Brain cannabinoid CB2 receptor in schizophrenia.
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.


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 x 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.
Ishiguro
Hiroki
H
Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. hishigur@md.tsukuba.ac.jp
Horiuchi
Yasue
Y
Ishikawa
Maya
M
Koga
Minori
M
Imai
Keiko
K
Suzuki
Yoshimi
Y
Morikawa
Miyuki
M
Inada
Toshiya
T
Watanabe
Yuichiro
Y
Takahashi
Makoto
M
Someya
Toshiyuki
T
Ujike
Hiroshi
H
Iwata
Nakao
N
Ozaki
Norio
N
Onaivi
Emmanuel S
ES
Kunugi
Hiroshi
H
Sasaki
Tsukasa
T
Itokawa
Masanari
M
Arai
Makoto
M
Niizato
Kazuhiro
K
Iritani
Shyuji
S
Naka
Izumi
I
Ohashi
Jun
J
Kakita
Akiyoshi
A
Takahashi
Hitoshi
H
Nawa
Hiroyuki
H
Arinami
Tadao
T
D000818:Animals; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D016022:Case-Control Studies; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*
D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; D000242:Cyclic AMP; C094023:iodopravadoline; C402944:JHW 015