomotor activity in mice. In conclusion, our data demonstrated that modulators of the L-arginine-NO-cGMP pathway may differently affect the development of sensitization to the locomotor stimulant effects of mephedrone. Inhibition of neuronal nitric oxide synthase (NOS) seems to prevent this process quite profoundly, non-selective inhibition of NOS may have a dual effect, whereas inhibition of soluble guanylate cyclase may only partially suppress the development of sensitization to the mephedrone-induced effects.