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

Abstract

The possible role of the CB 2 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 (CB 2 KO) 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-a 2C (a 2C r), serotonergic 5-HT 2A and 5-HT 2C 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 CB 2 KO mice. CB 2 KO mice presented increased D 2 r and a 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 a 2C r gene expression unchanged, decreased D 2 r gene expression (15 mg/kg), and decreased 5-HT 2C r and 5-HT 2A r in PFC and DR. In CB 2 KO, the gene expression of D 2 r in the PFC, of a 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.

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

“…This is consistent with our previous findings that systemic or local administration of JWH133 into the nucleus accumbens inhibits cocaine self-administration (22), and that transgenic up-regulation of brain CB 2 Rs attenuates cocaine self-administration and cocaine-induced increased locomotion (19). The present findings are also congruent with recent reports that brain CB 2 Rs have important roles in other DArelated functions and/or CNS disorders (12,25,51,52).…”

“…This finding is supported by recent studies demonstrating that systemic administration of the CB 2 R agonist O-1966 inhibited cocaine-induced conditioned place preference in WT mice, but not in CB 2 −/− mice (23), and that increased CB 2 R expression in mouse brain attenuates cocaine self-administration and cocaine-enhanced locomotion (19). In addition, brain CB 2 Rs may be involved in several DA-related CNS disorders, such as Parkinson's disease (24), schizophrenia (25), anxiety (26), and depression (27). The cellular mechanisms underlying CB 2 R modulation of DA-related behaviors and diseases are unclear, however.…”

Differential Pharmacological Regulation of Sensorimotor Gating Deficit in CB1 Knockout Mice and Associated Neurochemical and Histological Alterations

“…Several studies in animal models have demonstrated that dopaminergic activation (eg, apomorphine treatment, deletion of DAT) induces PPI disruption that is blocked by dopaminergic antagonists such as typical or atypical antipsychotics (Swerdlow and Geyer, 1993). In our study, treatment with risperidone or haloperidol did not modify PPI values in CB1KO mice, whereas a tendency toward an impairment effect was obtained in WT mice as shown previously (Ortega-Alvaro et al, 2011). Interestingly, the administration of the psychostimulant methylphenidate significantly improved PPI in CB1KO mice.…”

“…As our knowledge about the neurobiology of preattentional deficit-related disorders from human studies is limited, it is quite difficult to decide which model best represents the PPI disruption of a specific psychiatric disorder. Recently, we used a phenotype-based approach in CB2r knockout (CB2KO) mice to explore the role of the CNR2 gene in a particular phenotype related to schizophrenia because of the amelioration effect achieved with the risperidone treatment (Ortega-Alvaro et al, 2011). In the case of the CNR1 gene, we found a different behavioral phenotype in CB1r knockout (CB1KO) mice.…”

Targeted zwitterionic near infrared fluorescent probe for improved imaging of type 2 cannabinoid receptors

“…2 In a number of additional cell types under disease conditions, CB 2 R expression is greatly up-regulated. 3 The richness of CB 2 R involvement has positioned the receptor as an attractive therapeutic target for treating an array of pathologies, such as cancers, 4,5 neurodegenerative diseases, 2,6 inflammation, 7,8 pain, 9 osteoporosis, 10 immunological disorders, [11][12][13] and drug abuse. 14 As such, there has been an explosion of research over the past 12 years that focused on the biology and therapeutic promises of CB 2 R. However, the precise role of CB 2 R in the regulation of diseases remains unclear.…”