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

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-α_2C (α_2Cr), serotonergic 5-HT_2A and 5-HT_2C receptors (5-HT_2Ar and 5-HT_2Cr) 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 α_2Cr gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT_2Cr gene expression in the dorsal raphe (DR), and 5-HT_2Ar gene expression in the PFC. Chronic risperidone treatment in WT mice left α_2Cr gene expression unchanged, decreased D₂r gene expression (15 μg/kg), and decreased 5-HT_2Cr and 5-HT_2Ar in PFC and DR. In CB₂KO, the gene expression of D₂r in the PFC, of α_2Cr in the LC, and of 5-HT_2Cr and 5-HT_2Ar in PFC was reduced; 5-HT_2Cr and 5-HT_2Ar 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.