Improving translation of animal models of addiction and relapse by reverse translation


Critical features of human addiction are increasingly being incorporated into complementary animal models, including escalation of drug intake, punished drug seeking and taking, intermittent drug access, choice between drug and non-drug rewards, and assessment of individual differences based on criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Combined with new technologies, these models advanced our understanding of brain mechanisms of drug self-administration and relapse, but these mechanistic gains have not led to improvements in addiction treatment. This problem is not unique to addiction neuroscience, but it is an increasing source of disappointment and calls to regroup. Here we first summarize behavioural and neurobiological results from the animal models mentioned above. We then propose a reverse translational approach, whose goal is to develop models that mimic successful treatments: opioid agonist maintenance, contingency management and the community-reinforcement approach. These reverse-translated ‘treatments’ may provide an ecologically relevant platform from which to discover new circuits, test new medications and improve translation.

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Fig. 1: Addiction phase and animal models.
Fig. 2: Brain circuits that play a role in drug taking and drug seeking in different animal models.
Fig. 3: Effect of heroin withdrawal and buprenorphine or methadone maintenance on drug choice in rhesus monkeys.
Fig. 4: Addiction treatment and animal models.


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The writing of this Review was supported by a grant from the US NIDA (K99DA047976 to M.V.), the Intramural Research Program of the NIH, NIDA (D.H.E. and Y.S.), UG3DA050311, R01DA026946 and UH3DA041146 from NIDA (M.L.B.), and the Swedish Research Council (M.H.). The authors thank S. Negus for helpful comments on the Review.

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The authors contributed equally to the writing of the review.

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Correspondence to Marco Venniro or Yavin Shaham.

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The authors declare no competing interests.

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Nature Reviews Neuroscience thanks Robert Gould, who co-reviewed with Kimberly Holter; Paul Kenny and the other anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information



Resumption of drug-taking behaviour during self-imposed (voluntary) or forced abstinence in humans and laboratory animals.

Compulsive drug use

Continued use of a drug despite (known) adverse consequences.

Drug craving

An affective state described as an urge for drug; it can be induced in human drug users by exposure to the self-administered drug, drug cues or stress.

Predictive validity

The extent to which laboratory-animal behaviour induced by an experimental manipulation predicts human behaviour induced by a similar event in the modelled condition; it often refers to a model’s ability to prospectively identify treatments that are effective in humans.

Postdictive validity

The ability of a laboratory model to retrospectively demonstrate an established human phenomenon.

Forward translation

The process of using mechanistic discoveries from animal models to develop new treatments for the modelled human condition.

Contingency management

A learning-based treatment in which abstinence is maintained by providing non-drug rewards (monetary vouchers, prizes or other incentives, usually tangible/material and given promptly and predictably) in exchange for negative drug test results.

The community-reinforcement approach

A learning-based treatment developed for alcohol addiction in the 1970s, where the goal is to replace drug use with non-drug social rewards (family support and employment) contingent on decrease or cessation of drug use.

Binge self-administration

Self-administration characterized by irregular (variable) interinfusion intervals, with alternating periods of high responding and no responding.

Progressive ratio reinforcement schedule

A schedule of reinforcement in which a reinforcer is presented only on the completion of a set number of responses. The number of required responses progressively increases after each presented reinforcement.


A consequence that follows an operant response that decreases the likelihood that the response will occur in the future.

Q 0

A measure, in behavioural economics, of maximal consumption when the ‘price’ of a commodity is zero or at the lowest price possible (that is, FR1 reinforcement schedule in self-administration studies).

P max

A measure, in behavioural economics, of the maximum ‘price’ that maintains maximal responding and represents the inflection point (that is, slope of −1) between inelastic and elastic demand (in other words, the price at which a proportional change in price results in an equal proportional change in consumption of the commodity).


A measure, in behavioural economics, of the elasticity of a demand curve or how quickly consumption of a commodity falls with increases in ‘price’ (response requirement divided by unit drug dose in self-administration studies).

Demand elasticity

In behavioural economics, how quickly demand falls with increases in ‘price’ (response requirements in self-administration studies).

Second-order reinforcement schedules

Reinforcement schedules in which completion of the response requirements of one schedule (the unit schedule) is treated as a unitary response that is reinforced according to another schedule.

Disconnection procedure

A procedure in which a role of a neuronal pathway or projection in a given behaviour is inferred when behaviour is disrupted by the contralateral, but not ipsilateral, inactivation of two anatomically connected brain regions.

Opioid maintenance therapy

Pharmacological treatment method in which long-acting opioid agonists such as methadone or buprenorphine are administered orally or via depot formulation, producing few or no acute subjective effects in tolerant patients but reducing craving for, and use of, other opioids.

ABA renewal

The resumption of a conditioned response in the original training context after extinction in a different context (also called ‘context-induced reinstatement’).

Sign tracking

Behaviour directed towards a stimulus as a result of a learned association between the stimulus and the reward. Sign-tracking responses develop even though reward delivery is not contingent on a response.

Reverse translation

The use of data from humans (for example, that a treatment is effective for a condition) to develop animal models whose goals are to uncover underlying mechanisms and identify new treatments.

G-protein-biased MOR agonist

An agonist of µ opioid receptor (MOR) that preferentially activates the G-protein-coupled intracellular pathway over the β-arrestin pathway.

Daun02 inactivation procedure

A pharmacogenetic lesion approach (conversion of Daun02 into cytotoxic daunorubicin by β-galactosidase) to determine the behavioural relevance of FOS-expressing neuronal ensembles in FOSlacZ rats that express FOS and β-galactosidase in activated neurons.


Also known as intermediate phenotype, a quantitative trait unseen by the unaided eye, located along the pathway between a genomic locus that contributes to the heritability of a complex disease phenotype and the disease itself.

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Venniro, M., Banks, M.L., Heilig, M. et al. Improving translation of animal models of addiction and relapse by reverse translation. Nat Rev Neurosci 21, 625–643 (2020).

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