title: Response perseveration in stimulant dependence is associated with striatal dysfunction and can be ameliorated by a D(2/3) receptor agonist.
abstract: BACKGROUND
  Compulsivity is a hallmark of drug addiction and in animal models is measured by consecutive incorrect responses to a previously rewarded stimulus during reversal learning. The aim of this study was to measure behavioral and neural markers of compulsivity in stimulant-dependent individuals and to test whether these markers could be modulated by treatment with drugs targeting the dopamine system.
  
  
  METHODS
  In a randomized, double-blind, placebo-controlled, crossover design, stimulant-dependent individuals (SDIs; n = 18) and healthy volunteers (n = 18) received single doses of dopamine D(2/3) receptor antagonist (amisulpride, 400 mg) and agonist (pramipexole, 0.5 mg) drugs. To examine compulsivity and its dopaminergic modulation more generally, patients with obsessive-compulsive disorder (OCD; n = 18) were also included in the study.
  
  
  RESULTS
  SDIs made significantly more perseverative responses to the previously correct stimulus immediately following reversal, compared with both healthy volunteers and patients with OCD. Across all participants, the number of perseverative errors was negatively correlated with functional activation in right fronto-striato-parietal networks-in particular, the right caudate nucleus. In SDIs, perseveration-related caudate activation was abnormally reduced in the placebo condition, but the dopamine D(2/3) agonist pramipexole normalized both perseverative responding and related activation of the right caudate.
  
  
  CONCLUSIONS
  Perseveration during reversal learning was associated specifically with stimulant dependence rather than with compulsive behaviors more generally. The beneficial effects of a dopamine agonist drug challenge on both behavior and associated brain activation in SDIs may indicate new avenues for pharmacologic treatment in stimulant dependence.
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom. Electronic address: ke220@cam.ac.uk.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Ersche
authors.affiliation: Institute of Cognitive Neuroscience, University College London, Cambridge, United Kingdom.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Roiser
authors.affiliation: Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom; Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sanja
authors.initials: S
authors.lastname: Abbott
authors.affiliation: Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Craig
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Suckling
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Cinly
authors.initials: C
authors.lastname: Ooi
authors.affiliation: GlaxoSmithKline, Clinical Unit, Cambridge, United Kingdom.
authors.forename: Shaila S
authors.initials: SS
authors.lastname: Shabbir
authors.affiliation: Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom; Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Luke
authors.initials: L
authors.lastname: Clark
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sahakian
authors.affiliation: Department of Psychiatry, Queen Elizabeth II Hospital, Welwyn Garden City, United Kingdom.
authors.forename: Naomi A
authors.initials: NA
authors.lastname: Fineberg
authors.affiliation: Neurosciences Centre for Excellence in Drug Discovery, Verona, Italy.
authors.forename: Emilio V
authors.initials: EV
authors.lastname: Merlo-Pich
authors.affiliation: Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom; Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom; GlaxoSmithKline, Clinical Unit, Cambridge, United Kingdom.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
mesh_terms: D000328:Adult; D000077582:Amisulpride; D019969:Amphetamine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D052160:Benzothiazoles / Q000627:therapeutic use; D001931:Brain Mapping / Q000379:methods / Q000523:psychology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D003192:Compulsive Behavior / Q000188:drug therapy* / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D018491:Dopamine Agonists / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods / Q000523:psychology*; D008297:Male; D009771:Obsessive-Compulsive Disorder / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D000077487:Pramipexole; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D052160:Benzothiazoles; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D013469:Sulpiride; D000077582:Amisulpride; D000077487:Pramipexole