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: 6.31). 10/2008; 363(1507):3125-35. DOI: 10.1098/rstb.2008.0089
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Jeffrey W Dalley, Aug 18, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 4.16 Impact Factor
  • Source
    • "Recent animal models for the transition from occasional to escalating ATS use suggest that individual differences in limbic cortical-striatal brain circuits and associated functions predict the propensity to escalate drug use and develop addictive use patterns (Everitt et al., 2008; George and Koob, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug addiction is a chronic, relapsing brain disorder. The identification of biomarkers that render individuals vulnerable for the transition from occasional drug use to addiction is of key importance to develop early intervention strategies. The aim of the present study was to prospectively assess brain structural markers for escalating drug use in two independent samples of occasional amphetamine-type stimulant users. At baseline occasional users of amphetamine and 3,4-methylenedioxymethamphetamine (cumulative lifetime use ≤10 units) underwent structural brain imaging and were followed up at 12 months and 24 months (Study 1, n = 38; Study 2, n = 28). Structural vulnerability markers for escalating amphetamine-type drug use were examined by comparing baseline grey matter volumes of participants who increased use with those who maintained or reduced use during the follow-up period. Participants in both samples who subsequently increased amphetamine-type drugs use displayed smaller medial prefrontal cortex volumes and, additionally, in the basolateral amygdala (Study 1) and dorsal striatum (Study 2). In both samples the baseline volumes were significantly negatively correlated with stimulant use during the subsequent 12 and 24 months. Additional multiple regression analyses on the pooled data sets revealed some evidence of a compound-specific association between the baseline volume of the left basolateral amygdala and the subsequent use of amphetamine. These findings indicate that smaller brain volumes in fronto-striato-limbic regions implicated in impulsivity and decision-making might render an individual vulnerable for the transition from occasional to escalating amphetamine-type stimulant use. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 05/2015; 138(7). DOI:10.1093/brain/awv113 · 10.23 Impact Factor
  • Source
    • "Being able to adjust behavior to the desired consequences in a certain situation is a core ability of flexible behavior that is assumed to be impaired in several psychological disorders such as e . g . , obsessive - compulsory disorder ( Gillan et al . , 2011 ) and addiction ( Everitt et al . , 2008 ) . Yet , in spite of its behavioral relevance little is known about the neural basis that enables people to flexibly adjust their behavior to outcomes they want to reach ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Goal-directed behavior is based on representations of contingencies between a certain situation (S), a certain (re)action (R) and a certain outcome (O). These S-R-O representations enable flexible response selection in different situations according to the currently pursued goal. Importantly however, the successful formation of such representations is a necessary but not sufficient precondition for goal-directed behavior which additionally requires the actual usage of the contingency information for action control. The present fMRI study aimed at identifying the neural basis of each of these two aspects: representing vs. explicitly using experienced S-R-O contingencies. To this end, we created three experimental conditions: S-R-O contingency present and used for outcome-based response selection, S-R-O contingency present but not used, and S-R-O contingency absent. The comparison between conditions with and without S-R-O contingency revealed that the angular gyrus is relevant for representing S-R-O contingencies. The explicit usage of learnt S-R-O representations in turn was associated with increased functional coupling between angular gyrus and several subcortical (hippocampus, caudate head), prefrontal (lateral orbitofrontal cortex, rostrolateral prefrontal cortex) and cerebellar areas, which we suggest represent different explicit and implicit processes of goal-directed action control. Hence, we ascribe a central role to the angular gyrus in associating actions to their sensory outcomes which is used to guide behavior through coupling of the angular gyrus with multiple areas related to different aspects of action control.
    Frontiers in Human Neuroscience 03/2015; 9. DOI:10.3389/fnhum.2015.00180 · 2.90 Impact Factor
Show more