Endocannabinoid signalling in reward and addiction

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.