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


OBJECTIVE
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.
Rhodes
J S
JS
Department of Zoology, University of Wisconsin, Madison 53706, USA. rhodesju@ohsu.edu
Garland
T
T
D000818:Animals; D021461:Animals, Outbred Strains; D001058:Apomorphine / Q000494:pharmacology / Q000627:therapeutic use; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use; D001947:Breeding / Q000379:methods; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000145:classification / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006948:Hyperkinesis / Q000188:drug therapy; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D020891:Raclopride / Q000494:pharmacology / Q000627:therapeutic use; D012641:Selection, Genetic; D013045:Species Specificity; D013997:Time Factors
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D008774:Methylphenidate; D020891:Raclopride; D001058:Apomorphine