Neural systems of reinforcement for drug addiction: from actions to habits to compulsion

Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use—when a drug is voluntarily taken because it has reinforcing, often hedonic, effects—through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.*Note: In the version of this article initially published, there is an error in Figure 1. Please see the PDF for details.

[1]  Effects of d-amphetamine on responding of squirrel monkeys maintained under second-order schedules of food presentation, electric shock presentation or stimulus-shock termination. , 1981, The Journal of pharmacology and experimental therapeutics.

[2]  Robert S. Lockhart,et al.  Learning and Motivation , 1981 .

[3]  Christopher D. Adams,et al.  The Effect of the Instrumental Training Contingency on Susceptibility to Reinforcer Devaluation , 1983 .

[4]  H. de Wit,et al.  Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. , 1984, Psychological review.

[5]  M. Bozarth Methods of Assessing the Reinforcing Properties of Abused Drugs , 1989, Springer New York.

[6]  Michael A. Bozarth Methods of assessing the reinforcing properties of abused drugs , 1987 .

[7]  J. Stewart,et al.  Reinstatement of Drug-Taking Behavior as a Method of Assessing Incentive Motivational Properties of Drugs , 1987 .

[8]  T. Robbins,et al.  Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues , 1991, Neuroscience.

[9]  T. Robbins,et al.  Functions of dopamine in the dorsal and ventral striatum , 1992 .

[10]  K. Berridge,et al.  The neural basis of drug craving: An incentive-sensitization theory of addiction , 1993, Brain Research Reviews.

[11]  Trevor W. Robbins,et al.  Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions ofd-amphetamine , 1993, Behavioural Brain Research.

[12]  B. Balleine,et al.  Motivational control of goal-directed action , 1994 .

[13]  C. Pennartz,et al.  The nucleus accumbens as a complex of functionally distinct neuronal ensembles: An integration of behavioural, electrophysiological and anatomical data , 1994, Progress in Neurobiology.

[14]  J. Wolffgramm,et al.  From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat , 1995, Behavioural Brain Research.

[15]  C. O'brien,et al.  Myths about the treatment of addiction , 1996, The Lancet.

[16]  H. Groenewegen,et al.  The nucleus accumbens: gateway for limbic structures to reach the motor system? , 1996, Progress in brain research.

[17]  R. See,et al.  Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine , 1997, Behavioural Brain Research.

[18]  T. Robbins,et al.  Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats , 1997, Psychopharmacology.

[19]  Theoretical Approaches to Obsessive-Compulsive Disorder , 1997 .

[20]  A. Leshner Addiction is a brain disease, and it matters. , 1997, Science.

[21]  G. Di Chiara A motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use. , 1998, Journal of psychopharmacology.

[22]  T. Robbins,et al.  Drug addiction: bad habits add up , 1999, Nature.

[23]  T. Robbins,et al.  Dissociation in Effects of Lesions of the Nucleus Accumbens Core and Shell on Appetitive Pavlovian Approach Behavior and the Potentiation of Conditioned Reinforcement and Locomotor Activity byd-Amphetamine , 1999, The Journal of Neuroscience.

[24]  J. Taylor,et al.  Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization , 1999, Psychopharmacology.

[25]  A. Dickinson,et al.  Neuronal coding of prediction errors. , 2000, Annual review of neuroscience.

[26]  T. Robbins,et al.  Dissociation in Conditioned Dopamine Release in the Nucleus Accumbens Core and Shell in Response to Cocaine Cues and during Cocaine-Seeking Behavior in Rats , 2000, The Journal of Neuroscience.

[27]  K. Berridge,et al.  Intra-Accumbens Amphetamine Increases the Conditioned Incentive Salience of Sucrose Reward: Enhancement of Reward “Wanting” without Enhanced “Liking” or Response Reinforcement , 2000, The Journal of Neuroscience.

[28]  T. Robbins,et al.  The effects of d-amphetamine, chlordiazepoxide, α-flupenthixol and behavioural manipulations on choice of signalled and unsignalled delayed reinforcement in rats , 2000, Psychopharmacology.

[29]  Jeffrey W Grimm,et al.  Contingent access to stimuli associated with cocaine self-administration is required for reinstatement of drug-seeking behavior , 2000, Psychobiology.

[30]  Nikolaus R. McFarland,et al.  Striatonigrostriatal Pathways in Primates Form an Ascending Spiral from the Shell to the Dorsolateral Striatum , 2000, The Journal of Neuroscience.

[31]  T. Robbins,et al.  Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour , 2000, Psychopharmacology.

[32]  T. Robbins,et al.  The effects of excitotoxic lesions of the basolateral amygdala on the acquisition of heroin-seeking behaviour in rats , 2000, Psychopharmacology.

[33]  S. R. Vorel,et al.  Relapse to Cocaine-Seeking After Hippocampal Theta Burst Stimulation , 2001, Science.

[34]  A. Dickinson,et al.  Involvement of the central nucleus of the amygdala and nucleus accumbens core in mediating Pavlovian influences on instrumental behaviour , 2001, The European journal of neuroscience.

[35]  P. Kalivas,et al.  The Circuitry Mediating Cocaine-Induced Reinstatement of Drug-Seeking Behavior , 2001, The Journal of Neuroscience.

[36]  N. Denzin Commentary and Debate , 1997, American Journal of Sociology.

[37]  A. Dickinson,et al.  The neuropsychological basis of addictive behaviour , 2001, Brain Research Reviews.

[38]  Jeffrey W Grimm,et al.  Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior , 2001, Psychopharmacology.

[39]  B. Everitt,et al.  Differential Involvement of NMDA, AMPA/Kainate, and Dopamine Receptors in the Nucleus Accumbens Core in the Acquisition and Performance of Pavlovian Approach Behavior , 2001, The Journal of Neuroscience.

[40]  M. Nader,et al.  Progression of Changes in Dopamine Transporter Binding Site Density as a Result of Cocaine Self-Administration in Rhesus Monkeys , 2001, The Journal of Neuroscience.

[41]  T. Robbins,et al.  The effects of nucleus accumbens core and shell lesions on intravenous heroin self-administration and the acquisition of drug-seeking behaviour under a second-order schedule of heroin reinforcement , 2001, Psychopharmacology.

[42]  T. Robbins,et al.  Behavioral effects of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: locomotion, cocaine self-administration, and prepulse inhibition of startle. , 2001, Behavioral neuroscience.

[43]  Trevor W Robbins,et al.  Investigating the neurocognitive deficits associated with chronic drug misuse , 2001, Current Opinion in Neurobiology.

[44]  G. Koob,et al.  Drug Addiction, Dysregulation of Reward, and Allostasis , 2001, Neuropsychopharmacology.

[45]  G. Di Chiara,et al.  A Role for Dopamine D1 Receptors of the Nucleus Accumbens Shell in Conditioned Taste Aversion Learning , 2001, The Journal of Neuroscience.

[46]  S. Floresco,et al.  Modulation of Hippocampal and Amygdalar-Evoked Activity of Nucleus Accumbens Neurons by Dopamine: Cellular Mechanisms of Input Selection , 2001, The Journal of Neuroscience.

[47]  S. Salloway,et al.  The frontal lobes and neuropsychiatric illness , 2001 .

[48]  K. Berridge,et al.  The Neuroscience of Natural Rewards: Relevance to Addictive Drugs , 2002, The Journal of Neuroscience.

[49]  Barry J. Everitt,et al.  Psychomotor Stimulant Addiction: A Neural Systems Perspective , 2002, The Journal of Neuroscience.

[50]  A. Dickinson,et al.  Alcohol Seeking by Rats: Action or Habit? , 2002, The Quarterly journal of experimental psychology. B, Comparative and physiological psychology.

[51]  Y. Shaham,et al.  The reinstatement model of drug relapse: history, methodology and major findings , 2003, Psychopharmacology.

[52]  David P. Friedman,et al.  Effects of Cocaine Self-administration on Striatal Dopamine Systems in Rhesus Monkeys: Initial and Chronic Exposure , 2002, Neuropsychopharmacology.

[53]  T. Robbins,et al.  Dopamine Release in the Dorsal Striatum during Cocaine-Seeking Behavior under the Control of a Drug-Associated Cue , 2002, The Journal of Neuroscience.

[54]  R. J. McDonald,et al.  Multiple Parallel Memory Systems in the Brain of the Rat , 2002, Neurobiology of Learning and Memory.

[55]  Rita Z. Goldstein,et al.  Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. , 2002, The American journal of psychiatry.

[56]  G. Schoenbaum,et al.  Encoding Predicted Outcome and Acquired Value in Orbitofrontal Cortex during Cue Sampling Depends upon Input from Basolateral Amygdala , 2003, Neuron.

[57]  P. Kalivas,et al.  Prefrontal Glutamate Release into the Core of the Nucleus Accumbens Mediates Cocaine-Induced Reinstatement of Drug-Seeking Behavior , 2003, The Journal of Neuroscience.

[58]  P. O’Donnell Dopamine gating of forebrain neural ensembles , 2003, The European journal of neuroscience.

[59]  Kent C. Berridge,et al.  Pleasures of the brain , 2003, Brain and Cognition.

[60]  B. Balleine,et al.  The role of prelimbic cortex in instrumental conditioning , 2003, Behavioural Brain Research.

[61]  W. Schultz,et al.  Discrete Coding of Reward Probability and Uncertainty by Dopamine Neurons , 2003, Science.

[62]  B. Everitt,et al.  Lesions of the Orbitofrontal but not Medial Prefrontal Cortex Disrupt Conditioned Reinforcement in Primates , 2003, The Journal of Neuroscience.

[63]  A. Dickinson,et al.  Oral cocaine seeking by rats: action or habit? , 2003, Behavioral neuroscience.

[64]  P. Kalivas,et al.  Brain circuitry and the reinstatement of cocaine-seeking behavior , 2003, Psychopharmacology.

[65]  S. Killcross,et al.  Coordination of actions and habits in the medial prefrontal cortex of rats. , 2003, Cerebral cortex.

[66]  B. Everitt,et al.  The Effects of Selective Orbitofrontal Cortex Lesions on the Acquisition and Performance of Cue‐Controlled Cocaine Seeking in Rats , 2003, Annals of the New York Academy of Sciences.

[67]  B. Everitt,et al.  Differential control over drug-seeking behavior by drug-associated conditioned reinforcers and discriminative stimuli predictive of drug availability. , 2003, Behavioral neuroscience.

[68]  Kent A. Kiehl,et al.  Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task , 2003, NeuroImage.

[69]  R. Wise Dopamine, learning and motivation , 2004, Nature Reviews Neuroscience.

[70]  L. Parsons,et al.  Neurobiological mechanisms in the transition from drug use to drug dependence , 2004, Neuroscience & Biobehavioral Reviews.

[71]  T. Robbins,et al.  Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens , 2004, Psychopharmacology.

[72]  H. Critchley,et al.  Neural systems supporting interoceptive awareness , 2004, Nature Neuroscience.

[73]  B. Everitt,et al.  Direct Interactions between the Basolateral Amygdala and Nucleus Accumbens Core Underlie Cocaine-Seeking Behavior by Rats , 2004, The Journal of Neuroscience.

[74]  Karl J. Friston,et al.  Dissociable Roles of Ventral and Dorsal Striatum in Instrumental Conditioning , 2004, Science.

[75]  T. Robbins,et al.  Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates , 2004, Neuroscience & Biobehavioral Reviews.

[76]  P. Vezina,et al.  Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs , 2004, Neuroscience & Biobehavioral Reviews.

[77]  B. Everitt,et al.  Drug Seeking Becomes Compulsive After Prolonged Cocaine Self-Administration , 2004, Science.

[78]  T. Robbins,et al.  Differential control over cocaine-seeking behavior by nucleus accumbens core and shell , 2004, Nature Neuroscience.

[79]  R. Cardinal,et al.  Nucleus accumbens core lesions retard instrumental learning and performance with delayed reinforcement in the rat , 2005, BMC Neuroscience.

[80]  E. Rolls,et al.  RBITOFRONTAL CORTEX: NEURONAL REPRESENTATION OF ORAL EMPERATURE AND CAPSAICIN IN ADDITION TO TASTE AND EXTURE , 2004 .

[81]  B. Balleine,et al.  Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning , 2004, The European journal of neuroscience.

[82]  Y. Shaham,et al.  Incubation of cocaine craving after withdrawal: a review of preclinical data , 2004, Neuropharmacology.

[83]  B. Everitt,et al.  Neural and psychological mechanisms underlying appetitive learning: links to drug addiction , 2004, Current Opinion in Neurobiology.

[84]  Michael A. Nader,et al.  Behavioral/systems/cognitive Cocaine Self-administration Produces a Progressive Involvement of Limbic, Association, and Sensorimotor Striatal Domains , 2022 .

[85]  Hugh Garavan,et al.  Executive Dysfunction in Cocaine Addiction: Evidence for Discordant Frontal, Cingulate, and Cerebellar Activity , 2004, The Journal of Neuroscience.

[86]  S. Leucht Amisulpride a selective dopamine antagonist and atypical antipsychotic: results of a meta-analysis of randomized controlled trials. , 2004, The international journal of neuropsychopharmacology.

[87]  T. Robbins,et al.  Contrasting Roles of Basolateral Amygdala and Orbitofrontal Cortex in Impulsive Choice , 2004, The Journal of Neuroscience.

[88]  Nora D. Volkow,et al.  The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies , 2004, Neuropharmacology.

[89]  R. A. Fuchs,et al.  Differential Involvement of Orbitofrontal Cortex Subregions in Conditioned Cue-Induced and Cocaine-Primed Reinstatement of Cocaine Seeking in Rats , 2004, The Journal of Neuroscience.

[90]  S. J. Weiss,et al.  Sign-tracking (autoshaping) in rats: A comparison of cocaine and food as unconditioned stimuli , 2004, Learning & behavior.

[91]  B. Everitt,et al.  Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour , 2004, Neuropharmacology.

[92]  David Belin,et al.  Evidence for Addiction-like Behavior in the Rat , 2004, Science.

[93]  A. Grace,et al.  Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior , 2005, Nature Neuroscience.

[94]  T. Robbins,et al.  The biological, social and clinical bases of drug addiction: commentary and debate , 1996, Psychopharmacology.

[95]  A. Faure,et al.  Lesion to the Nigrostriatal Dopamine System Disrupts Stimulus-Response Habit Formation , 2005, The Journal of Neuroscience.

[96]  R. A. Fuchs,et al.  The Role of the Dorsomedial Prefrontal Cortex, Basolateral Amygdala, and Dorsal Hippocampus in Contextual Reinstatement of Cocaine Seeking in Rats , 2005, Neuropsychopharmacology.

[97]  B. Balleine,et al.  Lesions of Medial Prefrontal Cortex Disrupt the Acquisition But Not the Expression of Goal-Directed Learning , 2005, The Journal of Neuroscience.

[98]  B. Everitt,et al.  Involvement of the Dorsal Striatum in Cue-Controlled Cocaine Seeking , 2005, The Journal of Neuroscience.

[99]  Trevor W. Robbins,et al.  Time-limited modulation of appetitive Pavlovian memory by D1 and NMDA receptors in the nucleus accumbens , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[100]  B. Balleine,et al.  The role of the dorsomedial striatum in instrumental conditioning , 2005, The European journal of neuroscience.

[101]  S. Ikemoto,et al.  The Functional Divide for Primary Reinforcement of D-Amphetamine Lies between the Medial and Lateral Ventral Striatum: Is the Division of the Accumbens Core, Shell, and Olfactory Tubercle Valid? , 2005, The Journal of Neuroscience.

[102]  T. Robinson,et al.  Opposite effects of amphetamine self-administration experience on dendritic spines in the medial and orbital prefrontal cortex. , 2004, Cerebral cortex.

[103]  T. Robbins,et al.  Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement , 1996, Psychopharmacology.