Abstract
The possible role of the CB2 receptor (CB2r) in psychiatric disorders has been considered. Several animal models use knockout (KO) mice that display schizophrenia-like behaviors and this study evaluated the role of CB2r in the regulation of such behaviors. Mice lacking the CB2r (CB2KO) were challenged in open field, light–dark box, elevated plus-maze, tail suspension, step down inhibitory avoidance, and pre-pulse inhibition tests (PPI). Furthermore, the effects of treatment with cocaine and risperidone were evaluated using the OF and the PPI test. Gene expression of dopamine D2 (D2r), adrenergic-α2C (α2Cr), serotonergic 5-HT2A and 5-HT2C receptors (5-HT2Ar and 5-HT2Cr) were studied by RT-PCR in brain regions related to schizophrenia. Deletion of CB2r decreased motor activity in the OF test, but enhanced response to acute cocaine and produced mood-related alterations, PPI deficit, and cognitive impairment. Chronic treatment with risperidone tended to impair PPI in WT mice, whereas it ‘normalized’ the PPI deficit in CB2KO mice. CB2KO mice presented increased D2r and α2Cr gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT2Cr gene expression in the dorsal raphe (DR), and 5-HT2Ar gene expression in the PFC. Chronic risperidone treatment in WT mice left α2Cr gene expression unchanged, decreased D2r gene expression (15 μg/kg), and decreased 5-HT2Cr and 5-HT2Ar in PFC and DR. In CB2KO, the gene expression of D2r in the PFC, of α2Cr in the LC, and of 5-HT2Cr and 5-HT2Ar in PFC was reduced; 5-HT2Cr and 5-HT2Ar gene expressions in DR were increased after treatment with risperidone. These results suggest that deletion of CB2r has a relation with schizophrenia-like behaviors. Pharmacological manipulation of CB2r may merit further study as a potential therapeutic target for the treatment of schizophrenia-related disorders.
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Acknowledgements
This research was supported by grants from the Ministry of Science and Innovation (SAF 2008-01106) and Ministry of Health (RETICS RD06/0001/1004 and PNSD 2007/061) to JM. AOA is a postdoctoral fellow of ‘Fundación para la Investigación Sanitaria en Castilla La Mancha’ (FISCAM). MSGG and FN are predoctoral fellows from the Spanish Ministry of Science and Innovation, respectively. AAF is a predoctoral fellow from RETICS. We thank Patricia Rodríguez (FISCAM), Raquel Poveda (FISCAM), and Analía Rico (RETICS) for excellent technical assistance. We thank Dr. José Sánchez from ‘Servicio de Medicina Preventiva’ of ‘Hospital General Universitario de Alicante’ for statistical advice.
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Ortega-Alvaro, A., Aracil-Fernández, A., García-Gutiérrez, M. et al. Deletion of CB2 Cannabinoid Receptor Induces Schizophrenia-Related Behaviors in Mice. Neuropsychopharmacol 36, 1489–1504 (2011). https://doi.org/10.1038/npp.2011.34
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