Opposite effects of amphetamine on impulsive action with fixed and variable delays to respond

Impulsive action, the failure to withhold an inappropriate response, is treated clinically with dopamine agonists such as amphetamine. Despite the therapeutic efficacy, these drugs have inconsistent effects on impulsive action in rodents, causing improvements or disruptions in different tasks. Thus, we hypothesized that amphetamine is producing an effect by altering distinct cognitive processes in each task. To test this idea, we used the response inhibition (RI) task and trained rats to withhold responding for sucrose until a signal is presented. We then varied the duration that subjects were required to inhibit responding (short=4 s; long=60 s; or variable=1-60 s) and examined whether this influenced the pattern of premature responses. We also tested the effects of amphetamine (0.0, 0.125, 0.25, 0.5, and 1.0 mg/kg) on each task variant. The probability of premature responding varied across the premature interval with a unique pattern of time-dependent errors emerging in each condition. Amphetamine also had distinct effects on each version: the drug promoted premature responding when subjects expected a consistent delay, regardless of its duration, but reduced premature responding when the delay was unpredictable. We propose that the ability to inhibit a motor response is controlled by a different combination of cognitive processes in the three task conditions. These include timing, conditioned avoidance, and attention, which then interact with amphetamine to increase or decrease impulsive action. The effect of amphetamine on impulsive action, therefore, is not universal, but depends on the subject's experience and expectation of the task demands.