Differential sensitivity to acute administration of Ritalin, apormorphine, SCH 23390, but not raclopride in mice selectively bred for hyperactive wheel-running behavior

Rationale: Previous studies of mice (Mus domesticus) selectively bred for high voluntary wheel running have suggested that the hyperactivity is associated with dysfunction in the dopaminergic neuromodulatory system and that high-running mice may represent a useful genetic model for attention deficit hyperactivity disorder (ADHD). Objectives: We tested the hypothesis that mice from the four replicate hyperactive lines would respond differently to methylphenidate (Ritalin), apomorphine (non-selective dopamine agonist), SCH 23390 (selective D1-like dopamine antagonist), and raclopride (selective D2-like dopamine antagonist) than individuals from the four replicate, randomly bred, control lines. Methods: After animals were habituated (3 weeks) to their cages with attached wheels, drugs were administered via intraperitoneal injections, at night, during peak wheel-running activity. Revolutions on wheels 10-70 min post-injection were used to quantify drug responses. Results: Ritalin (15 mg/kg and 30 mg/kg) increased wheel running in control lines but decreased running in selected lines. A low-dose (0.125 mg/kg) of apomorphine reduced wheel running by a similar amount in control and selected lines; however, higher doses of apomorphine (0.25 mg/kg and 0.5 mg/kg) produced greater reductions in wheel running in the control lines. SCH 23390 (0.025, 0.05, and 0.1 mg/kg) caused greater reductions in wheel running in control than in selected lines. Raclopride (0.5, 1, and 2 mg/kg) reduced wheel running by a similar amount in control and selected lines. Conclusions: These results support the interpretation that genetically determined hyperactive wheel-running behavior is associated with altered dopaminergic function in this mouse model. More specifically, results suggest that D1-like (D1 or D5), but not D2-like (D2, D3, or D4), dopamine receptors have reduced function in the high-running mice. The fact that Ritalin decreased wheel running in selected lines further supports their use as an animal model of ADHD.