The dopamine inhibitor GBR12909 improves attention and compulsive behaviour in female rats

Stimulants such as methylphenidate are the first-line treatment for attention deficit hyperactivity disorder. A principal mechanism of action for these drugs is to reduce dopamine reuptake in the striatum. However, the ensuing risk of abuse with such stimulants means there is an urgent need for new, low-risk therapeutic agents. GBR12909 is a highly selective dopamine reuptake inhibitor, making it an important experimental tool. Indeed, this drug completed Phase II clinical trials for treatment of cocaine abuse. Researching the behavioural pharmacology of such drugs has the potential to expand our understanding of the striatal dopamine contribution to impulsivity, attention and compulsive behaviour and will help the development of novel targeted treatments for attention deficit hyperactivity disorder without an abuse risk. The aim of this work was to examine the role of low doses of GBR12909 on attention, impulsivity and compulsive behaviour as measured by the five-choice continuous performance task. Oldham's method was used to determine the presence of a treatment rate-dependent effect. Female Lister hooded rats were trained to criterion in the five-choice continuous performance task (>70% accuracy, <30% omission and <40% false alarms). The effects of GBR12909 (dose range 0.25-1.0 mg/kg) were investigated on attention, impulsivity and compulsive behaviour under challenging task conditions. The two lowest doses of GBR12909 improved selective attention in a rate-dependent manner while the highest dose of GBR 12909 showed a tendency toward improving compulsive behaviour in a baseline-dependent manner. However, GBR 12909 impaired waiting impulsivity in a baseline-dependent manner. GBR12909 has a clearly beneficial effect on attention and compulsive behaviour in the female rat. This study supports a contribution of the dopaminergic system in modulating five-choice continuous performance task performance measures. It provides evidence for the role of a selective dopamine reuptake inhibitor in modulating selective attention and inhibitory response control in the five-choice continuous performance task. Understanding the contribution of DAT to waiting impulsivity, selective attention and compulsive behaviour may help the development of selective therapeutic agents. Although group performance revealed no significant change in selective attention and compulsive behaviour, Oldham's method revealed a latent relationship between baseline compulsivity or accuracy and magnitude of improvement following selective activation of dopaminergic system. It is clear from these results that the effectiveness of GBR 12909 in improving selective attention and compulsive behaviour is dependent on dopaminergic system baseline activity. In this study, Oldham method revealed a relationship that would have otherwise gone unnoticed. The clockwise movement of the regression line indicates that, as the dose increases, the magnitude of improvement increases in a manner consistent with baseline performance. These findings support further clinical investigation of GBR-type dopamine uptake blockers or GBR analogues to facilitate the discovery of medications for inattentive subtype of attention deficit hyperactivity disorder, stimulant abuse, compulsive drug seeking behaviour and obsessive-compulsive disorder. The concept of rate dependency applies to effects of GBR 12909 on waiting impulsivity, selective attention and compulsive behaviour. Oldham's correlation method may present an opportunity to enhance the translational value of research in the preclinical laboratory to the clinic. This is the first study to take advantage of the variation in individual baseline performance to demonstrate the presence of a rate-dependent relationship between baseline performance and the magnitude of change following indirect activation of dopaminergic system. Adopting a correlative analysis (e.g., Oldham's method) may be particularly effective in revealing drug effects on behaviour and improve our understanding of the neurochemical basis of selective attention, waiting impulsivity and compulsive behaviour as measured by five-choice continuous performance task. Future work can expand the current study, for example, five-choice continuous performance task has been reverse translated to human, enabling selective attention and compulsive behaviour to be studied in both patients and rodents