Repeated intermittent oral amphetamine administration results in locomotor tolerance not sensitization

The phenomenon of locomotor sensitization to injected amphetamine is well-characterised. The increased locomotor activity found acutely is enhanced with repeated intermittent treatment. This effect arises due to hypersensitization of the dopaminergic system and is linked to drug addiction. A clinical population exposed to chronic repeated intermittent amphetamine treatment, such as is found for attention deficit hyperactivity disorder (ADHD), may be expected to be more at risk of addiction following this treatment. However, evidence suggests the opposite may be true. This suggests the route of administration may determine the direction of effects.

We aimed to establish how an oral amphetamine treatment regimen, similar to that used in ADHD, impacts on locomotor activity, specifically whether tolerance or sensitization would arise. Healthy hooded Lister rats were given amphetamine (2 mg/kg, 5 mg/kg and 10 mg/kg) or a vehicle solution once daily for 4 weeks with a 5 day on, 2 day off schedule. Locomotor activity was measured on the first day of treatment to establish the acute effects and on the final day of treatment to examine the chronic effects.

As expected, acute doses of amphetamine increased locomotor activity, although this only reached statistical significance for the 5 mg/kg and 10 mg/kg doses. By contrast, after chronic treatment, animals administered these doses showed reduced activity indicating drug tolerance rather than sensitization had occurred.

We suggest that the route of administration used in ADHD, which results in more stable and longer duration drug levels in the blood, results in tolerance rather than sensitization and that this effect could explain the reduced likelihood of substance addiction in those treated with psychostimulants for ADHD.