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 D2/D3 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.

Individual Differences in Attentional Bias Associated with Cocaine Dependence Are Related to Varying Engagement of Neural Processing Networks

“…The whole-brain analyses identified frontal, cingulate, parietal, and temporal cortical activations that mirrored a subset of the brain areas involved in the patterns of activation identified by the ICA. The observed mass univariate whole-brain activations related to cocaine use words share dorsal, medial and inferior frontal, and temporal, parietal, and posterior cingulate cortical activations with that of a previous fMRI study of attentional bias for drug-related words in stimulant-dependent individuals (Ersche et al, 2010). The posterior cingulate, medial and inferior frontal cortex, and cerebellum activations are shared by cigarette smokers exposed to smoking cues (Wilson et al, 2012).…”

“…For nicotine-dependent individuals, the level of attentional bias for smoking-related cues was positively correlated with activation of the limbic, paralimbic, and occipital brain regions associated with emotional salience, memory recall, interoceptive states, and visual processing (Janes et al, 2010). Stimulant-dependent individuals exhibited a significant attentional bias for drug-related word stimuli that was significantly correlated with greater activation of the left ventral prefrontal cortex and cerebellum (Ersche et al, 2010). Moreover, the right dorsal anterior cingulate cortex response to cocaine use-related stimuli predicted recent cocaine use at 3-month follow-up in treatment-engaged cocaine-dependent individuals (Marhe et al, 2013).…”

The dopamine theory of addiction: 40 years of highs and lows

“…A study in non-treatment seeking stimulant-dependent individuals 108 showed that the dopamine D2/3 receptor agonist pramipexole had different effects on psychological performance in a Stroop task and related functional MRI measures in individuals with high drug-related compulsivity versus individuals with low drug-related compulsivity. If this finding is replicated with cocaine and in people with other drug dependencies, it might lead to a more sophisticated view of dopamine in addiction and, potentially, to targeted interventions such as dopamine-promoting agents in people with addiction who exhibit impulsivity.…”

The role of learning-related dopamine signals in addiction vulnerability

“…Leyton et al (2002) showed that even in healthy subjects the variability in dopamine response to amphetamine relates to subjective ratings of "wanting". Franken et al (2004) showed that the dopamine receptor antagonist haloperidol can reduce attentional bias to drug cues amongst addicts, and Ersche et al (2010) showed that the effect of such dopaminergic manipulations (both agonistic and antagonistic) varies with compulsivity. The effect of haloperidol in the former and amisulpiride in the latter, both rather selective D 2 antagonists, is surprising given the drug-induced reductions in D 2 receptors (see above).…”