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Synaptic mechanisms underlying persistent cocaine craving

Nature Reviews Neuroscience volume 17, pages 351–365 (2016)Cite this article

Subjects

Key Points

  • Vulnerability to relapse that persists even after prolonged abstinence is a major problem in treating cocaine addiction. Mechanisms underlying this persistent vulnerability can be studied using rodent models of cue-induced cocaine craving during abstinence from cocaine self-administration.

  • Cue-induced cocaine craving in rodents progressively intensifies (incubates) over the first month of abstinence and remains high for months. Incubation of craving also occurs in human drug users.

  • Incubation of cocaine craving depends on an evolving series of neuroadaptations in the reward circuitry. Early adaptations in the ventral tegmental area and perhaps also the amygdala lead to more persistent changes in the nucleus accumbens, medial prefrontal cortex and central nucleus of the amygdala that increase the reactivity of neurons in these regions to cocaine cues and are ultimately required for the expression of incubated craving.

  • Increased reactivity of these regions of the rodent brain to cocaine cues presented during abstinence is important because neuroimaging studies in human cocaine users have found that heightened cue reactivity in related brain regions is associated with addiction severity and risk of relapse.

  • The relationship between cocaine craving and synaptic transmission has been most thoroughly studied in the nucleus accumbens, where abstinence is associated with changes in AMPA receptor subunit composition and silent synapse-based remodelling. Strengthening of excitatory synapses on nucleus accumbens neurons is particularly important for the maintenance of incubated craving after prolonged abstinence.

  • Dopamine transmission is altered during abstinence owing to plasticity within the ventral tegmental area and changes in dopamine receptor expression in dopaminergic projection areas, but many questions remain about the role of dopamine transmission in modulating synaptic plasticity and behaviour during abstinence.

  • Potential therapeutic strategies to prolong abstinence, identified through rodent studies, include the use of agonists of metabotropic glutamate receptor 2 (mGluR2) and/or mGluR3, mGluR1 positive allosteric modulators, serotonin (5-HT) receptor ligands (including 5-HT1B receptor agonists, 5-HT2C receptor agonists and 5-HT2A receptor antagonists), D3 dopamine receptor antagonists, environmental enrichment and interventions to normalize sleep patterns.

Abstract

Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here, I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and to further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction.

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Figure 1: Reward pathways and their roles in incubation of cue-induced cocaine craving.
Figure 2: Ca2+-permeable AMPA receptors in nucleus accumbens core synapses are required for expression of incubated cocaine craving.

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Acknowledgements

This Review includes work from my laboratory supported by US National Institutes of Health grants DA009621 and DA015835. I thank the members of my laboratory, Y. Shaham, R. Carelli and K. Szumlinski for helpful discussions.

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  1. The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, 60064, Illinois, USA

    Marina E. Wolf

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Supplementary information

Supplementary information S1 (box)

Mechanisms contributing to CP-AMPAR elevation in the NAc during incubation of cocaine craving (PDF 142 kb)

Supplementary information S2 (table)

AMPAR plasticity in NAc during abstinence from non-contingent cocaine* (PDF 166 kb)

Supplementary information S3 (table)

Detection of CP-AMPARs in NAc during abstinence from cocaine self-administration* (PDF 167 kb)

Supplementary information S4 (box)

Epigenetic mechanisms contribute to incubation of cocaine craving (PDF 94 kb)

PowerPoint slides

Glossary

Addiction

A chronic disease that involves cycles of drug use, abstinence and relapse. It is characterized by compulsive drug seeking and use, despite harmful consequences.

Relapse

Resumption of drug taking in human drug users after a period of abstinence. Triggers for relapse include certain emotional states, stress and exposure to cues or environments that are associated with prior drug use.

Incubation

A time-dependent increase in cue-induced drug seeking that is observed in laboratory animals that are tested after different periods of abstinence from drug self-administration. Incubation can also be revealed when animals are returned to the self-administration context in the absence of the discrete cue.

Non-contingent drug administration

A type of drug administration regimen whereby the drug is administered by the experimenter to a laboratory animal.

Drug craving

An affective state in humans that may lead to drug taking. In rodents, craving is inferred from the observed drug-seeking operant response.

Drug self-administration

An experimental paradigm during which animals are trained to perform an operant response (such as a lever press or nose poke) to receive an intravenous drug infusion that is often paired with a discrete cue (such as a tone or light) or a specific context.

Contingent drug administration

A type of drug administration regimen whereby a laboratory animal performs an operant response to obtain the drug.

Drug seeking

Behaviour that is assessed, after drug self-administration regimens in laboratory animals, by measuring the number of operant responses performed by an animal under conditions in which the operant responses (that previously delivered the drug) are no longer drug reinforced.

Extinction training

A procedure carried out after stable drug self-administration is established that leads to cessation of drug seeking. During the procedure, animals undergo repeated sessions during which the operant response no longer results in drug delivery.

Reinstatement test

An experimental procedure that is designed to model relapse in laboratory animals. It is performed after a drug self-administration regimen and a period of extinction training. During the reinstatement test, exposure to a drug-associated cue or context, a stressor or non-contingent drug injection leads to resumption of drug seeking.

Seeking test

An experimental procedure to assess drug craving and relapse in laboratory animals during abstinence from drug self-administration regimens (but without a period of extinction training). During a cue-induced seeking test, operant responses lead to presentation of the discrete cue that was previously paired with drug infusions but do not cause delivery of the drug.

Extended-access cocaine self-administration

Regimens that use longer daily sessions of self-administration (for example, 6 hours per session for 10–20 days) or shorter daily sessions (for example, 2 hours) for 1–2 months. Such regimens produce behavioural changes that are thought to model compulsive drug seeking in addicts.

Limited-access cocaine self-administration

Regimens during which cocaine is available for 1–2 hours per session for 1–2 weeks; these regimens are not thought to model compulsive drug seeking in addicts.

Withdrawal day

(WD). A term used to describe the duration of abstinence in experimental models.

Ca2+-permeable AMPA receptors

(CP-AMPARs). AMPARs that lack the GluA2 subunit (or that contain unedited GluA2) and therefore exhibit permeability to Ca2+. Compared to Ca2+-impermeable-AMPARs, they exhibit larger single-channel conductance and faster kinetics, and inward rectification owing to voltage-dependent block by intracellular polyamines.

Ca2+-impermeable AMPA receptors

(CI-AMPARs). AMPARs that contain an edited GluA2 subunit and are therefore impermeable to Ca2+. Most AMPARs in the brain are of this type.

Silent synapse

A synapse that contains NMDA receptors but not AMPA receptors, and is therefore silent at the hyperpolarized membrane potentials at which synaptic transmission is typically initiated.

Second-order schedule of reinforcement

A procedure designed to model 'real world' seeking of drugs by humans, which is highly driven by cues and only sporadically results in drug delivery. During the procedure, rats respond to a cocaine-associated cue for a prolonged period to obtain an infusion of cocaine.

Reversible inactivation

An experimental procedure during which drugs that inhibit neuronal activity are infused into a particular brain region of an experimental animal before a behavioural test in order to evaluate the requirement for that brain region in the expression of the behaviour.

Pavlovian-to-instrumental transfer

(PIT). The ability of a Pavlovian cue previously paired with a positive reinforcer to enhance operant (instrumental) responding for the same reinforcer when presented unexpectedly (independently of the operant response).

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Wolf, M. Synaptic mechanisms underlying persistent cocaine craving. Nat Rev Neurosci 17, 351–365 (2016). https://doi.org/10.1038/nrn.2016.39

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