Differential Sensitivity to Acute Administration of Cocaine, GBR 12909, and Fluoxetine in Mice Selectively Bred for Hyperactive Wheel-running Behavior

Rationale: To study the neural basis of genetic hyperactivity, we measured acute drug responses of mice (Mus domesticus) from four replicate lines that had been selectively bred (23-24 generations) for increased running-wheel activity.

Objectives: We tested the hypothesis that the high-running lines would respond differently to cocaine, GBR 12909, and fluoxetine (Prozac) compared with four replicate, random-bred, control lines. We also tested the hypothesis that the high-running lines would display hyperactivity in cages without wheels.

Methods: Drug trials were conducted at night, during peak activity, after animals were habituated (3 weeks) to their cages with attached wheels. Revolutions on wheels 10-40 min post-injection were used to quantify drug responses. In a separate study, total photobeam breaks (produced on the first and second 24-h period of exposure) were used to quantify basal activity in animals deprived of wheels.

Results: Cocaine and GBR 12909 decreased wheel running in selected lines by reducing the average speed but not the duration of running, but these drugs had little effect in control lines. Fluoxetine reduced running speed and duration in both selected and control animals, and the magnitude of the reduction was proportional to baseline activity. Basal activity in animals deprived of wheels (quantified using photobeam breaks) was significantly higher in selected than control lines on the second day of testing.

Conclusions: These results suggest an association between genetically determined hyperactive wheel-running behavior and dysfunction in the dopaminergic neuromodulatory system. Our selected lines may prove to be a useful genetic model for attention deficit hyperactivity disorder.