title: An investigation into aripiprazole's partial D₂ agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers.
abstract: BACKGROUND
  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 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.
  
  
  OBJECTIVE
  We 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Aripiprazole 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.
authors.affiliation: Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, University of Manchester, G.708 Stopford Building, Manchester, M13 9PT, UK. anna.murphy@manchester.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Murphy
authors.affiliation: Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Serdar
authors.initials: S
authors.lastname: Dursun
authors.affiliation: Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, University of Manchester, G.708 Stopford Building, Manchester, M13 9PT, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McKie
authors.affiliation: Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, University of Manchester, G.708 Stopford Building, Manchester, M13 9PT, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elliott
authors.affiliation: Neuroscience and Psychiatry Unit, Institute of Brain, Behaviour and Mental Health, University of Manchester, G.708 Stopford Building, Manchester, M13 9PT, UK.
authors.forename: John Francis William
authors.initials: JF
authors.lastname: Deakin
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology; D000068180:Aripiprazole / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D018967:Risperidone / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; C581293:DRD2 protein, human; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole; D018967:Risperidone; D004298:Dopamine
keywords: Antipsychotic; Aripiprazole; D2; Dopamine; Dorsolateral prefrontal; Partial agonism; Risperidone; Working memory; n-Back