A systematic, integrative review of the effects of the endocannabinoid system on inflammation and neurogenesis in animal models of affective disorders

The endocannabinoid (eCB) system is considered relevant in the pathophysiology of affective disorders, and a potential therapeutic target, as its hypoactivity is considered an important risk factor of depression. However, the biological mechanisms whereby the eCB system affects mood remain elusive. Through a systematic review, thirty-seven articles were obtained from the PubMed/Medline, Web of Science, Embase, PsychInfo, and CINAHL databases, investigating the role of the eCB system on the immune system and neurogenesis, as well as resulting behavioural effects in rodent models of affective disorders. Overall, activation of the eCB system appears to decrease depressive-like behaviour and to be anti-inflammatory, while promoting neuro- and synaptogenesis in various models. Activation of cannabinoid receptors (CBRs) is shown to be crucial in improving depressive-like and anxiety-like behaviour, although cannabidiol administration suggests a role of additional mechanisms. CB₁R signalling, as well as fatty acid amide hydrolase (FAAH) inhibition, are associated with decreased pro-inflammatory cytokines. Moreover, activation of CBRs is required for neurogenesis, which is also upregulated by FAAH inhibitors. This review is the first to assess the association between the eCB system, immune system and neurogenesis, alongside behavioural outcomes, across rodent models of affective disorders. We confirm the therapeutic potential of eCB system activation in depression and anxiety, highlighting immunoregulation as an important mechanism whereby dysfunctional behaviour and neurogenesis can be improved.