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

Abstract

AbstractMephedrone is a representative of synthetic cathinones that is known from its rewarding and psychostimulant effects. It exerts behavioural sensitization after repeated and then interrupted administration. In our study, we investigated a role of the L‐arginine‐NO‐cGMP‐dependent signalling in the expression of sensitization to hyperlocomotion evoked by mephedrone. The study was carried out in male albino Swiss mice. The tested mice received mephedrone (2.5 mg/kg) for 5 consecutive days and on the 20th day of the experiment (the ‘challenge’ day) animals received both mephedrone (2.5 mg/kg) and a given substance that affects the L‐arginine‐NO‐cGMP signalling, that is, L‐arginine hydrochloride (125 or 250 mg/kg), 7‐nitroindazole (10 or 20 mg/kg), L‐NAME (25 or 50 mg/kg) or methylene blue (5 or 10 mg/kg). We observed that 7‐nitroindazole, L‐NAME and methylene blue inhibited the expression of sensitization to the mephedrone‐induced hyperlocomotion. Moreover, we demonstrated that the mephedrone‐induced sensitization is accompanied by lowered levels of D1 receptors and NR2B subunits in the hippocampus, whereas a concurrent administration of L‐arginine hydrochloride, 7‐nitroindazole and L‐NAME with the mephedrone challenge dose reversed these effects. Methylene blue only reversed the mephedrone‐induced effects on hippocampal levels of the NR2B subunit. Our study confirms that the L‐arginine‐NO‐cGMP pathway contributes to mechanisms underlying the expression of sensitization to the mephedrone‐evoked hyperlocomotion.