An investigation into aripiprazole’s partial D(2) agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers

RATIONALE: Working memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D(2) receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D(2) receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory. OBJECTIVES: We probed the implications of the partial D(2) receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole’s prefrontal actions were compared with the D(2)/5-HT(2A) blocker risperidone to separate aripiprazole’s unique prefrontal D(2) agonist actions from its serotinergic and striatal D(2) actions that it shares with risperidone. METHOD: A double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning. RESULTS: Compared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d’) and speeded reaction times. In contrast to aripiprazole’s neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d’ and additionally had reduced errors of commission compared with placebo. CONCLUSION: Aripiprazole has unique DLPFC actions attributed to its prefrontal D(2) agonist action. Risperidone’s serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D(2) blockade. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00213-016-4234-9) contains supplementary material, which is available to authorized users.