1Psychiatr. Genet. 2000 Sep 10: 149-51
PMID11204352
TitleAssociation study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia.
AbstractCannabis can induce schizophrenic-like symptoms in healthy individuals. A principal active ingredient of cannabis, delta-9-tetrahydrocannabinol, acts in the brain on a specific receptor, termed the cannabinoid receptor 1 (CNR1). The human gene for CNR1 is mapped to chromosome 6q14-15, and linkage studies have produced evidence for a schizophrenia-susceptibility locus in this region. To explore a possible role for CNR1 in the pathogenesis of schizophrenic disorders, we used an association study to genotype the CNR1 polymorphism for 127 schizophrenic patients and 146 control subjects. The results demonstrate no association between CNR1 genotypes and schizophrenic disorders (P = 0.409), with these negative findings suggesting that, for Chinese populations, the (AAT)n triplet repeat in the promoter region of the CNR1 gene is not directly involved in the pathogenesis of schizophrenic disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
2Psychiatr. Genet. 2000 Sep 10: 149-51
PMID11204352
TitleAssociation study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia.
AbstractCannabis can induce schizophrenic-like symptoms in healthy individuals. A principal active ingredient of cannabis, delta-9-tetrahydrocannabinol, acts in the brain on a specific receptor, termed the cannabinoid receptor 1 (CNR1). The human gene for CNR1 is mapped to chromosome 6q14-15, and linkage studies have produced evidence for a schizophrenia-susceptibility locus in this region. To explore a possible role for CNR1 in the pathogenesis of schizophrenic disorders, we used an association study to genotype the CNR1 polymorphism for 127 schizophrenic patients and 146 control subjects. The results demonstrate no association between CNR1 genotypes and schizophrenic disorders (P = 0.409), with these negative findings suggesting that, for Chinese populations, the (AAT)n triplet repeat in the promoter region of the CNR1 gene is not directly involved in the pathogenesis of schizophrenic disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
3Mol. Psychiatry 2002 -1 7: 515-8
PMID12082570
TitleCNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia.
AbstractTo 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 3' 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
4Mol. Psychiatry 2002 -1 7: 515-8
PMID12082570
TitleCNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia.
AbstractTo 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 3' 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
5J. Pharmacol. Sci. 2004 Dec 96: 376-81
PMID15613777
TitleNew perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia.
AbstractCannabis consumption may induce psychotic states in normal individuals, worsen psychotic symptoms of schizophrenic patients, and may facilitate precipitation of schizophrenia in vulnerable individuals. Recent studies provide additional biological and genetic evidence for the cannabinoid hypothesis of schizophrenia. Examinations using [3H]CP-55940 or [3H]SR141716A revealed that the density of CB1 receptors, a central type of cannabinoid receptor, is increased in subregions of the prefrontal cortex in schizophrenia. Anandamide, an endogenous cannabinoid, is also increased in the CSF in schizophrenia. A genetic study revealed that the CNR1 gene, which encodes CB1 receptors, is associated with schizophrenia, especially the hebephrenic type. Individuals with a 9-repeat allele of an AAT-repeat polymorphism of the gene may have a 2.3-fold higher susceptibility to schizophrenia. Recent findings consistently indicate that hyperactivity of the central cannabinoid system is involved in the pathogenesis of schizophrenia or the neural mechanisms of negative symptoms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
6J. Pharmacol. Sci. 2004 Dec 96: 376-81
PMID15613777
TitleNew perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia.
AbstractCannabis consumption may induce psychotic states in normal individuals, worsen psychotic symptoms of schizophrenic patients, and may facilitate precipitation of schizophrenia in vulnerable individuals. Recent studies provide additional biological and genetic evidence for the cannabinoid hypothesis of schizophrenia. Examinations using [3H]CP-55940 or [3H]SR141716A revealed that the density of CB1 receptors, a central type of cannabinoid receptor, is increased in subregions of the prefrontal cortex in schizophrenia. Anandamide, an endogenous cannabinoid, is also increased in the CSF in schizophrenia. A genetic study revealed that the CNR1 gene, which encodes CB1 receptors, is associated with schizophrenia, especially the hebephrenic type. Individuals with a 9-repeat allele of an AAT-repeat polymorphism of the gene may have a 2.3-fold higher susceptibility to schizophrenia. Recent findings consistently indicate that hyperactivity of the central cannabinoid system is involved in the pathogenesis of schizophrenia or the neural mechanisms of negative symptoms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
7Schizophr. Res. 2006 Jun 84: 253-71
PMID16632332
TitleGene regulation by hypoxia and the neurodevelopmental origin of schizophrenia.
AbstractNeurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
8Eur Arch Psychiatry Clin Neurosci 2006 Oct 256: 437-41
PMID16788767
Title(AAT)n repeat in the cannabinoid receptor gene, CNR1: association with schizophrenia in a Spanish population.
AbstractThe cannabinoid receptor 1 gene (CNR1) has been associated with addictive disorders and schizophrenia in different studies. We have compared the frequencies of the alleles for the 3'-UTR CNR1 microsatellite in a sample of 113 Spanish schizophrenic patients, including 68 with comorbid substance abuse, and 111 healthy controls. We report that the frequency of the allele 4 of this microsatellite is significantly lower in schizophrenia patients when compared with controls (chi(2) = 7.858; df 1; P = 0.005). No differences have been found with respect to substance abuse.Thus, the allele 4 represents, in our sample, a protective factor against schizophrenia (odds ratio 0.468, 95% confidence interval (CI) 0.27-0.79). The population attributable genetic risk for the allele 4 absence is 30% (95% CI = 17-41%) and the attributable risk for the allele 4 absence in those with schizophrenia is 53% (95% CI = 20-73%). Our results suggest that, independent of substance abuse, differences in the cannabinoid system function could be involved in the vulnerability to schizophrenia in Spanish population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
9Eur Arch Psychiatry Clin Neurosci 2006 Oct 256: 437-41
PMID16788767
Title(AAT)n repeat in the cannabinoid receptor gene, CNR1: association with schizophrenia in a Spanish population.
AbstractThe cannabinoid receptor 1 gene (CNR1) has been associated with addictive disorders and schizophrenia in different studies. We have compared the frequencies of the alleles for the 3'-UTR CNR1 microsatellite in a sample of 113 Spanish schizophrenic patients, including 68 with comorbid substance abuse, and 111 healthy controls. We report that the frequency of the allele 4 of this microsatellite is significantly lower in schizophrenia patients when compared with controls (chi(2) = 7.858; df 1; P = 0.005). No differences have been found with respect to substance abuse.Thus, the allele 4 represents, in our sample, a protective factor against schizophrenia (odds ratio 0.468, 95% confidence interval (CI) 0.27-0.79). The population attributable genetic risk for the allele 4 absence is 30% (95% CI = 17-41%) and the attributable risk for the allele 4 absence in those with schizophrenia is 53% (95% CI = 20-73%). Our results suggest that, independent of substance abuse, differences in the cannabinoid system function could be involved in the vulnerability to schizophrenia in Spanish population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
10Br J Psychiatry 2007 Nov 191: 402-7
PMID17978319
TitleGenotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use.
AbstractGenetic variations might modify associations between schizophrenia and cannabis or tobacco use.
To examine whether variants within the cannabinoid receptor (CNR1) and alpha(7) nicotinic receptor (CHRNA7) genes are associated with schizophrenia, and whether these effects vary according to cannabis or tobacco use. We also examined a putative interaction between cannabis and Val(158)Met within the catechol-O-methyltransferase gene (COMT).
Genotype effects of CHRNA7 and CNR1were studied in a case-control sample of 750 individuals with schizophrenia and 688 controls, with interactions for these genes studied in small subsamples. A case-only design of 493 ofthe schizophrenia group was used to examine interactions between cannabis use and COMT.
There was no evidence of association between schizophrenia and CNR1 (OR=0.97, 95% CI 0.82-1.13) or CHRNA7 (OR=1.07, 95% CI 0.77-1.49) genotypes, or of interactions between tobacco use and CHRNA7, or cannabis use and CNR1or COMT genotypes.
Neither CNR1 nor CHRNA7 variation appears to alter the risk of schizophrenia. Furthermore, our results do not support the presence of different effects of cannabis use on schizophrenia according to variation within COMT.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
11Neurosci. Lett. 2007 Oct 426: 29-33
PMID17881126
TitleNo association of CNR1 gene variations with susceptibility to schizophrenia.
Abstractschizophrenia is one of the most common psychiatric disorders. There is a growing body of evidence associating dysregulation of the endogenous cannabinoid system with the pathogenesis of schizophrenia. In order to test the hypothesis that mutations in the central cannabinoid receptor-1 (CNR1) gene confer susceptibility to the development of schizophrenia, we performed an association study in a group of 104 German patients with schizophrenia and 140 healthy controls, using three polymorphisms within and flanking the coding exon of CNR1 (rs6454674, rs1049353, AL136096). In addition, we analyzed the whole coding region of the CNR1 gene of 50 of the patients by capillary sequencing to detect rare mutations. Our adequately powered study failed to reveal a statistically significant segregation of CNR1 polymorphisms to the diseased or control group. Furthermore, capillary sequencing of CNR1 in a subgroup of study subjects did not show any non-synonymous mutations predicting malfunction of CNR1 in patients with schizophrenia. In conclusion, we could not detect a statistically significant association between mutations in the CNR1 gene and the predisposition to develop schizophrenia. However, further studies are necessary to unravel the relationship between mutations in the CNR1 gene and the genetic susceptibility for the manifestation of certain subtypes or schizophrenia i.e. the predominance of negative or positive symptoms or as predictors of the clinical course.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
12Eur Neuropsychopharmacol 2008 Jan 18: 34-40
PMID17669634
TitleThe CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia.
AbstractNeurobiological research suggests a significant role of the endocannabinoid system in schizophrenia vulnerability and also in the quality of response to antipsychotics. Genetics offer an opportunity to disentangle its involvement in the disease vulnerability vs an influence on antipsychotics' effects. The possible role of a tag SNP (the 1359G/A polymorphism) of the gene encoding the cannabinoid receptor type 1 (CNR1) in schizophrenia and/or therapeutic response to atypical antipsychotics was assessed in a cohort of 133 French schizophrenic patients compared to 141 normal control subjects. No difference in 1359G/A polymorphism was observed between patients and control subjects, and no relationships were noted between this polymorphism and any clinical parameter considered as potential intermediate factor. However, the G allele frequency was significantly higher among non-responsive vs responsive patients, with a dose effect of the G allele. In contrast, no association was found for three other genetic polymorphisms of the CNR1 gene. The G allele of the CNR1 gene polymorphisms could be a psychopharmacogenetic rather than a vulnerability factor regarding schizophrenia and its treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
13Eur Neuropsychopharmacol 2008 Jan 18: 34-40
PMID17669634
TitleThe CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia.
AbstractNeurobiological research suggests a significant role of the endocannabinoid system in schizophrenia vulnerability and also in the quality of response to antipsychotics. Genetics offer an opportunity to disentangle its involvement in the disease vulnerability vs an influence on antipsychotics' effects. The possible role of a tag SNP (the 1359G/A polymorphism) of the gene encoding the cannabinoid receptor type 1 (CNR1) in schizophrenia and/or therapeutic response to atypical antipsychotics was assessed in a cohort of 133 French schizophrenic patients compared to 141 normal control subjects. No difference in 1359G/A polymorphism was observed between patients and control subjects, and no relationships were noted between this polymorphism and any clinical parameter considered as potential intermediate factor. However, the G allele frequency was significantly higher among non-responsive vs responsive patients, with a dose effect of the G allele. In contrast, no association was found for three other genetic polymorphisms of the CNR1 gene. The G allele of the CNR1 gene polymorphisms could be a psychopharmacogenetic rather than a vulnerability factor regarding schizophrenia and its treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
14Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Apr 147: 279-84
PMID18186055
TitleCannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia.
AbstractFunctional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n-repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family-based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for "hebephrenia." Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n-repeat marker of the CNR1 (multi-allelic P = 0.0368). Our hypothesis that an association with the (AAT)n-repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid-induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
15Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Apr 147: 279-84
PMID18186055
TitleCannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia.
AbstractFunctional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n-repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family-based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for "hebephrenia." Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n-repeat marker of the CNR1 (multi-allelic P = 0.0368). Our hypothesis that an association with the (AAT)n-repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid-induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
16Rom J Intern Med 2009 -1 47: 9-18
PMID19886064
TitleThe implication of CNR1 gene's polymorphisms in the modulation of endocannabinoid system effects.
AbstractThe endocannabinoid system (ECS) represents one of the most important physiologic systems involved in organism homeostasis, having various implications upon individual behavior and metabolic phenotype. It is composed of cannabinoid receptors CB1 and CB2, and their genes (CNR1 and CNR2), their endogenous ligands and the enzymes which mediate endogenous ligands' biosynthesis and degradation. Anandamide and 2-arachidonoylglycerol are two endogenous agonists of the cannabinoid receptors. It is considered that ECS connects physical and emotional response to stress with appetite and energy balance, functioning like an after stress recovery system which remains inactive in repose physiologic conditions. It is involved in several physiologic processes like nociception, motor control, memory, learning, appetite, food intake and energy balance. This review analyzes the implication of 11 polymorphisms of CNR1 gene in the modulation of the ECS metabolic and central effects. A lot of studies show that rs12720071, rs1049353, rs806381, rs10485170, rs6454674, rs2023239 polymorphisms are associated with metabolic effects. From them rs12720071, rs104935, rs6454674, rs2023239 polymorphisms are also associated with central effects of ECS (substance addiction, impulsivity, resistance to antidepressive treatment). Other studies indicate that rs806368, rs1535255, (AAT)9,(AAT)12 and (AAT)n are correlated only with central effects (schizophrenia, substance addiction, impulsivity, Parkinson syndrome). The discovery of ECS and its signaling pathways opens a door towards the understanding of several important physiologic processes regarding appetite, food intake, metabolism, weight gain, motor control, memory, learning, drug addiction and nociception. The detailed analysis and validation of the ECS functioning can bring us very close to the discovery of new diagnosis and treatment methods for obesity, drugs abuse and numerous psychic diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
17Psychopharmacology (Berl.) 2009 Nov 206: 531-49
PMID19629449
TitleRole of cannabis and endocannabinoids in the genesis of schizophrenia.
AbstractCannabis abuse and endocannabinoids are associated to schizophrenia.
It is important to discern the association between schizophrenia and exogenous Cannabis sativa, on one hand, and the endogenous cannabinoid system, on the other hand.
On one hand, there is substantial evidence that cannabis abuse is a risk factor for psychosis in genetically predisposed people, may lead to a worse outcome of the disease, or it can affect normal brain development during adolescence, increasing the risk for schizophrenia in adulthood. Regarding genetic predisposition, alterations affecting the cannabinoid CNR1 gene could be related to schizophrenia. On the other hand, the endogenous cannabinoid system is altered in schizophrenia (i.e., increased density of cannabinoid CB1 receptor binding in corticolimbic regions, enhanced cerebrospinal fluid anandamide levels), and dysregulation of this system can interact with neurotransmitter systems in such a way that a "cannabinoid hypothesis" can be integrated in the neurobiological hypotheses of schizophrenia. Finally, there is also evidence that some genetic alterations of the CNR1 gene can act as a protectant factor against schizophrenia or can induce a better pharmacological response to atypical antipsychotics.
Cannabis abuse is a risk factor for psychosis in predisposed people, it can affect neurodevelopment during adolescence leading to schizophrenia, and a dysregulation of the endocannabinoid system can participate in schizophrenia. It is also worth noting that some specific cannabinoid alterations can act as neuroprotectant for schizophrenia or can be a psychopharmacogenetic rather than a vulnerability factor.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
18Neuropsychopharmacology 2010 May 35: 1315-24
PMID20107430
TitleA common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia.
AbstractAntipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. 'T' allele carriers (CT+TT) gained more weight (5.96%), than the CC carriers (2.76%, p=0.008, FDR q-value=0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT+TT, 2.21+/-4.51 vs 4.33+/-3.89 kg; p=0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p=0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-Arnt-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
19CNS Drugs 2011 Dec 25: 1035-59
PMID22133326
TitleAtypical antipsychotic-induced weight gain: insights into mechanisms of action.
AbstractPrescriptions for second-generation antipsychotics (SGAs) have surpassed those for first-generation agents in the treatment of schizophrenia and bipolar disorder. While SGAs have the benefit of a much reduced risk of causing movement disorders, they have been associated with weight gain and metabolic effects. These adverse reactions are not uncommon, and threaten to have a significant impact on the patient's health over the long-term treatment that the patient requires. Currently, the aetiology of these effects is not known. This article reviews the data exploring the weight gain phenomenon. The literature was reviewed from searches of PubMed and the references of major articles in the field. The SGAs present a heterogeneous risk for weight gain. In addition, different individuals receiving the same drug can exhibit substantially different weight changes. This pattern suggests that a group of factors are associated with the weight gain phenomenon rather than a single mechanism. Coupled with the genetic profile that the patient brings to the treatment, the risk for SGA-induced weight gain will be different for different drugs and different individuals. Targets for exploration of the weight gain phenomenon include receptor interactions involving serotonin, histamine, dopamine, adrenergic, cannabinoid and muscarinic receptors. The association of SGA-induced weight gain and the role of orexigenic and anorexigenic peptides are reviewed. Also, a brief discussion of genetic factors associated with SGA-induced weight gain is presented, including that of the serotonin 5-HT(2C) receptor gene (HTR2C) and the cannabinoid 1 receptor gene (CNR1). The most promising data associated with SGA-induced weight gain include investigations of the histamine H(1), 5-HT(2A), 5-HT(2C), muscarinic M(3) and adrenergic receptors. In addition, work in the genetic area promises to result in a better understanding of the variation in risk associated with different individuals.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
20Acta Psychiatr Scand 2011 Oct 124: 250-61
PMID21916860
TitleEndocannabinoid system dysfunction in mood and related disorders.
AbstractThe endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders.
An overview is presented of the literature focussed on the functions of the EC system, its dysfunction in mood disorders and the therapeutic potential of exogenous cannabinoids.
We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement.
Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
21Neurosci. Lett. 2011 May 496: 60-4
PMID21513772
TitleAssociation between a cannabinoid receptor gene (CNR1) polymorphism and cannabinoid-induced alterations of the auditory event-related P300 potential.
AbstractNumerous studies demonstrated a close relationship between cannabis abuse and schizophrenia with similar impairments in cognitive processing, particularly in P300 generation. Recently, an (AAT)n triplet repeat polymorphism within the cannabinoid receptor gene CNR1 has been found to be associated with both schizophrenia and substance dependence, and to modulate the P300 potential. As previously reported, both acute oral ?(9)-tetrahydrocannabinol (?(9)-THC), the main psychoactive constituent of cannabis, and standardized cannabis extract containing ?(9)-THC and cannabidiol (CBD) revealed a significant reduction of P300 amplitudes in healthy subjects but did not show any differences among each other. The aim of this study was to investigate whether the (AAT)n polymorphism differentially modulates the effects of ?(9)-THC and cannabis extract on P300 generation in 20 healthy volunteers during an auditory choice reaction task. For the >10/>10 genotype, there was a significant decrease of P300 amplitude as well as a significant prolongation of P300 latency under pure ?(9)-THC but not under cannabis extract. Moreover, we found a significant correlation between the number of AAT repeats and P300 variables for the ?(9)-THC condition. Our data thus indicate that the CNR1 gene seems to be involved in the regulation of the P300 wave as a marker of selective attention and working memory. Moreover, it appears that variations within CNR1 may differentially alter the sensitivity to the acute effects of cannabinoids on P300 generation in healthy subjects.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
22Schizophr. Res. 2011 May 128: 66-75
PMID21420833
TitleCannabinoid receptor 1 gene polymorphisms and marijuana misuse interactions on white matter and cognitive deficits in schizophrenia.
AbstractMarijuana exposure during the critical period of adolescent brain maturation may disrupt neuro-modulatory influences of endocannabinoids and increase schizophrenia susceptibility. Cannabinoid receptor 1 (CB1/CNR1) is the principal brain receptor mediating marijuana effects. No study to-date has systematically investigated the impact of CNR1 on quantitative phenotypic features in schizophrenia and inter-relationships with marijuana misuse. We genotyped 235 schizophrenia patients using 12 tag single nucleotide polymorphisms (tSNPs) that account for most of CB1 coding region genetic variability. Patients underwent a high-resolution anatomic brain magnetic resonance scan and cognitive assessment. Almost a quarter of the sample met DSM marijuana abuse (14%) or dependence (8%) criteria. Effects of CNR1 tSNPs and marijuana abuse/dependence on brain volumes and neurocognition were assessed using ANCOVA, including co-morbid alcohol/non-marijuana illicit drug misuse as covariates. Significant main effects of CNR1 tSNPs (rs7766029, rs12720071, and rs9450898) were found in white matter (WM) volumes. Patients with marijuana abuse/dependence had smaller fronto-temporal WM volumes than patients without heavy marijuana use. More interestingly, there were significant rs12720071 genotype-by-marijuana use interaction effects on WM volumes and neurocognitive impairment; suggestive of gene-environment interactions for conferring phenotypic abnormalities in schizophrenia. In this comprehensive evaluation of genetic variants distributed across the CB1 locus, CNR1 genetic polymorphisms were associated with WM brain volume variation among schizophrenia patients. Our findings suggest that heavy cannabis use in the context of specific CNR1 genotypes may contribute to greater WM volume deficits and cognitive impairment, which could in turn increase schizophrenia risk.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
23Mol. Psychiatry 2012 Sep 17: 887-905
PMID22584867
TitleConvergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction.
AbstractWe have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
24Curr. Pharm. Des. 2012 -1 18: 5024-35
PMID22716151
TitleGene-environment interactions underlying the effect of cannabis in first episode psychosis.
AbstractCannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
25Mol. Psychiatry 2012 Mar 17: 242-66
PMID21894153
TitlePharmacogenetics of antipsychotic-induced weight gain: review and clinical implications.
AbstractSecond-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
26Psychiatry Res 2012 Mar 196: 160
PMID22370152
TitleThe CNR1 gene in depression and schizophrenia - is there an association with early improvement and response?
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
27Pharmacogenomics J. 2012 Jun 12: 260-6
PMID21266946
TitleAssociation study of cannabinoid receptor 1 (CNR1) gene in tardive dyskinesia.
AbstractTardive dyskinesia (TD) is a severe, debilitating movement disorder observed in 25-30% of the patients treated with typical antipsychotics. Cannabinoid receptor 1 (CNR1) activators tend to inhibit movement, an effect prevented by rimonabant and other selective CNR1 antagonists. Furthermore, CNR1 receptor is downregulated in Huntington's disease and upregulated in Parkinson's disease. Twenty tagSNPs spanning the CNR1 gene were analyzed in schizophrenia patients of European ancestry (n=191; 74 with TD). Significant genotypic (P=0.012) and allelic (P=0.012) association was observed with rs806374 (T>C). Carriers of the CC genotype were more likely to be TD positive (CC vs TT+TC, odds ratio=3.4 (1.5-7.8), P=0.003) and had more severe TD (CC vs TT+TC; 9.529.2 vs 5.626.9, P=0.046). These results indicate a possible role of CNR1 in the development of TD in our patient population. However, these observations are marginal after correcting for multiple testing and need to be replicated in a larger patient population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
28J. Biol. Chem. 2012 Apr 287: 12828-34
PMID22362764
TitleAllele-specific differences in activity of a novel cannabinoid receptor 1 (CNR1) gene intronic enhancer in hypothalamus, dorsal root ganglia, and hippocampus.
AbstractPolymorphisms within intron 2 of the CNR1 gene, which encodes cannabinoid receptor 1 (CB(1)), have been associated with addiction, obesity, and brain volume deficits. We used comparative genomics to identify a polymorphic (rs9444584-C/T) sequence (ECR1) in intron 2 of the CNR1 gene that had been conserved for 310 million years. The C-allele of ECR1 (ECR1(C)) acted as an enhancer in hypothalamic and dorsal root ganglia cells and responded to MAPK activation through the MEKK pathway but not in hippocampal cells. However, ECR1(T) was significantly more active in hypothalamic and dorsal root ganglia cells but, significantly, and in contrast to ECR1(C), was highly active in hippocampal cells where it also responded strongly to activation of MAPK. Intriguingly, rs9444584 is in strong linkage disequilibrium with two other SNPs (rs9450898 (r(2) = 0.841) and rs2023239 (r(2) = 0.920)) that have been associated with addiction, obesity (rs2023239), and reduced fronto-temporal white matter volumes in schizophrenia patients as a result of cannabis misuse (rs9450898). Considering their high linkage disequilibrium and the increased response of ECR1(T) to MAPK signaling when compared with ECR1(C), it is possible that the functional effects of the different alleles of rs9444584 may play a role in the conditions associated with rs9450898 and rs2023239. Further analysis of the different alleles of ECR1 may lead to a greater understanding of the role of CNR1 gene misregulation in these conditions as well as chronic inflammatory pain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
29Mol Brain 2013 -1 6: 42
PMID24093505
TitleHINT1 protein cooperates with cannabinoid 1 receptor to negatively regulate glutamate NMDA receptor activity.
AbstractG protein-coupled receptors (GPCRs) are the targets of a large number of drugs currently in therapeutic use. Likewise, the glutamate ionotropic N-methyl-D-aspartate receptor (NMDAR) has been implicated in certain neurological disorders, such as neurodegeration, neuropathic pain and mood disorders, as well as psychosis and schizophrenia. Thus, there is now an important need to characterize the interactions between GPCRs and NMDARs. Indeed, these interactions can produce distinct effects, and whereas the activation of Mu-opioid receptor (MOR) increases the calcium fluxes associated to NMDARs, that of type 1 cannabinoid receptor (CNR1) antagonizes their permeation. Notably, a series of proteins interact with these receptors affecting their responses and interactions, and then emerge as novel therapeutic targets for the aforementioned pathologies.
We found that in the presence of GPCRs, the HINT1 protein influences the activity of NMDARs, whereby NMDAR activation was enhanced in CNR1+/+/HINT1-/- cortical neurons and the cannabinoid agonist WIN55,212-2 provided these cells with no protection against a NMDA insult. NMDAR activity was normalized in these cells by the lentiviral expression of HINT1, which also restored the neuroprotection mediated by cannabinoids. NMDAR activity was also enhanced in CNR1-/-/HINT1+/+ neurons, although this activity was dampened by the expression of GPCRs like the MOR, CNR1 or serotonin 1A (5HT1AR).
The HINT1 protein plays an essential role in the GPCR-NMDAR connection. In the absence of receptor activation, GPCRs collaborate with HINT1 proteins to negatively control NMDAR activity. When activated, most GPCRs release the control of HINT1 and NMDAR responsiveness is enhanced. However, cannabinoids that act through CNR1 maintain the negative control of HINT1 on NMDAR function and their protection against glutamate excitotoxic insult persists.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
30J Clin Psychopharmacol 2013 Apr 33: 186-92
PMID23422373
TitleCNR1 gene and risk of the metabolic syndrome in patients with schizophrenia.
AbstractMetabolic disturbances are more prevalent in patients with schizophrenia (SCZ) than in the general population. The endocannabinoid system plays an important role in the regulation of dopamine transmission and several metabolic pathways, and the endocannabinoid receptor type 1 gene (CNR1) is considered a candidate gene for both SCZ and metabolic disorders. We examined whether genetic variation in CNR1 was associated with metabolic syndrome (MetS) in a naturalistic cohort of 407 patients with SCZ. The minor alleles of rs6928499, rs1535255, and rs2023239 were nominally associated with a lower risk of MetS [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.37-0.84; P = 0.006; OR, 0.56; 95% CI, 0.37-0.84; P = 0.006; and OR, 0.44; 95% CI, 0.27-0.72; P = 0.001, respectively, adjusted for age, sex, duration of illness, clozapine or olanzapine treatment). These differences were mainly due to differences in high-density lipoprotein cholesterol and fasting glucose but not in body mass index or waist circumference. No significant association of the other polymorphisms (rs806377, rs1049353, rs6454674, and rs806379) with MetS was found. These results provide evidence that the prevalence of MetS is associated with the CNR1 gene in patients with SCZ during long-term treatment with antipsychotic treatment. Further studies are needed to uncover the exact molecular basis for this association, which could provide novel treatment targets for the MetS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
31Eur Neuropsychopharmacol 2013 Jul 23: 749-59
PMID22920733
TitleInvestigation of endocannabinoid system genes suggests association between peroxisome proliferator activator receptor-? gene (PPARA) and schizophrenia.
Abstractschizophrenia (SZ) is a complex psychiatric disorder with a large genetic burden and an estimated hereditability of 80%. A large number of neuroanatomical and psychopharmacological studies suggest a central role of the endocannabinoid (eCB) system in the susceptibility of the disease. To further investigate this hypothesis, we performed an association study with genes codifying for key elements of the eCB system in a sample of 170 schizophrenic patients and 350 healthy controls of Italian ancestry. A total of 57 Tag SNPs (tSNPs) were selected using HapMap CEU population SNP database spanning the following genes: cannabinoid receptor 1 (CNR1), peroxisome proliferator activator receptor-? (PPARA), fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). Seven out of the 32 tSNPs within PPARA (rs4253765, rs4263776, rs6007662, rs1800206, rs4253763, rs6008197 and rs4253655) and 3 out of 12 tSNPs within CNR1 (rs1049353, rs7766029 and rs806366) were nominally associated with SZ (uncorrected p<0.05). The same pattern of association was observed in the genotype analysis, with rs4253765 showing the highest level of significance (uncorrected p=210(-3)). None of these associations survived after permutation test. Our findings suggest a potential role for PPARA in the susceptibility to SZ, but further studies on larger independent samples are warranted in order to clarify the involvement of this gene in the pathophysiology of SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
32Eur Neuropsychopharmacol 2013 Jul 23: 749-59
PMID22920733
TitleInvestigation of endocannabinoid system genes suggests association between peroxisome proliferator activator receptor-? gene (PPARA) and schizophrenia.
Abstractschizophrenia (SZ) is a complex psychiatric disorder with a large genetic burden and an estimated hereditability of 80%. A large number of neuroanatomical and psychopharmacological studies suggest a central role of the endocannabinoid (eCB) system in the susceptibility of the disease. To further investigate this hypothesis, we performed an association study with genes codifying for key elements of the eCB system in a sample of 170 schizophrenic patients and 350 healthy controls of Italian ancestry. A total of 57 Tag SNPs (tSNPs) were selected using HapMap CEU population SNP database spanning the following genes: cannabinoid receptor 1 (CNR1), peroxisome proliferator activator receptor-? (PPARA), fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). Seven out of the 32 tSNPs within PPARA (rs4253765, rs4263776, rs6007662, rs1800206, rs4253763, rs6008197 and rs4253655) and 3 out of 12 tSNPs within CNR1 (rs1049353, rs7766029 and rs806366) were nominally associated with SZ (uncorrected p<0.05). The same pattern of association was observed in the genotype analysis, with rs4253765 showing the highest level of significance (uncorrected p=210(-3)). None of these associations survived after permutation test. Our findings suggest a potential role for PPARA in the susceptibility to SZ, but further studies on larger independent samples are warranted in order to clarify the involvement of this gene in the pathophysiology of SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
33Psychol Med 2013 Mar 43: 619-31
PMID22850347
TitleMAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse.
AbstractAdolescent marijuana use is associated with increased risk for schizophrenia. We previously reported that marijuana misuse in conjunction with specific cannabinoid receptor 1 (CNR1) genetic variants (rs12720071-G-allele carriers) contributed to white-matter (WM) brain volume deficits in schizophrenia patients. In this study, we assessed the influence of another cannabinoid-related gene, mitogen-activated protein kinase 14 (MAPK14), and potential MAPK14-CNR1 gene-gene interactions in conferring brain volume abnormalities among schizophrenia patients with marijuana abuse/dependence. MAPK14 encodes a member of the MAPK family involved in diverse cellular processes, including CNR1-induced apoptosis.
We genotyped 235 schizophrenia patients on nine MAPK14 tag single nucleotide polymorphisms (tSNPs). Approximately one quarter of the sample had marijuana abuse or dependence. Differential effects of MAPK14 tSNPs on brain volumes across patients with versus without marijuana abuse/dependence were examined using ANCOVA.
Of the MAPK14 tSNPs, only rs12199654 had significant genotype effects and genotype marijuana misuse interaction effects on WM volumes. rs12199654-A homozygotes with marijuana abuse/dependence had significantly smaller total cerebral and lobar WM volumes. The effects of MAPK14 rs12199654 on WM volume deficits remained significant even after controlling for the CNR1 rs12720071 genotype. There were significant main effects of the MAPK14 CNR1 diplotype and diplotype marijuana interaction on WM brain volumes, with both genetic variants having additive contributions to WM volume deficits only in patients with marijuana misuse.
Given that CNR1-induced apoptosis is preceded by increased MAPK phosphorylation, our study suggests that potential MAPK14-CNR1 gene-gene interactions may mediate brain morphometric features in schizophrenia patients with heavy marijuana use.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
34Psychiatr. Genet. 2014 Oct 24: 225-9
PMID25014618
TitleGenetic association analysis of CNR1 and CNR2 polymorphisms with schizophrenia in a Korean population.
AbstractLocated on 6q15 and 1p36.11, cannabinoid receptor 1 (CNR1) and cannabinoid receptor 2 (CNR2) genes are considered to be a positional and functional candidate gene for the development of mental disorders such as schizophrenia because CNR1 is known as a regulator of dopamine signaling in the hippocampus and the cerebral cortex. However, few genetic studies have been carried out to investigate an association of CNR1 and CNR2 polymorphisms and the risk of schizophrenia. In this study, although the result indicates that CNR1 and CNR2 variations are unlikely to influence schizophrenia susceptibility in a Korean population, the findings would provide meaningful information for further genetic studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
35Neurobiol. Dis. 2014 Mar 63: 210-21
PMID24239560
TitleThe role of cannabinoid 1 receptor expressing interneurons in behavior.
Abstractschizophrenia is a devastating neurodevelopmental disorder that affects approximately 1% of the population. Reduced expression of the 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of the disease and is encoded by the GAD1 gene. In schizophrenia, GAD67 downregulation occurs in multiple interneuronal subpopulations, including the cannabinoid receptor type 1 positive (CNR1+) cells, but the functional consequences of these disturbances are not well understood. To investigate the role of the CNR1-positive GABA-ergic interneurons in behavioral and molecular processes, we employed a novel, miRNA-mediated transgenic mouse approach. We silenced the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of CNR1 bacterial artificial chromosome. Behavioral characterization of our transgenic mice showed elevated and persistent conditioned fear associated with an auditory cue and a significantly altered response to an amphetamine challenge. These deficits could not be attributed to sensory deficits or changes in baseline learning and memory. Furthermore, HPLC analyses revealed that CNR1/Gad1 mice have enhanced serotonin levels, but not dopamine levels in response to amphetamine. Our findings demonstrate that dysfunction of a small subset of interneurons can have a profound effect on behavior and that the GABA-ergic, monoamine, and cannabinoid systems are functionally interconnected. The results also suggest that understanding the function of various interneuronal subclasses might be essential to develop knowledge-based treatment strategies for various mental disorders including schizophrenia and substance abuse.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
36Neuroscience 2015 Dec 310: 723-30
PMID26475744
TitleThe CCDC55 couples cannabinoid receptor CNR1 to a putative DISC1 schizophrenia pathway.
AbstractOur previous study suggested that the coiled coil domain-containing 55 gene (CCDC55), also named as NSRP1 (nuclear speckle splicing regulatory protein 1 (NSRP1)), was encompassed in a haplotype block spanning over the serotonin transporter (5-HTT) gene in patients with schizophrenia (SCZ). However, the neurobiological function of CCDC55 gene remains unknown. This study aims to uncover the potential role of CCDC55 in SCZ-associated molecular pathways.
Using molecular cloning, sequencing and immune blotting to identify basic properties, yeast two-hybrid screening and glutathione S-transferase (GST) pull-down assay to test protein-protein interaction, and confocal laser scanning microscopy (CSLM) to show intracellular interaction of proteins.
(i) CCDC55 is expressed as a nuclear protein in human neuronal cells; (ii) Protein-protein interaction analyses showed CCDC55 physically interacted with Ran binding protein 9 (RanBP9) and disrupted in schizophrenia 1 (DISC1); (iii) CCDC55 and RanBP9 co-localized in the nucleus of human neuronal cells; (iv) CCDC55 also interacted with the cannabinoid receptor 1 (CNR1), and with the brain cannabinoid receptor-interacting protein 1a (CNRIP1a); (v) CNR1 activation in differentiated human neuronal cells resulted in an altered RanBP9 localization.
CCDC55 may be involved in a functional bridging between the CNR1 activation and the DISC1/RanBP9-associated pathways.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
37Psychiatry Res 2015 Aug 233: 112-9
PMID26071625
TitleBrain structural and clinical changes after first episode psychosis: Focus on cannabinoid receptor 1 polymorphisms.
AbstractCannabinoid receptor 1 (CNR1) gene polymorphisms have been associated with central and peripheral effects of cannabis and schizophrenia pathophysiology. Here, we have tested whether three CNR1 variants (rs1049353, rs1535255 and rs2023239) are associated with changes in brain volumes, body mass index (BMI) or psychopathological scores in a 3-year longitudinal study of 65 first-episode psychosis patients. The rs1049353 at-risk allele was significantly associated with a greater reduction of caudate volume, and the rs2023239 T/C polymorphism showed a significant decrease in thalamic volume after the 3-year period. For those who were not cannabis users, the rs1535255 and rs2023239 polymorphisms had effects in lateral ventricle (LV), and LV and white matter, respectively. The rs2023239 variant also was associated with significant improvements in positive and negative symptoms of schizophrenia. There was no significant effect of any of the variants on changes in BMI over the 3-year study. Finally, an interaction between all three polymorphisms was found involving evolution of positive symptoms. These findings suggest that the cannabinoid pathway is associated with schizophrenia evolution over time. However, further studies using larger cohorts are needed to confirm these results. If confirmed, the present findings could lead in subsequent investigations for identification of novel drug targets for improved treatment of patients suffering from schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
38Neuropsychopharmacology 2015 May 40: 1353-63
PMID25418810
TitleDissociable deficits of executive function caused by gestational adversity are linked to specific transcriptional changes in the prefrontal cortex.
AbstractPoor-quality maternal diet during pregnancy, and subsequent gestational growth disturbances in the offspring, have been implicated in the etiology of multiple neurodevelopmental disorders, including ADHD, schizophrenia, and autism. These disorders are characterized, in part, by abnormalities in responses to reward and errors of executive function. Here, we demonstrate dissociable deficits in reward processing and executive function in male and female mice, solely due to maternal malnutrition via high-fat or low-protein diets. Gestational exposure to a high-fat diet delayed acquisition of a fixed ratio response, and decreased motivation as assessed by progressive ratio. In contrast, offspring of a low-protein diet displayed no deficits in operant learning, but were more prone to assign salience to a cue that predicts reward (sign-tracking) in a Pavlovian-conditioned approach task. In the 5-choice serial reaction time task (5-CSRTT), gestational exposure to a high-fat diet promoted impulsivity, whereas exposure to a low-protein diet led to marked inattention. These dissociable executive function deficits are known to be mediated by the medial prefrontal cortex (PFC), which displays markers of epigenetic dysregulation in neurodevelopmental disorders. Following behavioral characterization, we assayed PFC gene expression using a targeted PCR array and found that both maternal diets increased overall transcription in PFC. Cluster analysis of the relationships between individual transcripts and behavioral outcomes revealed a cluster of primarily epigenetic modulators, whose overexpression was linked to executive function deficits. The overexpression of four genes, DNA methyltransferase 1 (DNMT1), ?-opioid receptor (OPRD1), cannabinoid receptor 1 (CNR1), and catechol-o-methyltransferase (COMT), was strongly associated with overall poor performance. All 5-CSRTT deficits were associated with DNMT1 upregulation, whereas impulsive behavior could be dissociated from inattention by overexpression of OPRD1 or COMT, respectively, as well as a distinct cluster of epigenetic regulators. These data provide molecular support for dissociable domains of executive function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics