Response Perseveration in Stimulant Dependence Is Associated with Striatal Dysfunction and Can Be Ameliorated by a D_2/3 Receptor Agonist

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• 作者：Karen D.  ; Ersche^a ;   ; ^b ;   ; ^{ke220@cam.ac.uk} ; Jonathan P.  ; Roiser^d ; Sanja  ; Abbott^b ;   ; ^c ; Kevin J.  ; Craig^b ; Ulrich  ; Mü ; ller^a ; John  ; Suckling^a ;   ; ^b ; Cinly  ; Ooi^a ;   ; ^b ; Shaila S.  ; Shabbir^e ; Luke  ; Clark^b ;   ; ^c ; Barbara J.  ; Sahakian^a ;   ; ^b ; Naomi A.  ; Fineberg^g ; Emilio V.  ; Merlo-Pich^f ; Trevor W.  ; Robbins^b ;   ; ^c ; Edward T.  ; Bullmore^a ;   ; ^b ;   ; ^e
• 关键词：Dopamine ; fMRI ; obsessive-compulsive disorder ; pramipexole ; probabilistic reversal learning ; substance dependence
• 刊名：Biological Psychiatry
• 出版年：2011
• 出版时间：15 October 2011
• 年：2011
• 卷：70
• 期：8
• 页码：754-762
• 全文大小：1158 K

文摘

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¡ªin 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.