Mephedrone is a cathinone derivative that possesses powerful psychostimulant and hallucinogenic effects. It has been speculated that mephedrone may act by increasing release and reuptake inhibition of serotonine and dopamine. However, the precise mechanisms underlying its psychomimetic action remain unclear. Nitric oxide (NO), synthesized from L-arginine by a reaction catalyzed by NO synthase, is involved in different central function and can participate in the mechanisms of drug tolerance and dependence. NO acts as an activator of soluble guanylyl cyclase (sGC) and thereby increases the level of an intracellular second messenger, cGMP. The purpose of the present study was to determine the role of NO in the development of tolerance to mephedrone. Tolerance to hyperlocomotor activity was induced by chronic administration of mephedrone (5 mg/kg ip, 6 days) in male albino Swiss mice. The following drugs were used to modify the NO:cGMP pathway: NG-nitro-L-arginine methyl ester (L-NAME; 25, 50 mg/kg, ip) – NO synthase inhibitor and methylene blue (5, 10 mg/kg ip) – sGC inhibitor. Locomotor activity was measured for 10 and 30 min, 20 min after administration of drugs. The present experiments demonstrated that chronic coadministration of L-NAME and methylene blue with mephedrone attenuates the development of tolerance to mephedrone. These findings suggest that NO:sGC pathway may be involved in the tolerance to mephedrone in mice.
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