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Query Topic: CNR1

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receptor type 1(15)

Cannabinoid receptor type 2 gene is associated with comorbidity of schizophrenia and cannabis dependence and fatty acid amide hydrolase gene is associated with cannabis dependence in the Spanish population.
The endocannabinoid system has been associated with various psychiatric disorders, such as schizophrenia or addictive disorders. Recent studies have found that some polymorphisms in the cannabinoid receptor type 2 (CNR2), cannabinoid receptor type 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes could play an important role as risk factors in the etiology of these diseases. We analysed different cannabinoid gene polimorphisms from non-substance using patients diagnosed with schizophrenia (n = 379), schizophrenic patients with cannabis use disorders (n = 124), cannabis users who did not have psychoses (n = 71), and 316 controls from various Spanish hospitals and health centres. We found a statistical association between polymorphisms rs35761398 and rs12744386 in the CNR2 gene and comorbidity of schizophrenia and cannabis dependence, as well as an association between loss of heterozygosity (overdominance) for polymorphism rs324420 in the FAAH gene and cannabis dependence in a Spanish population sample. The rs35761398 and rs12744386 polymorphisms in the CNR2 gene are genetic risk factors for schizophrenia in cannabis-dependent subjects. Loss of heterozygosity for polymorphism rs324420 in the FAAH gene is a genetic risk factor for cannabis dependence in this population. El sistema cannabinoide se ha asociado con varios trastornos psiquiátricos como la esquizofrenia y las adicciones. Diversos estudios han observado que algunos polimorfismos del receptor cannabinoide tipo 2 (CNR2), del receptor cannabinoide tipo 1 (CNR1) y del gen de la enzima amido hidrolasa de ácidos grasos (FAAH) pueden ser factores de riesgo de estos trastornos. Hemos analizado diversos polimorfismos del sistema cannabinoide en pacientes diagnosticados de esquizofrenia sin trastorno por uso de sustancias (n = 379), esquizofrenia con trastorno por uso de cannabis (n = 124), dependientes de cannabis sin psicosis asociada (n = 71) y un grupo de control (316) procedentes de diversos hospitales y centros de asistencia sanitaria españoles. Hemos encontrado una asociación entre los polimorfismos rs35761398 y rs12744386 del CNR2 con la presencia de esquizofrenia y trastorno por uso de cannabis comórbido y una pérdida de heterocigosidad en el polimorfismo rs324420 del gen FAAH con la dependencia de cannabis en población española. Los polimorfismos rs35761398 y rs12744386 en CNR2 son factores de riesgo para esquizofrenia en sujetos dependientes de cannabis. La pérdida de heterocigosidad en el polimorfismo rs324420 en el gen FAAH es un factor de riesgo para la dependencia de cannabis.
Publication Date: 2021-06-26
Journal: Adicciones


Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia.
Beyond being one the most widely used psychoactive drugs in the world, cannabis has been identified as an environmental risk factor for psychosis. Though the relationship between cannabis use and psychiatric disorders remains controversial, consistent association between early adolescent cannabis use and the subsequent risk of psychosis suggested adolescence may be a particularly vulnerable period. Previous findings on gene by environment interactions indicated that cannabis use may only increase the risk for psychosis in the subjects who have a specific genetic vulnerability. The type 1 cannabinoid receptor (CB1), encoded by the CNR1 gene, is a key component of the endocannabinoid system. As the primary endocannabinoid receptor in the brain, CB1 is the main molecular target of the endocannabinoid ligand, as well as tetrahydrocannabinol (THC), the principal psychoactive ingredient of cannabis. In this study, we have examined mRNA expression and DNA methylation of CNR1 in human prefrontal cortex (PFC), hippocampus, and caudate samples. The expression of CNR1 is higher in fetal PFC and hippocampus, then drops down dramatically after birth. The lifespan trajectory of CNR1 expression in the DLPFC differentially correlated with age by allelic variation at rs4680, a functional polymorphism in the COMT gene. Compared with COMT methionine
Publication Date: 2020-05-21
Journal: Translational psychiatry

type 1 cnr1(14)

Dopamine Related Genes Differentially Affect Declarative Long-Term Memory in Healthy Humans.
In humans, monetary reward can promote behavioral performance including response times, accuracy, and subsequent recognition memory. Recent studies have shown that the dopaminergic system plays an essential role here, but the link to interindividual differences remains unclear. To further investigate this issue, we focused on previously described polymorphisms of genes affecting dopaminergic neurotransmission: DAT1 40 base pair (bp), DAT1 30 bp, DRD4 48 bp, and cannabinoid receptor type 1 (CNR1). Specifically, 669 healthy humans participated in a delayed recognition memory paradigm on two consecutive days. On the first day, male vs. female faces served as cues predicting an immediate monetary reward upon correct button presses. Subsequently, participants performed a remember/know recognition memory task on the same day and 1 day later. As predicted, reward increased accuracy and accelerated response times, which were modulated by DAT 30 bp. However, reward did not promote subsequent recognition memory performance and there was no interaction with any genotype tested here. Importantly, there were differential effects of genotype on declarative long-term memory independent of reward: (a) DAT1 40 bp was linked to the quality of memory with a more pronounced difference between recollection and familiarity in the heterozygous and homozygous 10-R as compared to homozygous 9-R; (b) DAT1 30 bp was linked to memory decay, which was most pronounced in homozygous 4-R; (c) DRD4 48 bp was linked to overall recognition memory with higher performance in the short allele group; and (d) CNR1 was linked to overall memory with reduced performance in the homozygous short group. These findings give new insights into how polymorphisms, which are related to dopaminergic neuromodulation, differentially affect long-term recognition memory performance.
Publication Date: 2020-12-18
Journal: Frontiers in behavioral neuroscience


[Study on mechanism of Valerianae Jatamansi Rhizoma et Radix against post-traumatic stress disorder based on molecular docking and network pharmacology].
This paper aims to investigate the active components and mechanism of Valerianae Jatamansi Rhizoma et Radix against post-traumatic stress disorder(PTSD) based on network pharmacology and molecular docking. The main components and targets of Valerianae Jatamansi Rhizoma et Radix were obtained by literature mining methods, SwissTargetPrediction, BATMAN and ETCM database. PTSD-related genes were collected from DrugBank, TTD and CTD databases. The protein-protein interaction(PPI) network was constructed based on STRING, and the core targets of Valerianae Jatamansi Rhizoma et Radix in the treatment of PTSD were selected according to the topological parameters. Cytoscape 3.7.2 was used to construct the compound-target network. DAVID database was used for GO enrichment analysis and KEGG enrichment analysis. The relationship network of "compound-target-pathway" was constructed through Cytoscape 3.7.2 to analyze and obtain the key targets and their corresponding components in the network, and their results were verified by molecular docking. The results showed that a total of 47 components(such as valeraldehyde, dihydrovalerin, valerate, chlorovaltrate K, 8-hydroxypinoresinol, 6-hydroxyluteolin, apigenin, farnesin, vanillin, luteolin, kaempferol, glycosmisic acid and pogostemon) of Valerianae Jatamansi Rhizoma et Radix may act on 94 key targets such as CNR1, MAOA, NR3 C1, MAPK14, MAPK8, HTR2 C and DRD2. Totally 29 GO terms were obtained by GO functional enrichment analysis(P<0.05), and 20 signaling pathways were obtained from KEGG pathway enrichment, mainly involving neuroactive ligand-receptor interaction, serotonergic synapse, calcium signaling pathway, cAMP signaling pathway, dopaminergic synapse, retrograde endocannabinoid signaling, neurotrophin signaling pathway, gap junction, cholinergic synapse, estrogen signaling pathway, glutamatergic synapse and long-term potentiation. Molecular docking analysis showed that hydrogen bonding, π-π interaction and hydrophobic effecting may be the main forms of interaction. This study used the network of compound-target-pathway and molecular docking technology to screen the effective components of Valerianae Jatamansi Rhizoma et Radix against PTSD, and explore its anti-PTSD mechanism, so as to provide scientific basis for exploring the anti-PTSD drugs from traditional Chinese medicine and clarifying its mechanism of action.
Publication Date: 2021-05-29
Journal: Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica


The association of endocannabinoid receptor genes (CNR1 and CNR2) polymorphisms with depression: A meta-analysis.
Studies investigating the association between gene variants and depression susceptibility found inconsistent data. The present study aimed to clarify whether CNR1rs1049353, CNR1 AAT triplet repeat, and CNR2rs2501432 polymorphisms confer higher risk for depressive disorder.Literature from PubMed, Medline, Embase, Scopus, Cochrance Library, and Wanfang databases was searched (up to August 20, 2018). Seven case-control studies with various comorbidities were eligible. We targeted CNR single-nucleotide polymorphisms (SNPs) that have been reported by 2 or more studies to be involved in the current meta-analysis, resulting in a final list of 3 SNPs: CNR1rs1049353, CNR1 AAT triplet repeat polymorphism, and CNR2rs2501432. Odds ratios (ORs) and 95% confidence intervals (CIs) for allele and homozygote comparisons, dominant and recessive models, and triplet repeat polymorphism ((AAT)n≥5, ≥5 vs (AAT)n<5, <5 or <5, ≥5) were assessed using a random effect model as measures of association. Heterogeneity among included studies was analyzed using sensitivity test. Publication bias was also explored by Egger and rank correlation test.overall, no significant association was found between depression and CNR1rs1049353 (G vs A: OR [95% CI] = 1.09 [0.61-1.95]; GG vs AA: 1.29 [0.73-2.26]; GG vs GA+AA: 1.10 [0.57-2.10]; GG+GA vs AA: 1.25 [0.72-2.18]; and AAT triplet repeat polymorphism ((AAT)n≥5, ≥5 vs (AAT)n<5, <5 or <5, ≥5): 1.92 [0.59-6.27]. In contrast, a significant association between CNR2rs2501432 and depression was detected, and the ORs and 95% CIs are as follows: allele contrast (OR = 1.39, 95% CI = [1.12-1.72], P = .003); homozygous (OR = 2.19, 95% CI = [1.34-3.59], P = .002); dominant (OR = 1.93,95% CI = [1.23-3.04], P = .005); and recessive (OR = 1.41, 95% CI = [1.04-1.92], P = .03).This meta-analysis revealed that CNR1rs1049353 or AAT triplet repeat polymorphism had no association with susceptibility to depression, while CNR2rs2501432 polymorphism was a remarkable mark for depression patients.
Publication Date: 2019-11-15
Journal: Medicine

cannabinoid type 1(13)

The associations of CNR1 SNPs and haplotypes with vulnerability and treatment response phenotypes in Han Chinese with major depressive disorder: A case-control association study.
Understanding how genetic polymorphisms are associated with the pathophysiology of major depressive disorder (MDD) may aid in diagnosis and the development of personalized treatment strategies. CNR1 is the gene coding Cannabinoid type 1 receptor which is highly involved in emotional processing and in regulating neurotransmitter releases. We aimed to investigate the associations of CNR1 single-nucleotide polymorphisms (SNPs) with MDD susceptibility and treatment response. The study reported data on 181 Han Chinese with MDD and 80 healthy controls. The associations of CNR1 genetic polymorphisms with MDD susceptibility and treatment response were examined, wherein the MDD patients were subgrouped further by responding to antidepressant treatment, compared with healthy controls separately. The CNR1 SNPs rs806367 and rs6454674 and haplotype C-T-T-C of rs806366, rs806367, rs806368, and rs806370 were associated with increased susceptibility for MDD and antidepressant treatment resistance, but the association was not detected in other SNPs or the haplotype block of rs806368 and rs806370. The CNR1 is a promising candidate for the genetic association study of MDD. Larger and well-characterized samples are required to confirm the genetic association of CNR1 with MDD because of the limitations such as relatively small sample size and lack of information for correcting confounding factors.
Publication Date: 2021-08-07
Journal: Molecular genetics & genomic medicine

- mice(12)

Differential role of cannabinoids in the pathogenesis of skin cancer.
Cannabinoids (CB) like ∆(9)-tetrahydrocannabinol (THC) can induce cancer cell apoptosis and inhibit angiogenesis. However, the use of cannabinoids for the treatment of malignant diseases is discussed controversially because of their immunomodulatory effects which can suppress anti-tumor immunity. Here we investigated the role of exogenous and endogenous cannabinoids in mouse skin cancer. First we examined the effect of THC, which binds to CB receptors (CB1, CB2), on the growth of the mouse melanoma cell lines B16 and HCmel12 in vitro and in vivo in wild type (WT) and CB1/CB2-receptor deficient mice (Cnr1/2(-/-)). Next we evaluated the role of the endogenous cannabinoid system by studying the growth of chemically induced melanomas, fibrosarcoma and papillomas in WT and Cnr1/2(-/-) mice. THC significantly inhibited tumor growth of transplanted HCmel12 melanomas in a CB receptor-dependent manner in vivo through antagonistic effects on its characteristic pro-inflammatory microenvironment. Chemically induced skin tumors developed in a similar manner in Cnr1/2(-/-) mice when compared to WT mice. Our results confirm the value of exogenous cannabinoids for the treatment of melanoma but do not support a role for the endogenous cannabinoid system in the pathogenesis of skin cancer.
Publication Date: 2015-04-30
Journal: Life sciences

g1359a polymorphism(12)

Effects of a High-Protein/Low-Carbohydrate versus a Standard Hypocaloric Diet on Weight and Cardiovascular Risk Factors during 9 Months: Role of a Genetic Variation in the Cannabinoid Receptor Gene (CNR1) (G1359A Polymorphism).
We decided to investigate the role of this polymorphism on cardiovascular risk factors and weight loss secondary to a high-protein/low-carbohydrate vs. a standard hypocaloric diet (1,000 kcal/day) over a period of 9 months. A nutritional evaluation was performed at the beginning and at the end of a 9-month period in which subjects received 1 of 2 diets (diet HP: high protein/low carbohydrate vs. S: standard diet). One hundred and four patients (54.7%) had the genotype G1359G and 86 (45.3%) patients had G1359A (77 patients, 25.8%) or A1359A (9 patients, 3.7%) (A-allele-carriers). In subjects with both genotypes, the body mass index, weight, fat mass, waist circumference and systolic blood pressures decreased with both diets. After the diet type HP and in subjects with both genotypes, the glucose, leptin, total cholesterol, LDL-cholesterol, insulin and HOMA-R levels decreased. After diet S and in all subjects, the total cholesterol, LDL cholesterol and leptin levels decreased, too. Our interventional study didn't show a relationship between the rs1049353 CNR-1 polymorphism and body weight response after two different hypocaloric (low carbohydrate/high protein vs. standard) diets over a period of 9 months. However, a low-carbohydrate/high-protein diet for 9 months improved glucose metabolism in subjects with both genotypes.
Publication Date: 2015-03-15
Journal: Annals of nutrition & metabolism

single-nucleotide polymorphisms snps(12)

Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme.
Understanding genetic factors that contribute to cannabis use disorder (CUD) is important, but to date, findings have been equivocal. Single-nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 gene (CNR1; rs1049353 and rs806378) and fatty acid amide hydrolase (FAAH) gene (rs324420) have been implicated in CUD. Their relationship to addiction endophenotypes such as cannabis-related state satiety, the salience of appetitive cues, and craving after acute cannabinoid administration has not been investigated. Forty-eight cannabis users participated in a double-blind, placebo-controlled, four-way crossover experiment where they were administered treatments in a randomized order via vaporization: placebo, Δ
Publication Date: 2019-04-24
Journal: Addiction biology


Disease-associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue-specific activity of the cannabinoid-1 receptor gene promoter; implications for cannabinoid pharmacogenetics.
Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response. Toward addressing the hypothesis that genetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we characterized the effects of disease-associated allelic variation within a conserved regulatory sequence (ECR1) in CNR1 intron 2 that had previously been shown to modulate cannabinoid response, alcohol intake, and anxiety-like behavior. We used primary cell analysis of reporters carrying different allelic variants of the human ECR1 and found that human-specific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in primary hippocampal cells than did the ancestral T-allele and demonstrated a differential response to CB1 agonism. We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity and evidence that the ancestral t-allele variant of ECR1 interacted with higher affinity with the insulator binding factor CTCF. The cell-specific approaches used in our study represent an important step in gaining a mechanistic understanding of the roles of noncoding polymorphic variation in disease and in the increasingly important field of cannabinoid pharmacogenetics.
Publication Date: 2019-10-15
Journal: Human mutation


Variability in cannabinoid receptor genes is associated with psychiatric comorbidities in anorexia nervosa.
The endocannabinoid system plays a key role in eating behavior regulating appetite and reward mechanisms, but the impact of its genetic variability has been scarcely studied in Anorexia Nervosa (AN). We aimed to analyze the association of genetic variants in cannabinoid receptors with the risk for AN and with psychiatric comorbidities that are commonplace in these patients. We screened 221 AN patients and 396 controls for 14 tag-SNPs in the CNR1 and CNR2 genes, coding for cannabinoids receptors CB1 and CB2, respectively. Patients were diagnosed according to DSM-5 criteria and interviewed with the SCL-90R and the EDI-2 inventories to identify AN-coupled and general psychopathology. None of the tag-SNPs was significantly related to AN risk. However, the rs806369-TT genotype and haplotype rs806368/rs1049353/rs806369 of CNR1 were respectively associated with lower weight (mean difference = - 4.92 kg, FDR-q = 0.044) and BMI (FDR-q = 0.042) in AN patients. CNR1 rs806374-TT and CNR2 rs3003335-AA and rs6658703-GG genotypes correlated with higher scores in the Positive Symptom Distress Index (PSDI, FDR-q = 0.011 and 0.009, respectively). These three genotypes were also linked to increased Hostility in the patients (FDR-q < 0.05). Remarkably, a proximal area of the CNR1 gene locus (positions 88,143,916-88,149,832) correlated with PSDI, Hostility, Asceticism and EDI-2 total scores after correcting by multiple testing (FDR-q < 0.05 in all instances). Finally, significant CNR1/CNR2 epistasis was observed in relation to Hostility (p < 0.01) and Maturity Fears (p < 0.001). The CNR1 and CNR2 genes, coding for cannabinoid receptors, may constitute important loci regarding psychiatric comorbidities in AN patients. Evidence obtained from well-designed cohort or case-control analytic studies.
Publication Date: 2021-02-13
Journal: Eating and weight disorders : EWD

candidate genes(11)

Single-step genome-wide association study for social genetic effects and direct genetic effects on growth in Landrace pigs.
In livestock social interactions, social genetic effects (SGE) represent associations between phenotype of one individual and genotype of another. Such associations occur when the trait of interest is affected by transmissible phenotypes of social partners. The aim of this study was to estimate SGE and direct genetic effects (DGE, genetic effects of an individual on its own phenotype) on average daily gain (ADG) in Landrace pigs, and to conduct single-step genome-wide association study using SGE and DGE as dependent variables to identify quantitative trait loci (QTLs) and their positional candidate genes. A total of 1,041 Landrace pigs were genotyped using the Porcine SNP 60K BeadChip. Estimates of the two effects were obtained using an extended animal model. The SGE contributed 16% of the total heritable variation of ADG. The total heritability estimated by the extended animal model including both SGE and DGE was 0.52. The single-step genome-wide association study identified a total of 23 QTL windows for the SGE on ADG distributed across three chromosomes (i.e., SSC1, SSC2, and SSC6). Positional candidate genes within these QTL regions included PRDM13, MAP3K7, CNR1, HTR1E, IL4, IL5, IL13, KIF3A, EFHD2, SLC38A7, mTOR, CNOT1, PLCB2, GABRR1, and GABRR2, which have biological roles in neuropsychiatric processes. The results of biological pathway and gene network analyses also support the association of the neuropsychiatric processes with SGE on ADG in pigs. Additionally, a total of 11 QTL windows for DGE on ADG in SSC2, 3, 6, 9, 10, 12, 14, 16, and 17 were detected with positional candidate genes such as ARL15. We found a putative pleotropic QTL for both SGE and DGE on ADG on SSC6. Our results in this study provide important insights that can help facilitate a better understanding of the molecular basis of SGE for socially affected traits.
Publication Date: 2020-09-13
Journal: Scientific reports

cb 1(10)

The role of CB1 in immune modulation by cannabinoids.
There is clear evidence that CB(2), historically referred to as the peripheral cannabinoid receptor, mediates many of the immune modulatory effects of cannabinoids. However, cannabinoid receptors cannot be classified simply as central or peripheral since CB(2) has been shown to play a role in the central nervous system (CNS) and CB(1) mediates many immune system effects. Although Cnr1 mRNA and CB(1) protein expression is lower than Cnr2 mRNA or CB(2) protein expression in cells of the immune system, several studies have shown direct modulation of immune function via CB(1) by endogenous and exogenous cannabinoids in T cells, innate cells, and to a lesser extent, B cells. In addition, indirect, but CB(1)-dependent, mechanisms of immune modulation exist. In fact, the mechanism by which cannabinoids attenuate neuroinflammation via CB(1) is likely a combination of immune suppression and neuroprotection. Although many studies demonstrate that agonists for CB(1) are immune suppressive and anti-inflammatory, CB(1) antagonists also exhibit anti-inflammatory properties. Overall, the data demonstrate that many of the immune modulatory effects of cannabinoids are mediated via CB(1).
Publication Date: 2012-12-25
Journal: Pharmacology & therapeutics

0 05(10)

Cannabinoid Receptor Type 1 and mu-Opioid Receptor Polymorphisms Are Associated With Cyclic Vomiting Syndrome.
Cyclic vomiting syndrome (CVS) is a disorder defined by recurrent, unexplained episodes of severe nausea and vomiting. Our aim was to investigate whether CVS and pathophysiological mechanisms underlying this condition are associated with selected variations in genes encoding the components of the endogenous cannabinoid and opioid systems. This case-control study included 65 patients with CVS-16 male and 49 female, and 1,092 healthy controls-525 male and 567 female from the 1000 Genomes Project. CVS subjects filled out study-specific questionnaires. Single-nucleotide polymorphisms (SNPs) in genes encoding cannabinoid receptors (CNR1 and CNR2), fatty acid amide hydrolase (FAAH) and mu-opioid receptor (OPRM1) were analyzed using the TaqMan SNP genotyping assay. Correlations between SNP's and clinical characteristics of CVS were ascertained. Our study disclosed an increased risk of CVS among individuals with AG and GG genotypes of CNR1 rs806380 (P<0.01), whereas the CC genotype of CNR1 rs806368 and AG and GG genotypes of OPRM1 rs1799971 were associated with a decreased risk of CVS (P<0.05). In addition, AG and GG genotypes of OPRM1 rs1799971 were correlated with migraine episodes, AG and GG of OPRM1 rs1799971, and CT and CC of CNR1 rs806368 with a family history of migraines (second degree relatives), and CT and CC of CNR1 rs2023239 with a positive response to therapy. Our results show for the first time that the variations in CNR1 and OPRM1 genes are associated with CVS and that different genotypes may contribute to the risk of CVS.
Publication Date: 2017-03-30
Journal: The American journal of gastroenterology

receptor-1 cnr1(10)

Childhood obesity and the role of dopamine D2 receptor and cannabinoid receptor-1 gene polymorphisms.
The dopaminergic and endocannabinoid systems are involved in regulation of feeding behavior. The aim of the study is to examine the possible relation between polymorphisms of the dopamine D2 receptor (DRD2) and cannabinoid receptor-1 (CNR1) genes and childhood obesity. A hundred obese children and 100 healthy controls were analyzed for DRD2 Taq1A and Taq1B and CNR1 1359G/A polymorphisms. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. There were no statistically significant differences in DRD2 Taq1A and DRD2 Taq1B genotypes or allelic frequencies between obese children and controls (p>0.05). In patients with Taq1B2 allele, morbid obesity was less frequent (p=0.010). The frequency of the A allele of CNR1 1359G/A polymorphism was significantly higher in obese children than in controls (21.0% vs. 13.0%, p=0.0166). The frequency of genotypes AG and GG of the CNR1 1359G/A SNP was different between obese children and control subjects (for AG: 34.0% vs. 22.0%, p=0.0294; for GG: 62.0% vs. 76.0%, p=0.0162, respectively). No significant difference was found between genotypes and alleles of DRD2 Taq1A and DRD2 Taq1B polymorphism in patients and controls, while the CNR1 receptor 1359G/A polymorphism and the presence of the A allele may be one risk factor for susceptibility to obesity.
Publication Date: 2012-10-13
Journal: Genetic testing and molecular biomarkers

insulin resistance(10)

Knockout of CNR1 prevents metabolic stress-induced cardiac injury through improving insulin resistance (IR) injury and endoplasmic reticulum (ER) stress by promoting AMPK-alpha activation.
Obesity and diabetes are associated with diabetic cardiomyopathy (DCM). However, the pathogenesis of DCM is not fully understood. Cannabinoid receptor gene (CNR1) has been a drug target for the treatment of obesity. Here, we reported that CNR1 expression was increased in high fat diet (HFD)-induced heart of mice. Following, the wild type (CNR1
Publication Date: 2018-06-18
Journal: Biochemical and biophysical research communications

receptors cnr1(10)

Characterisation and localisation of the endocannabinoid system components in the adult human testis.
Heavy use of cannabis (marijuana) has been associated with decreased semen quality, which may reflect disruption of the endocannabinoid system (ECS) in the male reproductive tract by exogenous cannabinoids. Components of ECS have been previously described in human spermatozoa and in the rodent testis but there is little information on the ECS expression within the human testis. In this study we characterised the main components of the ECS by immunohistochemistry (IHC) on archived testis tissue samples from 15 patients, and by in silico analysis of existing transcriptome datasets from testicular cell populations. The presence of 2-arachidonoylglycerol (2-AG) in the human testis was confirmed by matrix-assisted laser desorption ionization imaging analysis. Endocannabinoid-synthesising enzymes; diacylglycerol lipase (DAGL) and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), were detected in germ cells and somatic cells, respectively. The cannabinoid receptors, CNR1 and CNR2 were detected at a low level in post-meiotic germ cells and Leydig- and peritubular cells. Different transcripts encoding distinct receptor isoforms (CB1, CB1A, CB1B and CB2A) were also differentially distributed, mainly in germ cells. The cannabinoid-metabolising enzymes were abundantly present; the α/β-hydrolase domain-containing protein 2 (ABHD2) in all germ cell types, except early spermatocytes, the monoacylglycerol lipase (MGLL) in Sertoli cells, and the fatty acid amide hydrolase (FAAH) in late spermatocytes and post-meiotic germ cells. Our findings are consistent with a direct involvement of the ECS in regulation of human testicular physiology, including spermatogenesis and Leydig cell function. The study provides new evidence supporting observations that recreational cannabis can have possible deleterious effects on human testicular function.
Publication Date: 2019-09-21
Journal: Scientific reports


Comparison and Functional Genetic Analysis of Striatal Protein Expression Among Diverse Inbred Mouse Strains.
C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains are highly variable genetically and differ in a large number of behavioral traits related to striatal function, including depression, anxiety, stress response, and response to drugs of abuse. The genetic basis of these phenotypic differences are, however, unknown. Here, we present a comparison of the striatal proteome between B6 and D2 and relate differences at the protein level to strain differences at the mRNA level. We also leverage a recombinant inbred BXD population derived from B6 and D2 strains to investigate the role of genetic variation on the regulation of mRNA and protein levels. Finally, we test the hypothesis that differential protein expression contributes to differential behavioral responses between the B6 and D2 strain. We detected the expression of over 2,500 proteins in membrane-enriched protein fractions from B6 and D2 striatum. Of these, 160 proteins demonstrated significant differential expression between B6 and D2 strains at a 10% false discovery level, including COMT, GABRA2, and cannabinoid receptor 1 (CNR1)-key proteins involved in synaptic transmission and behavioral response. Similar to previous reports, there was little overlap between protein and transcript levels (25%). However, the overlap was greater (51%) for proteins demonstrating genetic regulation of cognate gene expression. We also found that striatal proteins with significantly higher or lower relative expression in B6 and D2 were enriched for dopaminergic and glutamatergic synapses and processes involved in synaptic plasticity [e.g., long-term potentiation (LTP) and long-term depression (LTD)]. Finally, we validated higher expression of CNR1 in B6 striatum and demonstrated greater sensitivity of this strain to the locomotor inhibiting effects of the CNR1 agonist, Δ9-tetrahydrocannabinol (THC). Our study is the first comparison of differences in striatal proteins between the B6 and D2 strains and suggests that alterations in the striatal proteome may underlie strain differences in related behaviors, such as drug response. Furthermore, we propose that genetic variants that impact transcript levels are more likely to also exhibit differential expression at the protein level.
Publication Date: 2019-06-11
Journal: Frontiers in molecular neuroscience

body mass index(9)

Racial and sex differences in the polymorphisms of the endocannabinoid receptor genes in obesity.
Obesity is a global epidemic and prevalence of obesity is higher in African Americans (AAs) compared to Caucasians. The endocannabinoid system (EC) and polymorphism in the endocannabinoid receptor type 1 (CNR1) gene 3813A/G and 4895A/G and in the fatty acid amide hydrolase (FAAH) are associated with obesity. The objective was to explore racial and sex differences in these polymorphisms and the biochemical abnormalities seen in obesity. A cross-sectional study of 667 subjects (53.67% female; 49.18% AA; 69.72% were obese (body mass index [BMI] ≥30)) were screened for CNR1 3813, 4895 and FAAH 385 polymorphisms using a real-time polymerase chain reaction (PCR) system. Subjects with FAAH 385 polymorphisms were more likely to be obese (75.14% vs. 67.81, P = 0.046). There were no significant sex differences for CNR1 3813 and CNR1 4895; or between obese and control group. AAs had higher prevalence of CNR1 3813 (OR, 2.80, 95% CI, 1.95-4.04) and FAAH 385 (OR, 2.48, 95% CI, 1.82-3.38). Association between African American race and the three genotypes persisted after adjustment of all the variables (P < 0.001). FAAH 385 polymorphism is more likely seen in obese and in older subjects. AAs had higher prevalence of CNR1 3813 and FAAH 385 polymorphisms; and lower prevalence of CNR1 4895 polymorphism. These findings may explain some of the racial differences, but not the sex differences in the clinical expression of obesity.
Publication Date: 2020-08-01
Journal: Journal of diabetes and its complications


Uncovering the mechanisms of leech and centipede granules in the treatment of diabetes mellitus-induced erectile dysfunction utilising network pharmacology.
Diabetes mellitus-induced erectile dysfunction (DMED) is one of the most common complications of diabetes mellitus. Leech and centipede granules (LCG) have traditionally been used as blood-activating agents in various ethnomedicinal systems of East Asia, especially in China. It is often used to regulate bodily functions and considered as adjuvant therapy for promoting blood circulation, alleviating blood coagulation, activating meridians, and relieving stasis. This study aimed to identify potential genes and mechanisms of LCG on DMED from the network pharmacological perspective. The active components of LCG were identified by UHPLC-Q-TOF-MS, TCMID, and the BATMAN-TCM databases, and the disease targets of DMED were obtained from the DisGeNET, CooLGeN, GeneCards databases. After identifying DMED targets of LCG, a protein-protein interaction (PPI) network was constructed. Hub genes and significant modules were identified via the MCODE plug-in of Cytoscape software. Then, significant signaling pathways of the modules were identified using the Metascape database. The probable interaction mode of compounds-hub genes is examined using Molecular Operating Environment (MOE) docking software. Besides, we investigated the effects and mechanisms of LCG on improving erectile function in the streptozotocin (STZ)-induced diabetic rats model. Combined UHPLC-Q-TOF-MS analysis with network pharmacology study, 18 active compounds were selected for target prediction. There are 97 common target genes between LCG and DMED. Enrichment of the KEGG pathway mainly involves in the calcium signaling pathway, NF-kappa B signaling pathway, cGMP-PKG signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway, and mTOR signaling pathway. Nine hub genes were regulated by LCG in DMED, including CXCL8, NOS3, CRH, TH, BDNF, DRD4, ACE, CNR1, and HTR1A. The results of molecular docking analysis showed that the tyrosin, ursolic acid, and L-Histidine has a relatively stable interaction with corresponding hub genes via generating hydrogen bonds, H-π, and π-π interactions. Significantly, the results in docking predicted a higher affinity of vardenafil to the hub genes compared to the tyrosin, ursolic acid, and L-Histidine. Furthermore, LCG increased the testosterone, erection frequency, the ratio of ICP and MAP, SOD, cGMP, cAMP as well as decreased the MDA, and AGEs expression levels. And, LCG ameliorated the histological change of penile tissues in DMED rats. Hence, LCG attenuates oxidative stress, increases NO production; For the mechanism exploration, LCG could significantly upregulate the mRNA and protein expression of CNR1, NOS3, CRH, TH, BDNF, and DRD4, whereas CXCL8, ACE, and HTR1A levels were significantly higher than those in the DMED group. Moreover, LCG activates the NO/cGMP/PKG pathway, PI3K/Akt/nNOS pathway, cAMP/PKA pathway, and inhibits the HIF-1α/mTOR pathway to improve erectile function. Our results suggest that LCG maybe offer a new therapeutic basis for the treatment of DMED via altering the gene expression of involved metabolic pathways.
Publication Date: 2020-09-09
Journal: Journal of ethnopharmacology

p 0 05(8)

Exercise training and high-fat diet elicit endocannabinoid system modifications in the rat hypothalamus and hippocampus.
The purpose of the present study was to examine the effect of chronic exercise on the hypothalamus and hippocampus levels of the endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and of two AEA congeners and on the expression of genes coding for CB1, CB2 receptors (Cnr1 and Cnr2, respectively), and the enzymes responsible for eCB biosynthesis and degradation, in rats fed with a standard or high-fat diet. Male Wistar rats (n = 28) were placed on a 12-week high-fat (HFD) or standard diet period, followed by 12 weeks of exercise training for half of each group. Tissue levels of eCBs and related lipids were measured by liquid chromatography mass spectrometry, and expression of genes coding for CB1 and CB2 receptors and eCB metabolic enzymes was measured by quantitative real-time polymerase chain reaction (qPCR). HFD induced a significant increase in 2-AG (p < 0.01) in hypothalamus. High-fat diet paired with exercise training had no effect on AEA, 2-AG, and AEA congener levels in the hypothalamus and hippocampus. Cnr1 expression levels were significantly increased in the hippocampus in response to HFD, exercise, and the combination of both (p < 0.05). Our results indicate that eCB signaling in the CNS is sensitive to diet and/or exercise.
Publication Date: 2017-03-12
Journal: Journal of physiology and biochemistry

single nucleotide polymorphism(8)

The contributions of the endocannabinoid system and stress on the neural processing of reward stimuli.
The brain's endocannabinoid system plays a crucial role in reward processes by mediating appetitive learning and encoding the reinforcing properties of substances. Evidence also suggests that endocannabinoids are an important constituent of neuronal substrates involved in emotional responses to stress. Thus, it is critical to understand how the endocannabinoid system and stress may affect reward processes given their importance in substance use disorders. We examined the relationship between factors that regulate endocannabinoid system signaling (i.e., cannabinoid receptor genes and prolonged cannabis exposure) and stress on fMRI BOLD response to reward cues using multivariate statistical analysis. We found that proxies for endocannabinoid system signaling (i.e., endocannabinoid genes and chronic exposure to cannabis) and stress have differential effects on neural response to cannabis cues. Specifically, a single nucleotide polymorphism (SNP) variant in the cannabinoid receptor 1 (CNR1) gene, early life stress, and current perceived stress modulated reward responsivity in long-term, heavy cannabis users, while a variant in the fatty acid amide hydrolase (FAAH) gene and current perceived stress modulated cue-elicited response in non-using controls. These associations were related to distinct neural responses to cannabis-related cues compared to natural reward cues. Understanding the contributions of endocannabinoid system factors and stress that lead to downstream effects on neural mechanisms underlying sensitivity to rewards, such as cannabis, will contribute towards a better understanding of endocannabinoid-targeted therapies as well as individual risks for cannabis use disorder.
Publication Date: 2020-11-23
Journal: Progress in neuro-psychopharmacology & biological psychiatry

1 receptor gene(8)

Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy.
Diabetic nephropathy is a major cause of end-stage kidney disease, and overactivity of the endocannabinoid/cannabinoid 1 receptor (CB1R) system contributes to diabetes and its complications. Zucker diabetic fatty (ZDF) rats develop type 2 diabetic nephropathy with albuminuria, reduced glomerular filtration, activation of the renin-angiotensin system (RAS), oxidative/nitrative stress, podocyte loss, and increased CB1R expression in glomeruli. Peripheral CB1R blockade initiated in the prediabetic stage prevented these changes or reversed them when animals with fully developed diabetic nephropathy were treated. Treatment of diabetic ZDF rats with losartan, an angiotensin II receptor-1 (Agtr1) antagonist, attenuated the development of nephropathy and down-regulated renal cortical CB1R expression, without affecting the marked hyperglycemia. In cultured human podocytes, CB1R and desmin gene expression were increased and podocin and nephrin content were decreased by either the CB1R agonist arachydonoyl-2'-chloroethylamide, angiotensin II, or high glucose, and the effects of all three were antagonized by CB1R blockade or siRNA-mediated knockdown of CNR1 (the cannabinoid type 1 receptor gene). We conclude that increased CB1R signaling in podocytes contributes to the development of diabetic nephropathy and represents a common pathway through which both hyperglycemia and increased RAS activity exert their deleterious effects, highlighting the therapeutic potential of peripheral CB1R blockade.
Publication Date: 2014-11-26
Journal: Proceedings of the National Academy of Sciences of the United States of America

1 cannabinoid receptor(8)

Maternal high-fat diet up-regulates type-1 cannabinoid receptor with estrogen signaling changes in a sex- and depot- specific manner in white adipose tissue of adult rat offspring.
Obesity and high-fat (HF) diet are associated with over activation of the endocannabinoid system (ECS). We have demonstrated that maternal HF diet induces early obesity and modulates cannabinoid signaling in visceral (VIS) and subcutaneous (SUB) white adipose tissue (WAT) in weanling rat offspring. We hypothesized that perinatal maternal HF diet would program the expression of ECS in adipose tissue in a long-term way in parallel to alterations in epigenetic markers and sex hormone signaling. Progenitor female rats received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) for 8 weeks before mating, gestation, and lactation. All pups were weaned to C diet and they were euthanized at 180 days old. Maternal HF diet induced overweight and increased SUB WAT mass of male and female adult offspring. Maternal HF diet induced hypertrophy of VIS and SUB adipocytes only in female offspring associated with increased type 1 cannabinoid receptor protein (CB1) and mRNA (Cnr1) levels. These changes were associated with increased estrogen receptor α binding to Cnr1 promoter in SUB WAT of adult female offspring, which may contribute to higher expression of Cnr1. Increased CB1 signaling in adipose tissue might contribute to higher adiposity programmed by maternal HF diet because endocannabinoids stimulate the accumulation of fat in the adipose tissue. Our findings provide molecular insights into sex-specific targets for anti-obesity therapies based on the endocannabinoid system.
Publication Date: 2020-07-17
Journal: European journal of nutrition

cb1 cnr1(7)

Cannabinoid receptor 1/2 double-knockout mice develop epilepsy.
The endocannabinoid system has gained attention as an important modulator of activity in the central nervous system. Initial studies focused on cannabinoid receptor 1 (CB1), which is widely expressed in the brain, but recent work also implicates cannabinoid receptor 2 (CB2) in modulating neuronal activity. Both receptors are capable of reducing neuronal activity, generating interest in cannabinoid receptor agonists as potential anticonvulsants. CB1 (Cnr1) and CB2 (Cnr2) single-knockout mice have been generated, with the former showing heightened seizure sensitivity, but not overt seizures. Given overlapping and complementary functions of CB1 and CB2 receptors, we queried whether double-knockout mice would show an exacerbated neurological phenotype. Strikingly, 30% of double-knockout mice exhibited provoked behavioral seizures, and 80% were found to be epileptic following 24/7 video-electroencephalographic monitoring. Single-knockout animals did not exhibit seizures. These findings highlight the importance of the endocannabinoid system for maintaining network stability.
Publication Date: 2017-11-07
Journal: Epilepsia

p 0 01(6)

Gene variants and educational attainment in cannabis use: mediating role of DNA methylation.
Genetic and sociodemographic risk factors potentially associated with cannabis use (CU) were investigated in 40 cannabis users and 96 control subjects. DNA methylation analyses were also performed to explore the possibility of epigenetic changes related to CU. We conducted a candidate gene association study that included variants involved in the dopaminergic (ANKK1, NCAM1 genes) and endocannabinoid (CNR1, CNR2 gene) pathways. Sociodemographic data included gender, marital status, level of education, and body mass index. We used MeDIP-qPCR to test whether variations in DNA methylation might be associated with CU. We found a significant association between SNP rs1049353 of CNR1 gene (p = 0.01) and CU. Differences were also observed related to rs2501431 of CNR2 gene (p = 0.058). A higher education level appears to decrease the risk of CU. Interestingly, females were less likely to use cannabis than males. There was a significantly higher level of DNA methylation in cannabis users compared to controls in two of the genes tested: hypermethylation at exon 8 of DRD2 gene (p = 0.034) and at the CpG-rich region in the NCAM1 gene (p = 0.0004). Both genetic variants and educational attainment were also related to CU. The higher rate of DNA methylation, evidenced among cannabis users, may be either a marker of CU or a consequence of long-term exposure to cannabis. The identified genetic variants and the differentially methylated regions may represent biomarkers and/or potential targets for designs of pharmacological therapeutic agents. Our observations also suggest that educational programs may be useful strategies for CU prevention.
Publication Date: 2018-01-23
Journal: Translational psychiatry


Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis.
To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry. In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes. This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.
Publication Date: 2016-01-10
Journal: Rheumatology (Oxford, England)

95 ci(5)

The cannabinoid 1 receptor (CNR1) 1359 G/A polymorphism modulates susceptibility to ulcerative colitis and the phenotype in Crohn's disease.
Recent evidence suggests a crucial role of the endocannabinoid system, including the cannabinoid 1 receptor (CNR1), in intestinal inflammation. We therefore investigated the influence of the CNR1 1359 G/A (p.Thr453Thr; rs1049353) single nucleotide polymorphism (SNP) on disease susceptibility and phenotype in patients with ulcerative colitis (UC) and Crohn's disease (CD). Genomic DNA from 579 phenotypically well-characterized individuals was analyzed for the CNR1 1359 G/A SNP. Amongst these were 166 patients with UC, 216 patients with CD, and 197 healthy controls. Compared to healthy controls, subjects A/A homozygous for the CNR1 1359 G/A SNP had a reduced risk to develop UC (p = 0.01, OR 0.30, 95% CI 0.12-0.78). The polymorphism did not modulate CD susceptibility, but carriers of the minor A allele had a lower body mass index than G/G wildtype carriers (p = 0.0005). In addition, homozygous carriers of the G allele were more likely to develop CD before 40 years of age (p = 5.9x10(-7)) than carriers of the A allele. The CNR1 p.Thr453Thr polymorphism appears to modulate UC susceptibility and the CD phenotype. The endocannabinoid system may influence the manifestation of inflammatory bowel diseases, suggesting endocannabinoids as potential target for future therapies.
Publication Date: 2010-03-03
Journal: PloS one

waist circumference(5)

G1359A polymorphism in the cannabinoid receptor-1 gene is associated with metabolic syndrome in the Chinese Han population.
Recent studies suggest that endocannabinoids modulate food intake and lipogenesis through cannabinoid receptor-1 (CNR1). This study aims to determine the association between G1359A polymorphism of CNR1 and metabolic syndrome (MetS) in the Chinese Han population. A total of 382 subjects at risk for MetS and 136 healthy subjects from Tianjin, China were genotyped for the G1359A polymorphism of CNR1 using TaqMan assay. Anthropometric measurements and serum analyses were done for body mass index (BMI), waist circumference, blood pressure, serum triglycerides (TG), serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and plasma insulin levels. GG genotype of CNR1 has a higher incidence in MetS subjects than in control subjects. Logistic regression analysis shows that the GG genotype was significantly associated with the increased risk of developing MetS (OR 2.204, 95% CI 1.277-3.803, p = 0.005). Compared with CNR1 GG genotype in MetS subjects, CNR1 GA and AA genotypes in subjects with MetS had relatively lower levels of BMI, waist circumference, homeostasis model assessment of insulin resistance (HOMA-IR) and TG. Results suggest that the G1359A polymorphism of the CNR1 gene may contribute to MetS susceptibility in the Chinese Han population.
Publication Date: 2010-09-21
Journal: Archives of medical research

faah genes(5)

Impulsivity, variation in the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes, and marijuana-related problems.
Impulsivity is associated with increased marijuana use and subsequent marijuana-related problems among marijuana users. In addition, single nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes have been associated with cannabis-related phenotypes. This exploratory study tested whether the association between different aspects of impulsivity and the number of marijuana-related problems among users is explicated by variation in these putative cannabinoid-related genes. A total of 151 young adult regular marijuana users (used on M= 41.4% of the prior 60 days, SD = 24.3%) provided DNA and completed measures of trait (Barratt Impulsiveness Scale) and behavioral impulsivity (Stop Signal Task and Delay Discounting Questionnaire), as well as a self-report of marijuana-related problems. Three CNR1 and five FAAH SNPs were genotyped, tested for haplotype blocks, and subsequently examined for association with phenotypes described above. CNR1 variation significantly moderated the association between trait-level, but not behavioral, impulsivity and marijuana-related problems, such that the combination of higher trait impulsivity and CNR1 variation was associated with a greater number of marijuana-related problems. In contrast, there were no significant FAAH by impulsivity interactions; however, there was a main effect of FAAH on marijuana-related problems. These findings support an association with CNR1 and FAAH genes and marijuana-related problems among regular marijuana users. CNR1 variation emerged as a moderator of the relationship between trait impulsivity and marijuana problems, thus suggesting that marijuana users with CNR1 risk variants and a higher trait impulsivity are at greater risk for developing marijuana-related problems and supporting a role for CNR1 in a broader impulsivity phenotype.
Publication Date: 2013-11-01
Journal: Journal of studies on alcohol and drugs

cnr2 -(4)

ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice.
The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1(-/-) or Cnr2(-/-) mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.
Publication Date: 2014-07-18
Journal: Neuron

rs10485170 rs6454674(4)

Uremic Pruritus Is Not Associated with Endocannabinoid Receptor 1 Gene Polymorphisms.
Uremic pruritus (UP) is a frequent and bothersome symptom in hemodialysis patients. Its etiology is not fully understood and that is why there is no specific treatment. The endocannabinoid system plays a role in many pathological conditions. There is reliable evidence on the association between cannabinoid system and pruritus. In our study, we aimed to evaluate whether genetic variations in the endocannabinoid receptor 1 (CNR1) gene can affect UP. The rs12720071, rs806368, rs1049353, rs806381, rs10485170, rs6454674, and rs2023239 polymorphisms of the CNR1 gene were genotyped in 159 hemodialysis patients and 150 healthy controls using two multiplex polymerase chain reactions and the minisequencing technique. No statistically significant relationship was found in any of the evaluated genotypes between patients with and without UP, even after excluding patients with diabetes and dyslipidemia. There were no differences between patients with UP and the control group. However, in the group of all HD patients, a significantly higher incidence of GA genotype and lower incidence in GG genotype in the polymorphism rs806381s were revealed versus the control group (p = 0.04). It seems that polymorphisms of the CNR1 gene are not associated with uremic pruritus.
Publication Date: 2016-04-02
Journal: BioMed research international

1 receptor(3)

Anandamide inhibits Theiler's virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB(1) receptors.
VCAM-1 represents one of the most important adhesion molecule involved in the transmigration of blood leukocytes across the blood-brain barrier (BBB) that is an essential step in the pathogenesis of MS. Several evidences have suggested the potential therapeutic value of cannabinoids (CBs) in the treatment of MS and their experimental models. However, the effects of endocannabinoids on VCAM-1 regulation are poorly understood. In the present study we investigated the effects of anandamide (AEA) in the regulation of VCAM-1 expression induced by Theiler's virus (TMEV) infection of brain endothelial cells using in vitro and in vivo approaches. i) in vitro: VCAM-1 was measured by ELISA in supernatants of brain endothelial cells infected with TMEV and subjected to AEA and/or cannabinoid receptors antagonist treatment. To evaluate the functional effect of VCAM-1 modulation we developed a blood brain barrier model based on a system of astrocytes and brain endothelial cells co-culture. ii) in vivo: CB(1) receptor deficient mice (Cnr1(-/-)) infected with TMEV were treated with the AEA uptake inhibitor UCM-707 for three days. VCAM-1 expression and microglial reactivity were evaluated by immunohistochemistry. Anandamide-induced inhibition of VCAM-1 expression in brain endothelial cell cultures was mediated by activation of CB(1) receptors. The study of leukocyte transmigration confirmed the functional relevance of VCAM-1 inhibition by AEA. In vivo approaches also showed that the inhibition of AEA uptake reduced the expression of brain VCAM-1 in response to TMEV infection. Although a decreased expression of VCAM-1 by UCM-707 was observed in both, wild type and CB(1) receptor deficient mice (Cnr1(-/-)), the magnitude of VCAM-1 inhibition was significantly higher in the wild type mice. Interestingly, Cnr1(-/-) mice showed enhanced microglial reactivity and VCAM-1 expression following TMEV infection, indicating that the lack of CB(1) receptor exacerbated neuroinflammation. Our results suggest that CB(1) receptor dependent VCAM-1 inhibition is a novel mechanism for AEA-reduced leukocyte transmigration and contribute to a better understanding of the mechanisms underlying the beneficial role of endocannabinoid system in the Theiler's virus model of MS.
Publication Date: 2011-08-20
Journal: Journal of neuroinflammation

p 0 04(3)

Association of polymorphisms in the endocannabinoid system genes with myocardial infarction and plasma cholesterol levels.
The aim of this study was to investigate the relationship between selected symptoms of chronic heart failure (myocardial infarction, plasma cholesterol level) and single nucleotide polymorphisms (SNPs) in the FAAH and CNR1 genes. A case - control study involving 155 patients with chronic heart failure and 169 age- and sex-matched healthy subjects. We detected SNPs 385 C/A (rs324420) in the FAAH and 1359 G/A (rs1049353) in the CNR1 genes using the polymerase chain reaction and restriction analysis. Genotype and allele frequencies were compared between patients and controls as well as between patients with and without myocardial infarction. No significant differences in genotype or allelic frequencies between patients and controls were found (P > 0.05). Carriers of the FAAH A allele had a 2.37-fold increase in the risk of myocardial infarction (odds ratio 2.37, 95% confidence interval 1.36-6.93, P = 0.01). Homozygous carriers of genotype AA of CNR1 SNP 1359 had significantly higher plasma cholesterol levels than carriers of GG and GA genotypes in patients (P = 0.04). The study results suggest a role for allele A of the FAAH 385 variant as a risk factor for myocardial infarction. Genotype AA of CNR1 1359 variant probably affects plasma cholesterol levels. Pharmacological intervention in this system could modify the therapeutic approach to certain cardiovascular disorders.
Publication Date: 2014-10-02
Journal: Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia

homeostasis model assessment(3)

G1359A polymorphism in the cannabinoid receptor-1 gene is associated with the presence of coronary artery disease in patients with type 2 diabetes.
Previous studies demonstrated that G1359A polymorphism of cannabinoid receptor-1 (CNR1) was associated with cardiovascular risk factors including obesity, insulin resistance, dyslipidemia, and inflammation, which are also risk factors for developing type 2 diabetes mellitus (T2DM). Therefore, this study was aimed to determine whether G1359A polymorphism of CNR1 is associated with T2DM and the presence of coronary artery disease (CAD) in patients with T2DM. A total of 450 patients with T2DM (259 patients with CAD and 191 patients without CAD) and 94 healthy subjects were genotyped using polymerase chain reaction and restriction fragment length polymorphism method. No significant differences in genotype frequency of CNR1 were found between normal controls and patients with T2DM without CAD. GG genotype frequency of CNR1 was significantly higher in the patients with T2DM with CAD compared with those without CAD and healthy subjects (P = 0.003 and P = 0.005, respectively). Unconditional logistic regression analysis revealed that GG genotype was significantly associated with the presence of CAD in the patients with T2DM compared with GA and AA genotypes (odds ratio, 2.632; 95% confidence interval, 1.481-4.678; P < 0.001). In addition, GG genotype of CNR1 was significantly correlated with elevated levels of body mass index, systolic blood pressure, homeostasis model assessment of insulin resistance, and C-reactive protein, as well as decreased levels of high-density lipoprotein cholesterol in patients with T2DM. G1359A polymorphism of CNR1 may be not associated with T2DM but may contribute to the genetic risk for the presence of CAD in patients with T2DM of Chinese Han population.
Publication Date: 2011-12-06
Journal: Journal of investigative medicine : the official publication of the American Federation for Clinical Research

cnr1 comt(3)

Symptom Science: Omics Supports Common Biological Underpinnings Across Symptoms.
For precision health care to be successful, an in-depth understanding of the biological mechanisms for symptom development and severity is essential. Omics-based research approaches facilitate identification of the biological underpinnings of symptoms. We reviewed literature for omics-based approaches and exemplar symptoms (sleep disruption, cognitive impairment, fatigue, gastrointestinal [GI] distress, and pain) to identify genes associated with the symptom or symptoms across disease processes. The review yielded 27 genes associated with more than one symptom. ABCB1 (MDR1), APOE, BDNF, CNR1, COMT, DAT1 (SLC6A3), DRD4, ESR1, HLA-DRB1, IL10, IL1B, IL6, LTA, PTGS2 (COX-2), SLC6A4, and TNF were associated with cognitive impairment and pain, which had the most genes in common. COMT and TNF were related to all symptoms except sleep disruption. IL1B was associated with all symptoms except cognitive impairment. IL10, IL1A, IL1B, IL1RN, IL6, and IL8 (CXCL8) were linked with all the exemplar symptoms in various combinations. ABCB1 (MDR1) and SLC6A4 were associated with cognitive impairment, GI distress, and pain. IL10 and IL6 were linked to cognitive impairment, fatigue, and pain. APOE and BDNF were associated with sleep disruption, cognitive impairment, and pain. The 27 genes were associated with canonical pathways including immune, inflammatory, and cell signaling. The pathway analysis generated a 15-gene model from the 27 as well as 3 networks, which incorporated new candidate genes. The findings support the hypothesis of overlapping biological underpinnings across the exemplar symptoms. Candidate genes may be targeted in future omics research to identify mechanisms of co-occurring symptoms for potential precision treatments.
Publication Date: 2018-01-13
Journal: Biological research for nursing

drd2 drd3(3)

[Searching for Tourette's syndrome gene. Part 2. Patient's genome variability].
Gilles de la Tourette syndrome (GTS) is a complex, heterozygous genetic disorder. Twenty chromosomal rearrangements (7q22-q31, 8q13-q22, and 18q22) indicating genomic regions which may be involved in the etiology of the disorder have been reported in families with GTS. Moreover, pathogenic mutations responsible for GTS were found in the SLITRK1 and the L-histidine decarboxylase (HDC) genes. The W317X mutation in the HDC gene points to a possible role for histaminergic neurotransmission in the mechanism and modulation of tic disorder. The distribution of single nucleotide polymorphisms (SNPs) was examined in at least 14 candidate genes (DRD1, DRD2, DRD3, DRD4, DAT1, MAOA, 5HTR2A, 5HTR3A, TDO2, CNR1, HLA-DRB, IL1RA, MOG, and SGCE) using a case-control genetic association analysis. Still, a lack of replicated and consistent results was observed. Recently, rare structural variants of different genes involved in neurodevelopment determined by recurrent exonic copy number variations (CNVs) have been found in a subset of patients suffering from GTS.
Publication Date: 2012-03-01
Journal: Postepy higieny i medycyny doswiadczalnej (Online)

p 001(2)

A family-based study to identify genetic biomarkers of fibromyalgia: consideration of patients' subgroups.
Evidence from genome-wide and candidate gene association studies, familial aggregation and linkage analyses demonstrate the genetic contribution to fibromyalgia (FM) disease. This study aimed to identify genetic biomarkers of FM and its related comorbid disorders, by exploring 41 polymorphisms potentially involved in FM pathogenesis in families with at least one patient with FM. Core symptoms were assessed, and blood samples collected from 556 patients with FM and 395 healthy relatives. For the genetic study, a final sample of 401 FM patients and 232 healthy controls was selected, discarding patients with concomitant pathologies and controls with chronic pain. A family-based approach using DFAM test (Plink) and SNPs (single nucleotide polymorphisms) combination analyses to compare FM patients vs. controls were first applied. Second, the genotypic distribution of subgroups of FM patients, stratified by severe vs. mild symptoms of pain, depression and sleep impairment, was considered. No evidence of associations with FM per se were detected, using either a family-based approach or SNPs combination analyses. However, considering the subgroups of FM patients, the SNP rs6454674 (CNR1, cannabinoid receptor 1 gene) was found as a potential genetic marker of FM correlated with depression (p<.001). No significant associations using either the family-based analysis or the SNPs combination tests dissociated FM patients and their healthy relatives. FM patients with and without depression showed a significant difference in the genotypic distribution related to the SNP rs6454674 in the cannabinoid receptor 1 gene (CNR1) indicating that FM is not a homogenous disorder.
Publication Date: 2021-06-24
Journal: Clinical and experimental rheumatology

cnr1 2(2)

Cannabinoid Receptors Are Overexpressed in CLL but of Limited Potential for Therapeutic Exploitation.
The cannabinoid receptors 1 and 2 (CNR1&2) are overexpressed in a variety of malignant diseases and cannabinoids can have noteworthy impact on tumor cell viability and tumor growth. Patients diagnosed with chronic lymphocytic leukemia (CLL) present with very heterogeneous disease characteristics translating into highly differential risk properties. To meet the urgent need for refinement in risk stratification at diagnosis and the search for novel therapies we studied CNR expression and response to cannabinoid treatment in CLL. Expression levels of CNR1&2 were determined in 107 CLL patients by real-time PCR and analyzed with regard to prognostic markers and survival. Cell viability of primary CLL cells was determined in suspension and co-culture after incubation in increasing cannabinoid concentrations under normal and reduced serum conditions and in combination with fludarabine. Impact of cannabinoids on migration of CLL cells towards CXCL12 was determined in transwell plates. We found CNR1&2 to be overexpressed in CLL compared to healthy B-cells. Discriminating between high and low expressing subgroups, only high CNR1 expression was associated with two established high risk markers and conferred significantly shorter overall and treatment free survival. Viability of CLL primary cells was reduced in a dose dependent fashion upon incubation with cannabinoids, however, healthy cells were similarly affected. Under serum reduced conditions, no significant differences were observed within suspension and co-culture, respectively, however, the feeder layer contributed significantly to the survival of CLL cells compared to suspension culture conditions. No significant differences were observed when treating CLL cells with cannabinoids in combination with fludarabine. Interestingly, biologic activity of cannabinoids was independent of both CNR1&2 expression. Finally, we did not observe an inhibition of CXCL12-induced migration by cannabinoids. In contrast to other tumor entities, our data suggest a limited usability of cannabinoids for CLL therapy. Nonetheless, we could define CNR1 mRNA expression as novel prognostic marker.
Publication Date: 2016-06-02
Journal: PloS one

cnr1 faah(2)

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.
Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.
Publication Date: 2013-06-27
Journal: Translational psychiatry

cnr1 flox flox(1)

Cannabinoid receptor 1 in the vagus nerve is dispensable for body weight homeostasis but required for normal gastrointestinal motility.
The cannabinoid receptor 1 (CB(1)R) is required for body weight homeostasis and normal gastrointestinal motility. However, the specific cell types expressing CB(1)R that regulate these physiological functions are unknown. CB(1)R is widely expressed, including in neurons of the parasympathetic branches of the autonomic nervous system. The vagus nerve has been implicated in the regulation of several aspects of metabolism and energy balance (e.g., food intake and glucose balance), and gastrointestinal functions including motility. To directly test the relevance of CB(1)R in neurons of the vagus nerve on metabolic homeostasis and gastrointestinal motility, we generated and characterized mice lacking CB(1)R in afferent and efferent branches of the vagus nerve (Cnr1(flox/flox); Phox2b-Cre mice). On a chow or on a high-fat diet, Cnr1(flox/flox); Phox2b-Cre mice have similar body weight, food intake, energy expenditure, and glycemia compared with Cnr1(flox/flox) control mice. Also, fasting-induced hyperphagia and after acute or chronic pharmacological treatment with SR141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] (CB(1)R inverse agonist) paradigms, mutants display normal body weight and food intake. Interestingly, Cnr1(flox/flox); Phox2b-Cre mice have increased gastrointestinal motility compared with controls. These results unveil CB(1)R in the vagus nerve as a key component underlying normal gastrointestinal motility.
Publication Date: 2012-07-28
Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience

- cnr2(1)

Enhanced humoral immunity in mice lacking CB1 and CB2 receptors (Cnr1-/-/Cnr2-/- mice) is not due to increased splenic noradrenergic neuronal activity.
Peripheral sympathetic noradrenergic neurons originating in the celiac mesenteric plexus have axons that terminate in close proximity to antibody-producing B cells in the spleen. Norepinephrine (NE) released from these neurons is reported to augment antibody production in response to an immune challenge via an action at the β2-adrenergic receptor (β2AR). Cannabinoids are immunosuppressive, and mice lacking CB1 and CB2 receptors (Cnr1(-/-)/Cnr2(-/-) mice) have augmented cell-mediated immune responses. The purpose of this study was to determine if Cnr1(-/-)/Cnr2(-/-) mice also exhibit enhanced humoral immunity and if that is associated with corresponding changes in noradrenergic neurons terminating in the spleen. The results reveal that IgM and IgG are enhanced in Cnr1(-/-)/Cnr2(-/-) mice as compared to WT both in immunologically naïve and lipopolysaccharide (LPS)-treated mice. While the elevated antibody production was correlated with increased expression of β2AR on splenic B cells and increased splenic capsule NE concentrations, the activity of noradrenergic neurons was suppressed in spleens from Cnr1(-/-)/Cnr2(-/-) mice as compared with WT controls. Together, these results suggest that Cnr1(-/-)/Cnr2(-/-) mice exhibit enhanced NE vesicular storage in axon terminals in these neurons, which might limit the NE available to bind β2AR on target cells, such as B cells. The results also demonstrate that enhanced antibody responses in the absence of CB1 and CB2 receptors are not due to increased sympathetic noradrenergic neuronal activity in the spleen.
Publication Date: 2014-05-30
Journal: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

cnr1 rbm39(1)

Integrative bioinformatics analysis reveals miR-494 and its target genes as predictive biomarkers of trastuzumab-resistant breast cancer.
The focus of trastuzumab resistance biomarkers in recent decades has been on epigenetic and non-coding RNA-based mechanisms. In this study, the potential of miR-494 and its target genes as predictive biomarkers for breast cancer (BC) resistance to trastuzumab was identified. The microarray data were obtained from the GEO database, including GSE101841, GSE75669, and GSE66305. Data processing was conducted using GEO2R to obtain differentially expressed genes (DEGs). The data analysis using GEO2R revealed that DEGs from GSE101841 and GSE75669 consisted of 3 and 135 upregulated miRNAs, respectively. On the other hand, the same analysis revealed 8 and 226 downregulated miRNAs for DEGs from GSE101841 and GSE75669, respectively. A Venn diagram showed that one miR was detectable in serum and tissue samples, namely miR-494. The miR-494 target was predicted using the miRecords database and resulted in 69 target genes. A Venn diagram between miR-494 target genes from miRecords and the mRNA array from GSE66305 revealed three potential targets of CNR1, RBM39, and ZNF207. A Kaplan-Meier survival plot showed that BC patients with a high miR-494 level and a low ZNF207 mRNA level had significantly worse overall survival. Validation of target genes in BC samples and trastuzumab-resistant and -sensitive BC cells with GEPIA and ONCOMINE highlighted the potential of CNR1, RBM39, and ZNF207 as predictive biomarkers of trastuzumab resistance in BC cells. Taken together, these results suggest that miR-494 plays a role in the mechanism of BC resistance to trastuzumab by involving its target genes CNR1, RBM39, and ZNF207.
Publication Date: 2020-05-07
Journal: Journal of the Egyptian National Cancer Institute

th bdnf(1)

vs 13 0(1)

0 435 0 503(1)

Hepatocellular Carcinoma: Retrospective Evaluation of the Correlation Between Gadobenate Dimeglumine-Enhanced Magnetic Resonance Imaging and Pathologic Grade.
The aim of this study was to evaluate the usefulness of gadobenate dimeglumine-enhanced magnetic resonance imaging in characterizing the grade of hepatocellular carcinoma (HCC) using the signal intensity (SI) of the erector spinae as internal reference. Clinical data of 40 patients (a total of 44 lesions) confirmed by pathology for HCC were retrospectively reviewed. Gadobenate dimeglumine-enhanced magnetic resonance imaging was performed in all patients, and SI of lesions (SIles), liver parenchyma around the lesions (SIhep), erector spinae (SImus) and standard deviation of SI of the surrounding noise (SDnoi) on nonenhanced T2WI, nonenhanced T1WI, and contrast-enhanced T1WI (in both arterial and hepatobiliary phase [AP and HBP]) were measured, respectively. Contrast-to-noise ratio (CNR) were separately defined as CNR1 ([SIles - SIhep]/SDnoi) and CNR2 ([SIles - SImus]/SDnoi). Statistical analyses were performed using one-way analysis of variance, least significant difference test, logistic regression analysis, Spearman rank correlation, and receiver operating characteristic curves analysis. Forty-four HCCs, including 3 well-differentiated HCCs, 26 moderately differentiated HCCs, and 15 poorly differentiated (PD) HCCs, were confirmed. On logistic regression analysis, only CNR2 in the HBP was predictor of PD HCCs (P = 0.015, odds ratio = 1.040). The size of lesions, CNR1 in the AP, CNR2 in the AP, and CNR2 in the HBP, showed significant correlations with the degree of differentiation (correlation coefficients = -0.371, 0.435, 0.503, and 0.512, respectively; P = 0.013, 0.003, 0.001, and 0.000, respectively). Contrast-to-noise ratio 2 in the HBP with the cutoff of less than 4.56 could distinguish moderately differentiated HCCs from PD HCC with the sensitivity and specificity of 84.6% and 60.0%, respectively. Relatively low arterial enhancement and low CNR2 value in the HBP are predictive for poor histological grade of HCCs.
Publication Date: 2018-01-26
Journal: Journal of computer assisted tomography

ci 1 82-3 38(1)