The D1 receptor agonist SKF38393 improves waiting impulsivity in a baseline dependent manner

Abstract

AbstractRationaleStimulants are the first-line treatment for attention-deficit/hyperactivity disorder (ADHD). However, the ensuing risk of abuse with stimulants means there is an urgent need for new, low-risk therapeutic agents. D1 receptors play an important role in the cognitive enhancing effects of stimulants and thus may provide a therapeutic target. Previous pre-clinical studies have shown that selective activation of D1 receptors improves sustained attention in the 5C-CPT without improving waiting impulsivity (premature response).ObjectiveThe aim of the present experiment was to compare the effects of the selective D1 receptor agonist SKF 38393 to a standard ADHD treatment (amphetamine) on waiting impulsivity in the 5C-CPT under extended inter-trial intervals. Oldham’s method was used to determine the presence of a rate-dependent effect.MethodsAdult female Lister hooded rats were trained to criterion in the 5C-CPT (>70% accuracy, < 30% omission and < 40% false alarms). Effects of the selective D1 receptor agonist SKF 38393 (2-6 mg/kg) or amphetamine (0.1-0.4 mg/kg) were investigated under behavioural manipulations to challenge inhibitory response control.ResultsThe highest dose of SKF 38393 and the two highest doses of amphetamine improved waiting impulsivity in a baseline dependent manner. 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.ConclusionsThese findings support further clinical investigation of D1 receptor modulators to facilitate the discovery of improved medications for impulsive behaviour related disorders such as ADHD. The concept of rate dependency applies to effects of SKF 38393 or amphetamine on waiting impulsivity. Oldham’s correlation method may present an opportunity to enhance the translational value of research in the preclinical laboratory to the clinic.