Brain Cannabinoid CB2 Receptor in Schizophrenia
Brain Cannabinoid CB2 Receptor in Schizophrenia
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DOI：
10.1016/j.biopsych.2009.09.024
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发表时间：
2010-05-15
影响因子：
10.6
通讯作者：
Arinami, Tadao
中科院分区：
文献类型：
--
作者：
Ishiguro, Hiroki;Horiuchi, Yasue;Arinami, Tadao
背景：神经内源性大麻素功能似乎与精神分裂症有关。两种内源性大麻素受体CB 1和CB 2存在于大脑和身体的其他部位。我们调查CB 2在精神分裂症中的作用。材料与方法：在两个独立的病例对照人群中，进行了CNR 2基因编码CB 2受体和精神分裂症的标签单核苷酸多态性（SNP）之间的关联研究。在人类死后脑组织和培养细胞中分析相关SNP的等位基因差异。C57 BL/6 JJmsSlc小鼠与CB 2受体拮抗剂AM 630管理的前脉冲抑制和自发活动进行了检查。结果：在第一个群体中的分析显示精神分裂症和两个SNPs之间名义上显着的关联，并在第二个群体中复制的关联。与1920名对照组相比，1920名精神分裂症患者中rs 2501432（R63 Q）的R63等位基因（p = 0.001）、rs 12744386的C等位基因（p = 0.005）和R63-C等位基因的单倍型（p = 5 × 10 - 6）显著增加。与Q63相比，R63等位基因转染的CHO细胞对CB 2配体的反应显著降低，并且与11基因型相比，观察到CC和CT基因型rs 12744386在人脑中发现的CB 2受体mRNA和蛋白水平显著降低。AM 630加重MK-801或甲基苯丙胺诱导的干扰前脉冲抑制和多动症在C57 BL/6JJmsSlc.Conclusions：这些研究结果表明，精神分裂症的风险增加的人与低CB 2受体功能。
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 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 11 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.