Chronic blockade of cannabinoid CB 2 receptors induces anxiolytic-like actions associated with alterations in GABA A receptors

Abstract

BACKGROUND AND PURPOSE The aim of this study was to explore the effects of CB 2 receptor agonist and antagonist in the regulation of anxiety-like behaviours. EXPERIMENTAL APPROACHES Effects of acute and chronic treatment with the CB 2 receptor agonist JWH133 and CB 2 receptor antagonist AM630 were evaluated in the light-dark box (LDB) and elevated plus maze (EPM) tests in Swiss ICR mice. CB 2 receptor, GABA Aα 2 and GABA Aγ 2 gene 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 RESULTS Acute 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 CB 2 receptors, GABA Aα 2 and GABA Aγ 2 in 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 IMPLICATIONS The opposing behavioural and molecular changes observed after chronic treatment with AM630 or JWH133 support the key role of CB 2 receptors 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 CB 2 receptor as a new target in the treatment of anxiety-related disorders. © 2011 The British Pharmacological Society.