To examine the cannabinoid hypothesis for pathogenesis of schizophrenia, we examined two kinds of polymorphisms of the CNR1 gene, which encodes human CB1 receptor, a subclass of central cannabinoid receptors, in schizophrenics and age-matched controls in the Japanese population. Allelic and genotypic distributions of polymorphism 1359G/A at codon 453 in the coding region and AAT triplet repeats in the 3Ј flanking region in the Japanese population were quite different from those in Caucasians. Although the polymorphism 1359G/A was not associated with schizophrenia, the triplet repeat polymorphism of the CNR1 gene was significantly associated with schizophrenia, especially the hebephrenic subtype (P = 0.0028). Hebephrenic schizophrenia showed significantly increased rate of the 9 repeat allele (P = 0.032, OR = 2.30, 95% CI (1.91-2.69)), and decreased rate of the 17 repeat allele (P = 0.011, OR = 0.208, 95% CI (0.098-0.439)). The present findings indicated that certain alleles or genotypes of the CNR1 gene may confer a susceptibility of schizophrenia, especially of the hebephrenic type. Molecular Psychiatry (2002Psychiatry ( ) 7, 515-518. doi:10.1038 The cannabinoid hypothesis for the pathogenesis of schizophrenia is supposed to be based on the clinical facts that abuse of cannabis could precipitate the psychotic state, with hallucinations and delusions resembling schizophrenia 1-4 and worsen positive symptoms of schizophrenia, 5,6 even under regular medication of antipsychotics. 7 Cannabinoid consumption could result in poor outcome and liability to relapse for schizophrenics. [8][9][10] In addition, heavy cannabis users may develop an amotivational syndrome, reminiscent of some of the negative symptoms of schizophrenia. 11 A Swedish cohort study showed that cannabis use before 18 years of age raises the incidence rate of schizophrenia six-fold. 12 Another study showed that administration of delta-9-hydrocannabinol to normal volunteers induced cognitive impairment of three dimensions resembling closely that of schizophrenic patients. 13 The hallucinogenic action of cannabis and marijuana mediated the central cannabinoid receptor, G protein-coupled receptor CB1, which was discovered in 1988. 14 CB1 receptors were expressed abundantly throughout the brain, especially in substantia nigra, globus pallidus, hippocampus and cerebellum. 15,16 CB1 receptors are encoded by the CNR1 gene (MIM114610), which was cloned by Matsuda et al in 1992. 17 CB1 is located at 6q14-q15, which was included in a schizophrenia susceptibility locus, 6q13-q26, revealed by Cao et al 18 using two independent series of pedigrees, which was designated by Schizophrenia 5 (SCZ5, OMIM 603175). Recently, two polymorphisms, AAT repeats microsatellite in the 3Ј flanking region and 1359 G/A polymorphism at codon 453 in the coding exon of the CNR1 gene, were reported. 19,20 To examine the cannabinoid hypothesis for schizophrenia, we examined these two polymorphisms in the CNR1 gene of schizophrenia in the Japanese population.Genotypic distribution and a...

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Proper distribution of immune cells in the uterus is a prerequisite for successful implantation and subsequent placentation, but biochemical signals that govern such events have not been well characterized. In the present study, the cDNA of a chemokine, interferon (IFN)-gamma-inducible protein 10 kDa (IP-10), was identified from a cDNA subtraction study between uterine endometrial tissues from Day 17 pregnant and Day 15 cyclic ewes. The effect of IFN-tau on IP-10 expression and the involvement of IP-10 in the recruitment of immune cells were then investigated. Northern blot analysis revealed that large amounts of IP-10 mRNA were present during conceptus attachment to maternal endometrium and early placentation. IP-10 mRNA was localized to monocytes distributed in the subepithelial stroma of pregnant but not cyclic uteri. This finding was supported by the discovery of IP-10 mRNA expression in monocytes but not in lymphocytes, uterine epithelial cells, or stromal cells. Moreover, the expression of IP-10 mRNA by the monocytes was stimulated by IFN-alpha, IFN-gamma, and IFN-tau in a dose-dependent manner, but the expression of IP-10 mRNA by the endometrial explants was most stimulated by IFN-tau. In a chemotaxis assay, migration of peripheral blood mononuclear cells was stimulated by the addition of IFN-tau stimulated-endometrial culture medium, and the effect was significantly reduced by neutralization with an anti-IP-10 antibody. These results suggest that endometrial IP-10 regulated by conceptus IFN-tau regulates recruitment and/or distribution of immune cells seen in the early pregnant uterus.