Blockade of noradrenaline re-uptake sites improves accuracy and impulse control in rats performing a five-choice serial reaction time tasks

Abstract

Atomoxetine, reboxetine and methylphenidate all act at the noradrenaline transporter (NAT) and atomoxetine and methylphenidate are licensed for the treatment of ADHD. The five-choice serial reaction time task (5CSRTT) provides a valid model to study attention and impulsivity in rodents. Studies using this task have largely failed to demonstrate improvements in attention with atomoxetine and methylphenidate and reboxetine has not been investigated previously. The present study used modifications to the standard rat 5CSRTT and demonstrated that blockade of NAT improves attention and reduces premature responding. Rats were trained in a fixed inter-trial interval (ITI), 5CSRTT then tested at baseline and under conditions to acutely challenge attention and/or impulse control following vehicle or atomoxetine (0.3 mg/kg, i.p.). Atomoxetine (0.3 mg/kg, i.p.) significantly improved impulse control under all conditions (p < 0.05) but had no significant effects on accuracy. To increase the attentional demands of the task, rats were re-baselined in a non-paced, variable ITI task where presentations of the stimuli were unpredictable. In the VITI task, atomoxetine (0.0-0.3 mg/kg, i.p.) induced a dose-dependent improvement in accuracy (p < 0.05) and reduction in premature responses (p < 0.05). Reboxetine (0.0-1.0 mg/kg, i.p.) and methylphenidate (1-10 mg/kg, p.o.) did not significantly improve accuracy in the whole population but median split analysis revealed a significant improvement with both drugs, as well as atomoxetine, in the poor performing animals (p < 0.05). These data suggest that blockade of noradrenaline re-uptake sites is an important target in terms of enhancing both attention and impulse control.