title: Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence.
abstract: Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction.
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Murphy
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.|Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Nestor
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: McGonigle
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Louise
authors.identifier: http://orcid.org/0000-0001-9137-4419
authors.initials: L
authors.lastname: Paterson
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK.
authors.forename: Venkataramana
authors.initials: V
authors.lastname: Boyapati
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Ersche
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Remy
authors.initials: R
authors.lastname: Flechais
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK.
authors.forename: Shankar
authors.initials: S
authors.lastname: Kuchibatla
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK.
authors.forename: Antonio
authors.identifier: http://orcid.org/0000-0003-2258-4089
authors.initials: A
authors.lastname: Metastasio
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Csaba
authors.initials: C
authors.lastname: Orban
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Filippo
authors.initials: F
authors.lastname: Passetti
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Laurence
authors.initials: L
authors.lastname: Reed
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Dana
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: Suckling
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Taylor
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.|Department of Psychology, University of Cambridge, Cambridge, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Lingford-Hughes
authors.affiliation: Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nutt
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK.
authors.forename: John Fw
authors.initials: JF
authors.lastname: Deakin
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elliott
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000503:physiopathology* / Q000523:psychology; D059031:Anticipation, Psychological; D053961:Azabicyclo Compounds / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D001931:Brain Mapping; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000008:administration & dosage*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D012201:Reward; D019966:Substance-Related Disorders / Q000503:physiopathology* / Q000523:psychology; D055815:Young Adult
chemical_list: D053961:Azabicyclo Compounds; C000594007:GSK598809; D010080:Oxazoles; D050637:Receptors, Dopamine D3