Deletion of CB2 Cannabinoid Receptor Induces Schizophrenia-Related Behaviors in Mice

作者：Ortega Alvaro Antonio; Aracil Fernandez Auxiliadora; Garcia Gutierrez Maria S; Navarrete Francisco; Manzanares Jorge^*

来源：Neuropsychopharmacology, 2011, 36(7): 1489-1504.

DOI：10.1038/npp.2011.34

• cannabinoid
• CB2 receptor
• schizophrenia
• risperidone
• pre-pulse inhibition
• gene expression

The possible role of the CB2 receptor (CB(2)r) 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 CB(2)r in the regulation of such behaviors. Mice lacking the CB(2)r (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 D-2 (D(2)r), adrenergic-alpha(2C) (alpha(2C)r), serotonergic 5-HT2A and 5-HT2C receptors (5-HT(2A)r and 5-HT(2C)r) were studied by RT-PCR in brain regions related to schizophrenia. Deletion of CB(2)r 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 D(2)r and alpha(2C)r gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT(2C)r gene expression in the dorsal raphe (DR), and 5-HT(2A)r gene expression in the PFC. Chronic risperidone treatment in WT mice left alpha(2C)r gene expression unchanged, decreased D(2)r gene expression (15 mu g/kg), and decreased 5-HT(2C)r and 5-HT(2A)r in PFC and DR. In CB2KO, the gene expression of D(2)r in the PFC, of alpha(2C)r in the LC, and of 5-HT(2C)r and 5-HT(2A)r in PFC was reduced; 5-HT(2C)r and 5-HT(2A)r gene expressions in DR were increased after treatment with risperidone. These results suggest that deletion of CB(2)r has a relation with schizophrenia-like behaviors. Pharmacological manipulation of CB(2)r may merit further study as a potential therapeutic target for the treatment of schizophrenia-related disorders. Neuropsychopharmacology (2011) 36, 1489-1504; doi:10.1038/npp.2011.34; published online 23 March 2011

• 出版日期2011-6