title: Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study.
abstract: The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans.
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: ingeborg.bolstad@medisin.uio.no.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Bolstad
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Institute of Psychology, University of Oslo, Oslo, Norway.
authors.forename: Inge
authors.initials: I
authors.lastname: Groote
authors.affiliation: Department of Neuroradiology, Oslo University Hospital, Oslo, Norway.
authors.forename: Andres
authors.initials: A
authors.lastname: Server
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: Institute of Psychiatry, King׳s College, London, UK.
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Centre for Psychology, Kristianstad University, Kristianstad, Sweden.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Jensen
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D005260:Female; D006220:Haloperidol / Q000493:pharmacokinetics*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008032:Limbic System / Q000098:blood supply* / Q000187:drug effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009042:Motivation / Q000187:drug effects*; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D011569:Psychiatric Status Rating Scales; D011930:Reaction Time / Q000187:drug effects; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole; D006220:Haloperidol; D010100:Oxygen
keywords: Aripiprazole; Dopamine; Haloperidol; Healthy volunteers; Ventral striatum; fMRI