Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

Department of Experimental Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge, UK.
Philosophical Transactions of The Royal Society B Biological Sciences (Impact Factor: 7.06). 10/2008; 363(1507):3125-35. DOI: 10.1098/rstb.2008.0089
Source: PubMed


We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.

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    • "Impulsivity plays a critical role in the establishment and maintenance of drug addiction (Belin et al. 2011; Belin et al. 2008; Bird & Schenk, 2012; Everitt et al. 2008). Recently, studies have begun to examine whether increased impulsivity among substance-dependent individuals (SDI) is also associated with a greater propensity to relapse following treatment discharge (De Wilde et al. 2013; Stevens et al. 2014). "
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    ABSTRACT: Impulsivity is a hallmark characteristic of substance use disorders. Recently, studies have begun to explore whether increased impulsivity in substance-dependent individuals (SDIs) is associated with a greater propensity to relapse following treatment. Despite growing recognition of its multidimensional nature, however, most studies have treated impulsivity unilaterally. Accordingly, it remains unclear whether certain facets of impulsivity are more relevant to relapse than others. The aim of the current study was to examine the relationship between multiple facets of impulsivity and short-term relapse in SDIs. As a secondary aim, we explored the role of treatment retention in this relationship. A personality-based impulsivity questionnaire (UPPS) and three neurocognitive tasks of impulsivity [stop-signal task (SST), delay discounting task (DDT) and Iowa gambling task (IGT)] were administered in a heterogeneous sample of 70 SDIs shortly following their entry in an in-patient detoxification programme. Mediation analyses were performed to explore whether the effects of impulsivity on relapse were mediated by treatment retention. Performance on two neurocognitive indices of impulsive choice (i.e. delay discounting and impulsive decision-making) significantly predicted short-term relapse. The effects of delay discounting and impulsive decision-making on relapse propensity were mediated by treatment retention. Neurocognitive indices of impulsivity may be more sensitive to the prediction of relapse than trait-based self-report questionnaires. Post-treatment relapse in SDIs may be reduced by targeting the processes involved in impulsive choice and by improving treatment retention in SDIs with inflated impulsivity.
    Psychological Medicine 12/2015; 45(10). DOI:10.1017/S003329171500001X · 5.94 Impact Factor
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    • "Work with behaving rodents indicates that the transition from impulsive to compulsive drug use, and the corresponding transition of behavioral control from the ventral to the dorsolateral striatum, can be promoted by dopamine (Dalley et al. 2007; Belin and Everitt 2008; Belin et al. 2008). Dalley et al. (2007) have shown that ventral striatal D2-receptors density predicts individual difference in trait impulsivity, which itself predict propensity to cocaine seeking (Dalley et al. 2007) and addiction-like behavior (Belin et al. 2008). "
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    ABSTRACT: Interactions between motivational, cognitive, and motor regions of the striatum are crucial for implementing behavioral control. Work with experimental animals indicates that such interactions are sensitive to modulation by dopamine. Using systematic pharmacological manipulation of dopamine D2-receptors and resting-state functional imaging, we defined the functional architecture of the human striatum and quantified the effects of dopaminergic drugs on intrinsic effective connectivity between striatal subregions. We found that dopamine modulates interactions between motivational and cognitive regions, as well cognitive and motor regions of the striatum. Stimulation and blockade of the dopamine D2-receptor had opposite (increasing and decreasing) effects on the efficacy of those interactions. Furthermore, trait impulsivity was specifically associated with dopaminergic modulation of ventral-to-dorsal striatal connectivity. Individuals with high trait impulsivity exhibited greater drug-induced increases (after stimulation) and decreases (after blockade) of ventral-to-dorsal striatal connectivity than those with low trait impulsivity. These observations establish a key link between dopamine, intrinsic effective connectivity between striatal subregions, and trait impulsivity.
    Cerebral Cortex 10/2015; DOI:10.1093/cercor/bhv243 · 8.67 Impact Factor
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    • "simple-maineffectofCUSina10-minblockorbetweenhandledandCUS. inaquickbutprematurelearning.Thisideaissupported bythefacilitationofhabitualdrugseekingbyanimpulsive predisposition(Everittetal.,2008).Bycontrast,theSLsubgroup exhibitedtheoppositetraitinlearning,namelygreatercognitive persistenceorslowlearning.Thissubgroupcomprised16%of total,whichappearstobeexcessivelyhightodefinealearning disability,sothissubgroupmaytendtobemoreprudentor perserverative(=lessimpulsive),andtheymayrequirenumerous trialsanderrorstoprocessnewinformationormakedecisions.In consistentwiththis,ratscharacterizedatriskaversemakemore perseverativeerrorsonsetshifting(Shimpetal.,2015). "
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    ABSTRACT: Stress is a major factor in the development of major depressive disorder (MDD), but few studies have assessed individual risk based on pre-stress behavioral and cognitive traits. To address this issue, we employed appetitive instrumental lever pressing with a progressive ratio (PR) schedule to assess these traits in experimentally naïve Sprague-Dawley rats. Based on four distinct traits that were identified by hierarchical cluster analysis, the animals were classified into the corresponding four subgroups (Low Motivation, Quick Learner, Slow Learner, and Hypermotivation), and exposed to chronic unpredictable stress (CUS) before monitoring their post-stress responses for 4 weeks. The four subgroups represented the following distinct behavioral phenotypes after CUS: the Low Motivation subgroup demonstrated weight loss and a late-developing paradoxical enhancement in PR performance that may be related to inappropriate decision-making in human MDD. The Quick Learner subgroup exhibited a transient loss of motivation and the habituation of serum corticosterone (CORT) response to repeated stress. The Slow Learner subgroup displayed resistance to demotivation and a suppressed CORT response to acute stress. Finally, the Hypermotivation subgroup exhibited resistance to weight loss, habituated CORT response to an acute stress, and a long-lasting amotivation. Overall, we identified causal relationships between pre-stress traits in the performance of the instrumental training and post-stress phenotypes in each subgroup. In addition, many of the CUS-induced phenotypes in rats corresponded to or had putative relationships with representative symptoms in human MDD. We concluded that the consequences of stress may be predictable before stress exposure by determining the pre-stress behavioral or cognitive traits of each individual in rats.
    Frontiers in Behavioral Neuroscience 05/2015; 9(119):1-13. DOI:10.3389/fnbeh.2015.00119 · 3.27 Impact Factor
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