Invited reviewBehavioral endophenotypes of drug addiction: Etiological insights from neuroimaging studies
Introduction
The worldwide extent of drug use is estimated at 3.4 billion drug users and accounts for over 12% of all deaths each year (WHO, 2012). However, despite the high prevalence of use, fewer than 20% of drug users lose control over their drug intake and develop clinical signs of addiction (Waldorf et al., 1991). The intricate interplay of multiple genetic and environmental factors which potentially determine an individual's susceptibility to the development of addiction provides a significant challenge to understanding the etiological mechanisms of this disorder (Kreek et al., 2012, Uhl, 2006, Wong and Schumann, 2008). However, one approach that has proved fruitful in recent years has been the investigation of behavioral traits known to pre-dispose individuals to addiction (reviewed in Meyer-Lindenberg and Weinberger, 2006, Nader et al., 2012, Robbins et al., 2012). Such traits include impulsivity and novelty/sensation-seeking (Ersche et al., 2012a, Ersche et al., 2010, Kreek et al., 2005, Nigg et al., 2006, Verdejo-Garcia et al., 2008) and likely express causally-relevant neurobiological markers of the addiction syndrome (Dalley et al., 2011, Flagel et al., 2009, Piazza et al., 1998).
Neuroimaging approaches such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have had a major impact on the elucidation of biomarkers associated with addiction, impulsivity, and novelty/sensation-seeking (e.g. Parvaz et al., 2011, Soloff et al., 2003, Whelan et al., 2012) and, importantly, have revealed significant overlaps in candidate markers between addiction, sensation-seeking and impulsivity and disorders encompassing these behaivoural traits such as attention deficit hyperactivity disorder (ADHD) (e.g. Frodl, 2010) a prototypical disorder of impulsivity (Sonuga-Barke, 2002). However, due to ethical and interpretative constraints, it has not been possible to unambiguously determine causal relationships between impulsivity, novelty/sensation-seeking and addiction in humans (Rogers and Robbins, 2001). Experimental animal models overcome these limitations by enabling the pre-morbid assessment of behavioral traits and underlying neurobiological mechanisms, together with longitudinal scanning prior to and following drug exposure. Consequently, imaging studies that use clinically-relevant animal models of addiction have the potential to establish causal markers that can be readily translated to human addiction. Here we review converging evidence from pre-clinical and clinical neuroimaging studies on the neurobiological basis of impulsivity and sensation/novelty-seeking and discuss the relevance of these studies for the etiology of addiction.
Section snippets
Impulsivity and novelty/sensation-seeking: behavioral endophenotypes predicting risk for addiction
The behavioral traits of impulsivity and novelty/sensation-seeking have been widely associated with addiction to a broad range of drugs, including stimulants (Moeller et al., 2002, Semple et al., 2005), opiates (Madden et al., 1997, Maremmani et al., 2009), alcohol (Petry, 2001) and tobacco (Bickel et al., 1999). Significantly, the expression of these traits varies throughout the lifespan (e.g. enhanced impulsivity and sensation-seeking is observed during adolescence (Arnett, 1992, Spear, 2000)
Neuroimaging studies of impulsivity and novelty/sensation-seeking
The evidence reviewed above indicates a clear link between the behavioral traits of impulsivity and novelty/sensation-seeking, the initiation and maintenance of drug intake, and the development of addiction. On the basis of these relationships, an understanding of the neurobiological mechanisms underlying these behavioral traits might inform how these in turn confer risk for addiction. Neuroimaging studies provide a powerful approach to investigate the neurobiological substrates mediating such
Implications for the etiological basis of addiction
Convergent findings from neuroimaging studies on the neurobiological basis of impulsivity and sensation-seeking have enabled a greater understanding of the causal role played by these traits in addiction. These studies have revealed a significant degree of overlap in markers of addiction and those relating to striatal DA function, the frontal cortical systems, and perturbations in reward processing in impulsivity and novelty/sensation-seeking.
Reduced striatal D2/D3 receptor binding is a highly
Conclusions and future directions
It is now generally accepted that the transition to addiction must entail pre-existing individual neurobiological risk factors, modified and exacerbated by both drug exposure and environmental variables. As reviewed here, the behavioural traits of impulsivity and sensation-seeking critically influence disease progression and show remarkable overlap with addiction with respect to DA dysfunction, altered brain metabolism and structure, as detected by neuroimaging studies in both humans and animal
Acknowledgements
This work was supported by the Medical Research Council (G0701500) and by a joint award from the Medical Research Council and Wellcome Trust in support of the Behavioural and Clinical Neuroscience Institute at Cambridge University. The authors also acknowledge funding from the MRC Imperial College-Cambridge University-Manchester (ICCAM) strategic addiction cluster. BJ is supported by a postdoctoral fellowship from the National Health and Medical Research Council of Australia (1016313).
References (210)
- et al.
Impulsivity predicts the escalation of cocaine self-administration in rats
Pharmacol. Biochem. Behav.
(2009) Reckless behaviour in adolescence: a developmental perspective
Dev. Rev.
(1992)Sensation seeking: a new conceptualization and a new scale
Personality and Individual Differences
(1994)- et al.
Does delay discounting play an etiological role in smoking or is it a consequence of smoking?
Drug Alcohol Depend.
(2009) - et al.
Dissociable neural representations of future reward magnitude and delay during temporal discounting
Neuroimage
(2009) - et al.
Novelty seeking, incentive salience and acquisition of cocaine self-administration in the rat
Behav. Brain Res.
(2011) - et al.
Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum
Neuron
(2008) - et al.
Novelty seeking modulates medial prefrontal activity during the anticipation of emotional stimuli
Psychiatry Res.
(2008) - et al.
Dopamine D2/D3 receptor availability and venturesomeness
Psychiatry Res.
(2011) - et al.
The HR/LR model: further evidence as an animal model of sensation seeking
Neurosci. Biobehav. Rev.
(2009)
Ventro-striatal reductions underpin symptoms of hyperactivity and impulsivity in attention-deficit/hyperactivity disorder
Biol. Psychiatry
Striatal dopamine D(2)/D(3) receptor binding in pathological gambling is correlated with mood-related impulsivity
Neuroimage
Impulsivity, compulsivity, and top-down cognitive control
Neuron
Neurobehavioral mechanisms of impulsivity: fronto-striatal systems and functional neurochemistry
Pharmacol. Biochem. Behav.
Dopamine, serotonin and impulsivity
Neuroscience
Impulsive choice and impulsive action predict vulnerability to distinct stages of nicotine seeking in rats
Biol. Psychiatry
High impulsivity predicts relapse to cocaine-seeking after punishment-induced abstinence
Biol. Psychiatry
Neurobiology of decision making: a selective review from a neurocognitive and clinical perspective
Biol. Psychiatry
Drug addiction endophenotypes: impulsive versus sensation-seeking personality traits
Biol. Psychiatry
Decreased saliency processing as a neural measure of Barratt impulsivity in healthy adults
Neuroimage
Prefrontal cortical volume reduction associated with frontal cortex function deficit in 6-week abstinent crack-cocaine dependent men
Drug Alcohol Depend.
Impaired inhibitory control of behavior in chronic cocaine users
Drug Alcohol Depend.
Individual differences in the attribution of incentive salience to reward-related cues: implications for addiction
Neuropharmacology
Impaired response inhibition function in abstinent heroin dependents: an fMRI study
Neurosci. Lett.
Individual differences in personality traits reflect structural variance in specific brain regions
Brain Res. Bull
The psychogenetically selected Roman high- and low-avoidance rat lines: a model to study the individual vulnerability to drug addiction
Neurosci. Biobehav. Rev.
Regional brain cerebral glucose metabolism and temperament: a positron emission tomography study
Neurosci. Lett.
Neural correlates of choice behavior related to impulsivity and venturesomeness
Neuropsychologia
Sensation seeking and alcohol use: a meta-analytic review
Addict. Behav.
[18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey
Nucl. Med. Biol.
Dose-dependent frontal hypometabolism on FDG-PET in methamphetamine abusers
J. Psychiatr. Res.
Personality traits are differentially associated with patterns of reward and novelty processing in the human substantia nigra/ventral tegmental area
Biol. Psychiatry
Nothing to lose: processing blindness to potential losses drives thrill and adventure seekers
Neuroimage
Dysfunctional, but not functional, impulsivity is associated with a history of seriously violent behaviour and reduced orbitofrontal and hippocampal volumes in schizophrenia
Psychiatry Res.
Sensation seeking predicts brain responses in the old-new task: converging multimodal neuroimaging evidence
Int. J. Psychophysiol.
Chronic cocaine administration reduces striatal dopamine terminal density and striatal dopamine release which leads to drug-seeking behaviour
Neuroscience
Amphetamine-induced increases in extracellular dopamine, drug wanting, and novelty seeking: a PET/[11C]raclopride study in healthy men
Neuropsychopharmacology
Sex differences in anterior cingulate cortex activation during impulse inhibition and behavioral correlates
Psychiatry Res.
Behavior genetic investigation of the relationship between spontaneous locomotor activity and the acquisition of morphine self-administration behavior
Behav. Pharmacol.
The neural basis of inhibition in cognitive control
Neuroscientist
High-novelty-preference rats are predisposed to compulsive cocaine self-administration
Neuropsychopharmacology
Responses to novelty and vulnerability to cocaine addiction: contribution of a multi-symptomatic animal model
Cold Spring Harb Perspect. Med.
High impulsivity predicts the switch to compulsive cocaine-taking
Science
Changes in cerebral glucose metabolism during early abstinence from chronic methamphetamine abuse
Mol. Psychiatry
Impulsivity and cigarette smoking: delay discounting in current, never, and ex-smokers
Psychopharmacology (Berl)
Contribution of impulsivity and novelty-seeking to the acquisition and maintenance of MDMA self-administration
Addict Biol.
Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study
J. Neurosci.
Trait impulsive choice predicts resistance to extinction and propensity to relapse to cocaine seeking: a bidirectional investigation
Neuropsychopharmacology
Heightened heart rate response to alcohol intoxication is associated with a reward-seeking personality profile
Alcohol Clin. Exp. Res.
Dopaminergic network differences in human impulsivity
Science
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