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The transition to compulsion in addiction

Nature Reviews Neuroscience volume 21, pages 247–263 (2020)Cite this article

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Abstract

Compulsion is a cardinal symptom of drug addiction (severe substance use disorder). However, compulsion is observed in only a small proportion of individuals who repeatedly seek and use addictive substances. Here, we integrate accounts of the neuropharmacological mechanisms that underlie the transition to compulsion with overarching learning theories, to outline how compulsion develops in addiction. Importantly, we emphasize the conceptual distinctions between compulsive drug-seeking behaviour and compulsive drug-taking behaviour (that is, use). In the latter, an individual cannot stop using a drug despite major negative consequences, possibly reflecting an imbalance in frontostriatal circuits that encode reward and aversion. By contrast, an individual may compulsively seek drugs (that is, persist in seeking drugs despite the negative consequences of doing so) when the neural systems that underlie habitual behaviour dominate goal-directed behavioural systems, and when executive control over this maladaptive behaviour is diminished. This distinction between different aspects of addiction may help to identify its neural substrates and new treatment strategies.

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Fig. 1: Neural circuits engaged in drug seeking, drug taking and the transition to compulsion in addiction.
Fig. 2: Assessing compulsive drug-taking and drug-seeking behaviours in animal models.
Fig. 3: Circuits undergoing gain of function with oDASS.
Fig. 4: Two examples of the emergence of compulsion in rodents.

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Acknowledgements

The authors acknowledge the Swiss National Science Foundation and the European Research Council (C.L.) as well as the UK Medical Research Council (grant MR/N02530X/1) and the Wellcome Trust (Investigator Award WT 104631/Z/14/Z/) for financial support (B.J.E., T.W.R.). The authors thank D. Belin and M. Loureiro for help with the figures.

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Authors and Affiliations

  1. Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland

    Christian Lüscher

  2. Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, Geneva, Switzerland

    Christian Lüscher

  3. Behavioural and Clinical Neuroscience Institute, Department of Psychology, University of Cambridge, Cambridge, UK

    Trevor W. Robbins & Barry J. Everitt

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All authors researched data for the article, contributed substantially to discussion of the article’s content, wrote the article, and reviewed and edited the manuscript before submission.

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C.L. has no competing interests. T.W.R. consults for Cambridge Cognition, Unilever, Cassava and Greenfield BioVentures. He holds research grants from Shionogi & Co., Ltd and GlaxoSmithKline plc., and receives royalties from Cambridge Cognition for CANTAB. He also receives editorial honoraria from Springer and Elsevier. B.J.E. has no competing interests.

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Glossary

Titrated

Adjusted in intensity, to measure the effect of a stimulus on behaviour.

Escalation of drug intake

Increase of drug intake during extended (long-access) periods of self-administration.

Reward thresholds

The minimal stimulation intensities required to produce a reinforcing effect.

Natural reinforcers

Rewards such as food and sex that motivate behaviour in animals and humans. They may be distinguished from artificial rewards such as addictive drugs that may nevertheless depend on the same neural systems in the brain.

Interoceptive

Relating to internal, or bodily, states that are interpreted by the brain through a process called ‘interoception’. In the case of drugs, bodily changes (such as increases in heart rate caused by stimulants) are an important component of the subjective effects of drugs.

Stimulant

A drug that increases arousal and activity. Amphetamine is a typical example of a stimulant, sometimes called a ‘psychomotor stimulant’.

Locomotor sensitization

Enhanced motor responses to the same does of a stimulant drug that follows intermittent, repeated dosing.

Cue-elicited reinstatement

Reinstatement of performance of previously extinguished drug-taking responses, supported by drug cues acting as conditioned reinforcers.

Extended amygdala

Neuroanatomical term that includes the centromedial amygdala, bed nucleus of the stria terminalis and, according to some, the shell of the nucleus accumbens and a group of neurons in the basal forebrain that links these structures.

Dysphoria

A state of unhappiness or suboptimal mood in humans.

Pavlovian–instrumental transfer

(PIT). Transfer of learning whereby conditioned stimuli associated with a reward can increase a separately trained instrumental response for that reward (specific transfer) or for other rewards (general transfer).

Sign tracking

Behaviour whereby the animal approaches a conditioned stimulus predictive of reward — as opposed to approaching a reward (or goal) directly (‘goal tracking’).

Contingency degradation

Degradation of the predictive relationship between responses and outcomes; for example, by presentation of ‘free’ (that is, response-independent) outcomes or extinction.

Quinine

A bitter crystalline compound present in cinchona bark that is used to adulterate an otherwise readily ingested liquid.

Progressive ratio schedule

A behavioural procedure whereby the number of required responses increases after each reward delivery. The number of responses at which the animal ceases to respond is called the ‘break point’.

Analgesic

Relating to the effects of a drug that relieves pain (for example, morphine).

Value updating

The perception of a change in value of a reinforcer after an antecedent manipulation; for example, the value of food is decreased following ingestion of the food to satiety.

Incubation of cocaine craving

The increase in instrumental responding for a drug-associated conditioned stimulus that occurs the longer the period of abstinence from drug taking.

Direct pathway

Projection of dopamine D1 receptor-expressing medium spiny neurons in the striatum to the midbrain. The indirect pathway involves a striatal projection of dopamine D2 receptor-expressing medium spiny neurons to the pallidum.

Contingency management

A behavioural modification intervention that reinforces desired behaviour (such as abstinence) with incentives.

Reversal learning

Learning of a reversal of the reward contingencies of two options, reflecting behavioural adaptation to environmental change.

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Lüscher, C., Robbins, T.W. & Everitt, B.J. The transition to compulsion in addiction. Nat Rev Neurosci 21, 247–263 (2020). https://doi.org/10.1038/s41583-020-0289-z

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