Depression-resistant endophenotype in mice overexpressing cannabinoid CB 2 receptors

12 p., 5 figures, 2 tables and references.Background and purpose: The present study evaluated the role of CB 2 receptors in the regulation of depressive-like behaviours. Transgenic mice overexpressing the CB 2 receptor (CB2xP) were challenged with different types of acute and chronic experimental paradigms to evaluate their response in terms of depressive-like behaviours. Experimental approach: Tail suspension test (TST), novelty-suppressed feeding test (NSFT) and unpredictable chronic mild stress tests (CMS) were carried out in CB2xP mice. Furthermore, acute and chronic antidepressant-like effects of the CB 2 receptor-antagonist AM630 were evaluated by means of the forced swimming test (FST) and CMS, respectively, in wild-type (WT) and CB2xP mice. CB 2 gene expression, brain-derived neurotrophic factor (BDNF) gene and protein expressions were studied in mice exposed to CMS by real-time PCR and immunohistochemistry, respectively. Key results: Overexpression of CB 2 receptors resulted in decreased depressive-like behaviours in the TST and NSFT. CMS failed to alter the TST and sucrose consumption in CB2xP mice. In addition, no changes in BDNF gene and protein expression were observed in stressed CB2xP mice. Interestingly, acute administration of AM630 (1 and 3 mg·kg -1, i.p.) exerted antidepressant-like effects on the FST in WT, but not in CB2xP mice. Chronic administration of AM630 for 4 weeks (1 mg·kg -1; twice daily, i.p.) blocked the effects of CMS on TST, sucrose intake, CB 2 receptor gene, BDNF gene and protein expression in WT mice. Conclusion and implications: Taken together, these results suggest that increased CB 2 receptor expression significantly reduced depressive-related behaviours and that the CB 2 receptor could be a new potential therapeutic target for depressive-related disorders.This research was supported by grants from Ministry of Science and Innovation (SAF 2008-01106) and Ministry of Health (RETICS RD06/0001/1004 and PNSD 2007/061). MSGG is a predoctoral fellow of the Ministry of Science and Innovation. JMPO is a postdoctoral fellow of ‘Fundación para la Investigación y Salud de Castilla La Mancha’ (FISCAM).Peer reviewe