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Endocannabinoid signalling in reward and addiction

Nature Reviews Neuroscience volume 16, pages 579–594 (2015)Cite this article

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Key Points

  • Cannabinoid receptors and their endogenous ligands are widely expressed throughout the brain, with a particularly strong presence and influence in neuronal circuits such as the mesocorticolimbic pathways highly implicated in reward and addiction.

  • Cannabinoid 1 receptor (CB1R) signalling influences the motivation for both natural and drug rewards. In comparison to most drugs of abuse, CB1Rs exert only modest influence on psychostimulant intake.

  • Brain endocannabinoid (eCB) levels are increased by most drugs of abuse, although the nature of this effect differs between classes of drugs and across brain regions. The response contingency of drug exposure (volitional versus response-independent) seems to influence brain eCB production, suggesting contributions both of drug-related pharmacological effects and of neural activity engaged by active drug-seeking behaviour.

  • Chronic exposure to drugs of abuse generally results in impaired CB1R function, loss of eCB-mediated synaptic plasticity in addiction-related neural circuits, and negative affective states that can be ameliorated through pharmacologically enhanced eCB tone. The eCB system (ECS) has a strong role in modulating relapse-like behaviour induced by conditioned cues or reward priming, and this is evident for both natural and drug rewards.

  • Recent investigations of CNR1 (which encodes CB1R) and fatty acid amide hydrolase (FAAH) variants generally suggest an association with endophenotypes implicated in addiction susceptibility, including reward sensitivity, impulsivity and negative affect. However, confounding factors, including restricted sample size, ethnicity and polysubstance use, limit interpretational power, and the functional consequences of the variants (causal or linked) are currently unknown.

Abstract

Brain endocannabinoid (eCB) signalling influences the motivation for natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of addictive drugs. Pathological forms of natural and drug-induced reward are associated with dysregulated eCB signalling that may derive from pre-existing genetic factors or from prolonged drug exposure. Impaired eCB signalling contributes to dysregulated synaptic plasticity, increased stress responsivity, negative emotional states and cravings that propel addiction. Understanding the contributions of eCB disruptions to behavioural and physiological traits provides insight into the eCB influence on addiction vulnerability.

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Figure 1: Endocannabinoid biosynthesis, signalling and clearance.
Figure 2: Distribution of endocannabinoid signalling mechanisms within the brain reward circuits.
Figure 3: Endocannabinoid influences in the VTA and NAc contributing to approach and avoidance behaviours.
Figure 4: Drug-induced alterations in endocannabinoid-mediated synaptic plasticity.
Figure 5: CNR1 and FAAH genes and genetic variants associated with addiction.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health to L.H.P. (AA020404, AA006420, AA022249 and AA017447) and Y.L.H. (DA023214, DA030359 and DA033660). This is manuscript number 29049 from The Scripps Research Institute. The authors thank D. Lewis for his help during the preparation of this manuscript.

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Authors and Affiliations

  1. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Loren H. Parsons

  2. Departments of Psychiatry and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York City, 10029, New York, USA

    Yasmin L. Hurd

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  1. Loren H. Parsons
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Correspondence to Loren H. Parsons or Yasmin L. Hurd.

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Glossary

Synaptic plasticity

The process by which synaptic communication strengthens or weakens as a result of changes in morphology, composition or signal-transduction efficiency in response to intrinsic or extrinsic signals.

Limbic system

A collection of brain structures that includes the amygdala, hippocampus, limbic cortex, limbic midbrain areas and anterior thalamic nuclei, regulates autonomic and endocrine function and participates in the control of emotion, motivation, long-term memory and olfaction.

Intracranial self-stimulation

An operant behavioural paradigm in which subjects produce a behavioural response (such as a lever press or wheel turn) to receive brief electrical pulses into specific regions in the brain reward pathways.

Conditioned place preference

(CPP). A behavioural paradigm used to study the rewarding and aversive effects of drugs through Pavlovian conditioning.

Self-administered

In a medical sense, when a pharmacological substance is purposefully delivered by test subjects to themselves. Operant self-administration is a behavioural procedure in which experimental subjects learn to produce an operant response (for example, a lever press or nose poke) to receive a drug reward (such as an intravenous infusion, a small bolus for oral consumption or delivery of a discrete bolus of vapour that is inhaled).

Discriminative stimulus

A stimulus in a drug-discrimination paradigm that the animal has learned to associate with a predictable consequence (whether rewarding or unrewarding) and that increases the elicitation of a specific behaviour by the animal.

Non-contingent

Drug delivery that is involuntary (experimenter-administered) or is not dependent on a behavioural response by an experimental subject; sometimes referred to as forced administration.

Epigenetic mechanisms

Methods by which functionally relevant changes to the genome occur that do not involve disruptions in the nucleotide sequence of DNA; these include DNA methylation, histone modification and non-coding RNA-associated gene silencing

Extended amygdala

A grouping of brain regions that orchestrate emotional behavioural responses and includes the central nucleus of the amygdala, sublenticular substantia innominate, nucleus accumbens shell and the bed nucleus of the stria terminalis.

Conditioned reinforcement

The process through which neutral stimuli acquire motivational properties through association with a primary reinforcer.

Stochastic optical reconstruction microscopy

A super-resolution imaging technique that uses sequential activation and time-resolved localization of photoswitchable fluorophores to create high-resolution images enabling precise fluorophore localization with nanometre resolution.

Cytogenetic band

A distinct region on the chromosome (visible microscopically after special staining).

Endophenotype

A term used to separate behavioural symptoms into stable phenotypes with a clear genetic basis, typically applicable to heritable disorders.

Haplotype blocks

Sets of DNA variations (or polymorphisms) that tend to be inherited together.

Post-translational histone modification

A covalent modification of histones that package and order DNA into nucleosomes. These modifications occur during or after histone biosynthesis.

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Parsons, L., Hurd, Y. Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci 16, 579–594 (2015). https://doi.org/10.1038/nrn4004

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