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 Niizato & 7 others Shyuji 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

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Cannabinoid Receptor CB2
Schizophrenia
Brain
Alleles
Single Nucleotide Polymorphism
Endocannabinoids
Inbred C57BL Mouse
Population
Cultured Cells
Genotype
Cannabinoid Receptor CB1
Dizocilpine Maleate
Methamphetamine
CHO Cells
Locomotion
Haplotypes
Ligands
Messenger RNA
Genes

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Ishiguro, H., Horiuchi, Y., Ishikawa, M., Koga, M., Imai, K., Suzuki, Y., ... 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
Ishiguro, Hiroki ; Horiuchi, Yasue ; Ishikawa, Maya ; Koga, Minori ; Imai, Keiko ; Suzuki, Yoshimi ; Morikawa, Miyuki ; Inada, Toshiya ; Watanabe, Yuichiro ; Takahashi, Makoto ; Someya, Toshiyuki ; Ujike, Hiroshi ; Iwata, Nakao ; Ozaki, Norio ; Onaivi, Emmanuel S. ; Kunugi, Hiroshi ; Sasaki, Tsukasa ; Itokawa, Masanari ; Arai, Makoto ; Niizato, Kazuhiro ; Iritani, Shyuji ; Naka, Izumi ; Ohashi, Jun ; Kakita, Akiyoshi ; Takahashi, Hitoshi ; Nawa, Hiroyuki ; Arinami, Tadao. / Brain Cannabinoid CB2 Receptor in Schizophrenia. In: Biological Psychiatry. 2010 ; Vol. 67, No. 10. pp. 974-982.
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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.",
author = "Hiroki Ishiguro and Yasue Horiuchi and Maya Ishikawa and Minori Koga and Keiko Imai and Yoshimi Suzuki and Miyuki Morikawa and Toshiya Inada and Yuichiro Watanabe and Makoto Takahashi and Toshiyuki Someya and Hiroshi Ujike and Nakao Iwata and Norio Ozaki and Onaivi, {Emmanuel S.} and Hiroshi Kunugi and Tsukasa Sasaki and Masanari Itokawa and Makoto Arai and Kazuhiro Niizato and Shyuji Iritani and Izumi Naka and Jun Ohashi and Akiyoshi Kakita and Hitoshi Takahashi and Hiroyuki Nawa and Tadao Arinami",
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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, ES, Kunugi, H, Sasaki, T, Itokawa, M, Arai, M, Niizato, K, Iritani, S, Naka, I, Ohashi, J, Kakita, A, Takahashi, H, Nawa, H & Arinami, T 2010, 'Brain Cannabinoid CB2 Receptor in Schizophrenia', Biological Psychiatry, vol. 67, no. 10, pp. 974-982. https://doi.org/10.1016/j.biopsych.2009.09.024

Brain Cannabinoid CB2 Receptor in Schizophrenia. / Ishiguro, Hiroki; Horiuchi, Yasue; Ishikawa, Maya; Koga, Minori; Imai, Keiko; Suzuki, Yoshimi; Morikawa, Miyuki; Inada, Toshiya; Watanabe, Yuichiro; Takahashi, Makoto; Someya, Toshiyuki; Ujike, Hiroshi; Iwata, Nakao; Ozaki, Norio; Onaivi, Emmanuel S.; Kunugi, Hiroshi; Sasaki, Tsukasa; Itokawa, Masanari; Arai, Makoto; Niizato, Kazuhiro; Iritani, Shyuji; Naka, Izumi; Ohashi, Jun; Kakita, Akiyoshi; Takahashi, Hitoshi; Nawa, Hiroyuki; Arinami, Tadao.

In: Biological Psychiatry, Vol. 67, No. 10, 15.05.2010, p. 974-982.

Research output: Contribution to journalArticle

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T1 - Brain Cannabinoid CB2 Receptor in Schizophrenia

AU - Ishiguro, Hiroki

AU - Horiuchi, Yasue

AU - Ishikawa, Maya

AU - Koga, Minori

AU - Imai, Keiko

AU - Suzuki, Yoshimi

AU - Morikawa, Miyuki

AU - Inada, Toshiya

AU - Watanabe, Yuichiro

AU - Takahashi, Makoto

AU - Someya, Toshiyuki

AU - Ujike, Hiroshi

AU - Iwata, Nakao

AU - Ozaki, Norio

AU - Onaivi, Emmanuel S.

AU - Kunugi, Hiroshi

AU - Sasaki, Tsukasa

AU - Itokawa, Masanari

AU - Arai, Makoto

AU - Niizato, Kazuhiro

AU - Iritani, Shyuji

AU - Naka, Izumi

AU - Ohashi, Jun

AU - Kakita, Akiyoshi

AU - Takahashi, Hitoshi

AU - Nawa, Hiroyuki

AU - Arinami, Tadao

PY - 2010/5/15

Y1 - 2010/5/15

N2 - 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.

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Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y et al. Brain Cannabinoid CB2 Receptor in Schizophrenia. Biological Psychiatry. 2010 May 15;67(10):974-982. https://doi.org/10.1016/j.biopsych.2009.09.024