Brain Cannabinoid CB2 Receptor in Schizophrenia

Hiroki Ishiguro, Yasue Horiuchi, Maya Ishikawa, Minori Koga, Keiko Imai, Yoshimi Suzuki, Miyuki Morikawa, Toshiya Inada, Yuichiro Watanabe, Makoto Takahashi, Toshiyuki Someya, Hiroshi Ujike, Nakao Iwata, Norio Ozaki, Emmanuel S. Onaivi, Hiroshi Kunugi, Tsukasa Sasaki, Masanari Itokawa, Makoto Arai, Kazuhiro NiizatoShyuji Iritani, Izumi Naka, Jun Ohashi, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki Nawa, Tadao Arinami

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Abstract

Background: Neural endocannabinoid function appears to be involved in schizophrenia. Two endocannabinoid receptors, CB1 and CB2, are found in the brain and elsewhere in the body. We investigated roles of CB2 in schizophrenia. Materials and Methods: An association study was performed between tag single nucleotide polymorphisms (SNPs) in the CNR2 gene encoding the CB2 receptor and schizophrenia in two independent case-control populations. Allelic differences of associated SNPs were analyzed in human postmortem brain tissues and in cultured cells. Prepulse inhibition and locomotor activity in C57BL/6JJmsSlc mice with CB2 receptor antagonist AM630 administration was examined. Results: The analysis in the first population revealed nominally significant associations between schizophrenia and two SNPs, and the associations were replicated in the second population. The R63 allele of rs2501432 (R63Q) (p = .001), the C allele of rs12744386 (p = .005) and the haplotype of the R63-C allele (p = 5 × 10-6) were significantly increased among 1920 patients with schizophrenia compared with 1920 control subjects in the combined population. A significantly lower response to CB2 ligands in cultured CHO cells transfected with the R63 allele compared with those with Q63, and significantly lower CB2 receptor mRNA and protein levels found in human brain with the CC and CT genotypes of rs12744386 compared with TT genotype were observed. AM630 exacerbated MK-801- or methamphetamine-induced disturbance of prepulse inhibition and hyperactivity in C57BL/6JJmsSlc mice. Conclusions: These findings indicate an increased risk of schizophrenia for people with low CB2 receptor function.

Original languageEnglish
Pages (from-to)974-982
Number of pages9
JournalBiological Psychiatry
Volume67
Issue number10
DOIs
Publication statusPublished - 15-05-2010

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

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  • Cite this

    Ishiguro, H., Horiuchi, Y., Ishikawa, M., Koga, M., Imai, K., Suzuki, Y., Morikawa, M., Inada, T., Watanabe, Y., Takahashi, M., Someya, T., Ujike, H., Iwata, N., Ozaki, N., Onaivi, E. S., Kunugi, H., Sasaki, T., Itokawa, M., Arai, M., ... Arinami, T. (2010). Brain Cannabinoid CB2 Receptor in Schizophrenia. Biological Psychiatry, 67(10), 974-982. https://doi.org/10.1016/j.biopsych.2009.09.024