Karen D Ersche1, Jonathan P Roiser2, Sanja Abbott3, Kevin J Craig4, Ulrich Müller5, John Suckling6, Cinly Ooi6, Shaila S Shabbir7, Luke Clark3, Barbara J Sahakian6, Naomi A Fineberg8, Emilio V Merlo-Pich9, Trevor W Robbins3, Edward T Bullmore10. 1. 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. 2. Institute of Cognitive Neuroscience, University College London, Cambridge, United Kingdom. 3. Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom; Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom. 4. Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom. 5. Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. 6. Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom. 7. GlaxoSmithKline, Clinical Unit, Cambridge, United Kingdom. 8. Department of Psychiatry, Queen Elizabeth II Hospital, Welwyn Garden City, United Kingdom. 9. Neurosciences Centre for Excellence in Drug Discovery, Verona, Italy. 10. 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.
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.
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: Elise Lesage; Sarah E Aronson; Matthew T Sutherland; Thomas J Ross; Betty Jo Salmeron; Elliot A Stein Journal: JAMA Psychiatry Date: 2017-06-01 Impact factor: 21.596
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