Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence

Abstract

Context: There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges.

Objective: To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D(2)/D(3) receptor antagonist and agonist challenges.

Design: Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging.

Setting: Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England.

Participants: Stimulant-dependent individuals (n = 18) and healthy volunteers (n = 18).

Interventions: Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions.

Main outcome measures: Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire.

Results: Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups.

Conclusions: Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.

Figure 1

Schematic of the Stroop paradigms. A, In the drug-word Stroop task, participants were asked to identify the font colors of the drug-related words and the neutral words. B, In the color-word Stroop task, participants were asked to identify the font colors of the color words and the neutral words. C, Blocks of drug-related words, color words (which were always incongruent with their font color), and neutral words were interspersed with blocks of fixation for task presentation during functional magnetic resonance imaging.

Figure 2

Behavioral performance during the drug-word Stroop paradigm and task-related activation of a frontocerebellar system associated with attentional bias for drug words (in all participants). A, Drug users showed a significant attentional bias for drug-related words, as reflected in higher attentional interference scores compared with the healthy comparison volunteers. Attentional bias was measured by each volunteer’s median response latency of correctly identified colors of drug-related words minus the median response latency of correctly identified colors of matched neutral words. Pramipexole was given as pramipexole dihydrochloride. B, The red voxels indicate brain regions activated by the contrast between drug-related words and neutral words; yellow voxels indicate brain regions within this system where activation was positively correlated with attentional interference scores on the drug-word Stroop task. C, Scatterplot of median attentional interference score (y-axis) vs functional activation of the brain regions associated with attentional bias for drug words (x-axis), which are the left ventral prefrontal cortex (Montreal Neurological Institute coordinates [x, y, z] in millimeters: −46, 26, 12; −44, 22, −8; and −40, 6, 30) and right cerebellum (22, −80, −40). The spatial coordinates refer to the peak voxel where the effect size is greatest. BOLD indicates blood oxygen level dependent. D, Comparison of mean task-related (BOLD) activation in brain regions associated with attentional bias between stimulant-dependent individuals and healthy volunteers. Stimulant users show overactivation in the left ventral prefrontal cortex and right cerebellum compared with controls.

Figure 3

Behavioral performance and task-related activation of a frontocerebellar system during the drug-word Stroop task in high- and low-compulsivity drug users. Pramipexole was given as pramipexole dihydrochloride. A, High-compulsivity drug users showed a different profile in response to short-term dopaminergic treatment compared with low-compulsivity drug users, as reflected in greater attentional bias for drug-related words relative to neutral words. Attentional bias was measured by each volunteer’s median response latency of correctly identified colors of drug-related words minus the median response latency of correctly identified colors of matched neutral words. B, Dopaminergic drug effects on the left prefrontal cortex during the drug-word Stroop task are modulated by compulsivity of stimulant dependence. Box plots show functional activation associated with attentional bias for drug-related words in the left prefrontal cortex (Montreal Neurological Institute coordinates [x, y, z] in millimeters: −46, 26, 12; −44, 22, −8; and −40, 6, 30) and right cerebellum (22, −80, −40) in high- and low-compulsivity subgroups, indicating differential effects of pramipexole. The spatial coordinates refer to the peak voxel where the effect size is greatest.