BACKGROUND AND PURPOSEThe aim of this study was to explore the effects of CB2receptor agonist and antagonist in the regulation of anxiety‐like behaviours.EXPERIMENTAL APPROACHESEffects of acute and chronic treatment with the CB2receptor agonist JWH133 and CB2receptor antagonist AM630 were evaluated in the light‐dark box (LDB) and elevated plus maze (EPM) tests in Swiss ICR mice. CB2receptor, GABAAα2and GABAAγ2gene and protein expression in the cortex and amygdala of mice chronically treated with JWH133 or AM630 were examined by RT‐PCR and Western blot. Effects of chronic AM630 treatment were evaluated in spontaneously anxious DBA/2 mice in LDB.KEY RESULTSAcute JWH133 treatment failed to produce any effect. Acute AM630 treatment increased anxiety and was blocked by pre‐treatment with JWH133. Chronic JWH133 treatment increased anxiety‐like behaviour whereas chronic AM630 treatment was anxiolytic in LDB and EPM tests. Chronic AM630 treatment increased gene and reduced protein expression of CB2receptors, GABAAα2and GABAAγ2in cortex and amygdala. Chronic JWH133 treatment resulted in opposite gene and protein alterations. In addition, chronic AM630 administration decreased the anxiety of DBA/2 mice in the LDB test.CONCLUSIONS AND IMPLICATIONSThe opposing behavioural and molecular changes observed after chronic treatment with AM630 or JWH133 support the key role of CB2receptors in the regulation of anxiety. Indeed, the efficacy of AM630 in reducing the anxiety of the spontaneously anxious DBA/2 strain of mice strengthens the potential of the CB2receptor as a new target in the treatment of anxiety‐related disorders.