Dopaminergic modulation of manipulation processes in human working memory – critical involvement of D2 receptors and the ventral striatum

Abstract

The aim of this study was to further investigate the dopaminergic modulation of manipulation processes in human working memory using sulpiride (SUL), a dopamine D2 receptor antagonist, and methylphenidate (MPH), a dopamine enhancing psychostimulant, in combination with functional magnetic resonance imaging (fMRI). 20 healthy volunteers (age 19–33 years) were tested on four occasions using a 2×2 factorial design with randomised, double-blind and double-dummy administration of SUL 400mg, MPH 60mg, SUL 400mg plus MPH 60mg or placebo. Working memory testing included an event-related fMRI experiment. Significant SUL x MPH (x manipulation) interactions were observed for the letter-sequence manipulation (Lewis et al. 2003) and digit ordering task. Manipulation processes but not 'maintenance only' control conditions were consistently impaired by SUL and this impairment could be reversed by MPH. MPH alone had no effects on most performance parameters, possibly due to ceiling effects in high performing volunteers. MPH significantly attenuated working memory specific brain activity in the ventral striatum and this effect correlated with MPH plasma levels. SUL effects on working memory could not be localised in this study. Manipulation processes in human working memory are impaired by D2 receptor blockade and reversed by dopamine enhancement in the ventral striatum. This has important implications for the treatment of cognitive deficits in patients with schizophrenia and ADHD.