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Effect of the neuronal nitric oxide synthase inhibitor 7-nitroindazole on methylphenidate-induced hyperlocomotion in
1Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, FL 33136, USA. yitzhak@med.miami.edu
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.
Insights
Methylphenidate (MPD) effects on mouse activity depend on dose and environment. Neuronal nitric oxide synthase (nNOS) inhibition impacts MPD-induced sensitization and context-dependent locomotion.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Methylphenidate (MPD) is a psychostimulant used to treat attention-deficit/hyperactivity disorders (ADHD).
- Understanding MPD's effects on locomotor activity and the role of neuronal nitric oxide synthase (nNOS) is crucial for optimizing ADHD treatment.
Purpose of the Study:
- To investigate the impact of repeated methylphenidate (MPD) administration on locomotor activity in mice.
- To examine the influence of neuronal nitric oxide synthase (nNOS) inhibition on MPD-induced hyperlocomotion and associated behavioral changes.
Main Methods:
- Mice received repeated low (10 mg/kg) or high (40 mg/kg) doses of MPD.
- The nNOS inhibitor 7-nitroindazole (7-NI) was administered before MPD in different environmental contexts (test cage vs. home cage).
- Locomotor activity was assessed after a drug-free period to evaluate sensitization, tolerance, and context-dependent effects.
Main Results:
- Low-dose MPD induced sensitization, while high-dose MPD induced tolerance, with effects varying by administration environment.
- 7-NI blocked MPD-induced sensitization and context-dependent hyperlocomotion but did not affect tolerance to the high dose.
- Context-dependent hyperlocomotion occurred independently of sensitization to MPD.
Conclusions:
- MPD-induced sensitization and tolerance are dose- and environment-dependent.
- nNOS plays a significant role in MPD sensitization and conditioned locomotion.
- nNOS is not involved in the effects of high-dose MPD on locomotor activity.
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