Characterization of methylphenidate self-administration and reinstatement in the rat

Rationale Methylphenidate, which is used to treat attention deficit/hyperactivity disorder, increases extracellular dopamine by inhibiting the dopamine transporter. Methylphenidate has an abuse potential, and there are increasing reports of recreational use of methylphenidate. Little work has examined methylphenidate self-administration in rodent models. Objectives This work characterized intravenous methylphenidate self-administration in rats, determined whether dopamine mediates its reinforcing effects and examined the influence of route of administration on the ability of methylphenidate to reinstate extinguished drug-seeking behaviour. Materials and methods Rats were trained to self-administer methylphenidate ( 0.25 mg per infusion) via an intravenous catheter according to a fixed ratio 1 (FR1) or progressive ratio ( PR) schedule. The effects of manipulating the dose of methylphenidate and of treatment with the dopamine D1 receptor antagonist SCH23390 or the dopamine D2 receptor antagonist eticlopride ( both at 0.01 and 0.03 mg/kg) were examined. Finally, the ability of noncontingent administrations of methylphenidate ( intraperitoneal [IP] or gavage) to reinstate extinguished drug-seeking behaviour was examined. Results Rats readily self-administered methylphenidate dose dependently on FR1 and PR schedules. Treatment with SCH23390 or eticlopride increased the number methylphenidate infusions taken by rats on the FR1 schedule and reduced breaking points on the PR schedule. Following extinction of drug-seeking behaviour, methylphenidate reinstated responding and was more effective at doing so when administered IP. Conclusion These results demonstrate that intravenous methylphenidate is a reinforcer and that its reinforcing efficacy is related to increased dopamine activity at D1 and D2 receptors. Methylphenidate reinstates drug-seeking behaviour; the route of administration modifies this response suggesting that pharmacokinetic factors are important in determining methylphenidate-induced reinstatement.