Abstract
RationaleWorking 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 D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory.ObjectivesWe probed the implications of the partial D2 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 D2/5-HT2A blocker risperidone to separate aripiprazole’s unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone.MethodA 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.ResultsCompared 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.ConclusionAripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone’s serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4234-9) contains supplementary material, which is available to authorized users.
Highlights
Aim and rationaleElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.The aim of this study was to investigate the implications of the partial dopamine D2 receptor agonist properties of aripiprazole for the neural basis of working memory in healthy volunteers
In contrast to aripiprazole’s neural effects, the risperidone group demonstrated a trend for reduced dorsolateral prefrontal cortex (DLPFC) recruitment
Aripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action
Summary
The aim of this study was to investigate the implications of the partial dopamine D2 receptor agonist properties of aripiprazole for the neural basis of working memory in healthy volunteers. Impaired working memory is a core feature of schizophrenia which is not ameliorated by conventional antipsychotic drugs (Forbes et al 2009). Psychopharmacology (2016) 233:1415–1426 restore D2 neurotransmission to a low optimal level in prefrontal cortex in schizophrenia (Bolonna and Kerwin 2005). This would preserve or enhance working memory while antipsychotic effects are achieved by preventing overstimulation of D2 receptors in striatum. We investigated the effects of aripiprazole on the performance of a working memory task and its neural correlates using functional magnetic resonance imaging (fMRI). We compared the effects of aripiprazole with those of risperidone since both drugs have high affinity for the D2 receptor combined with serotonergic effects risperidone lacks the intrinsic D2 agonist activity of aripiprazole
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