Effect of the neuronal nitric oxide synthase inhibitor 7-nitroindazole on methylphenidate-induced hyperlocomotion in mice.

Abstract

The psychostimulant methylphenidate (MPD) is used for the treatment of attention-deficit/hyperactivity disorders (ADHD) in adolescents. In the present study we investigated the effect of repeated administration of a low (10 mg/kg) and a high (40 mg/kg) dose of MPD on the locomotor activity of Swiss Webster mice, and the influence of inhibition of the neuronal nitric oxide synthase (nNOS) on MPD-induced hyperlocomotion. In the first experiment, mice were administered either vehicle or the nNOS inhibitor 7-nitroindazole (7-NI; 25 mg/kg), prior to the administration of MPD (10 or 40 mg/kg), for five consecutive days; injections were paired with the test cage ('novel environment') on days 1 and 5. A challenge injection of MPD (10 or 40 mg/kg), given after a 10-day drug-free period, resulted in sensitization to the motor stimulating effect of the low dose of MPD but tolerance to the high dose of MPD. 7-NI blocked the induction of sensitization but had no effect on the development of tolerance. The place-dependent-hyperlocomotion (e.g. conditioning) that developed after the administration of either the low or high dose of MPD was blocked by pretreatment with the nNOS inhibitor. In the second experiment, mice were administered MPD (10 or 40 mg/kg; 5 days) in their home cage and after a 10-day drug-free period were challenged with either vehicle/MPD or 7-NI/MPD. The low dose of MPD elicited a sensitized response that was blocked by the co-administration of 7-NI. The high dose of MPD produced neither sensitization nor tolerance; 7-NI did not affect the response to the high dose of MPD. These findings suggest: (a) MPD-induced sensitization and tolerance are dependent on the dose of the drug and the environment where the drug is delivered (home cage versus test cage); (b) context-dependent hyperlocomotion developed in the absence of a sensitized response to the drug; (c) nNOS is involved in the induction and expression of sensitization to MPD as well as in the conditioned locomotion produced by the drug; (d) no involvement of nNOS in the effects of a high dose of MPD was detected.