Mechanism of Suoquanwan on Enuresis Based on Network Pharmacology and Experimental Verification / 中国实验方剂学杂志

Objective:To explore the targets and relevant signaling pathways of Suoquanwan in the treatment of enuresis using network pharmacology，and animal expriments are applied to further define its mechanism of action. Method:Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP） database was used to screen out active chemical components of Suoquanwan，varieties of systematic biological databases were integrated to construct the "active component-disease-target" network relationship，and the common protein protein interaction network（PPI） network genes were functionally enriched. Quantitative real time polymerase chain reaction（Real-time PCR） and Western blot were used to verify the effect of Suoquanwan on AVPR2 and DRD2 gene. Result:A total of 32 active ingredients were screened from Suoquanwan. These active ingredients were interacted with 131 potential targets relating to Enuresis，which contained 14 core target genes，namely arginine vasopressin receptor 2 （AVPR2）， neurotrophic receptor tyrosine kinase 1（NTRK1）， dopamine receptor D2（DRD2）， opioid receptor mu 1（OPRM1）， 5-hydroxytryptamine receptor 1A（HTR1A）， 5-hydroxytryptamine receptor 1B（HTR1B），solute carrier family 6 member 4（SLC6A4），Adrenoceptor Alpha 2A（ADRA2A）， prostaglandin-endoperoxide synthase 2（PTGS2）， cholinergic receptor muscarinic 2（CHRM2）， solute carrier family 6 member 3 （SLC6A3）， 5-hydroxytryptamine receptor 6（HTR6）， solute carrier family 6 member 2（SLC6A2）， cytochrome P450 family 2 subfamily C member 19（CYP2C19）. Gene enrichments mainly involved to G protein-coupled receptor signaling pathway，regulation of trans-synaptic signaling，regulation of neurotransmitter transport and neuroactive ligand-receptor interaction. Real-time PCR and Western blot results showed that Suoquanwan could enhance the expression of AVPR2 in rat kidney，and weaken the expression of DRD2 in rat adrenal. Conclusion:The main chemical constituents in Suoquanwan may alleviate enuresis by regulating AVPR2 and DRD2 and then participating in the G protein-coupled receptor signaling pathway，regulation of trans-synaptic signaling，regulation of neurotransmitter transport and other biological processes.

Homeobox Gene Six3 is Required for the Differentiation of D2-Type Medium Spiny Neurons / 神经科学通报·英文版

Medium spiny neurons (MSNs) in the striatum, which can be divided into D1 and D2 MSNs, originate from the lateral ganglionic eminence (LGE). Previously, we reported that Six3 is a downstream target of Sp8/Sp9 in the transcriptional regulatory cascade of D2 MSN development and that conditionally knocking out Six3 leads to a severe loss of D2 MSNs. Here, we showed that Six3 mainly functions in D2 MSN precursor cells and gradually loses its function as D2 MSNs mature. Conditional deletion of Six3 had little effect on cell proliferation but blocked the differentiation of D2 MSN precursor cells. In addition, conditional overexpression of Six3 promoted the differentiation of precursor cells in the LGE. We measured an increase of apoptosis in the postnatal striatum of conditional Six3-knockout mice. This suggests that, in the absence of Six3, abnormally differentiated D2 MSNs are eliminated by programmed cell death. These results further identify Six3 as an important regulatory element during D2 MSN differentiation.

Effects of lactagogue of four total alkaloids of barley malt via dopamine D2 receptor in postpartum hypogalactia rat / 中草药

Objective: To explore the regulatory effect of malt alkaloid on prolactin (PRL) secretion in the model rat with postpartum hypogalactia induced by bromocriptine based on dopamine D2 receptor, and determine the active fraction of the malt with galactogogue effect. Methods: The postpartum hypogalactia model was established by intragastric administration of bromocriptine mesylate. After the model was successfully established, all groups were given corresponding drug treatment. The concentration of serum PRL, estradiol (E2) and progesterone (P) in each group was detected by ELISA kits. HE staining was used to observe the pathologic changes of breast tissue. RT-PCR was used to determine the mRNA levels of prolactin receptor (PRLR) and dopamine D2 receptor (DRD2) in pituitary gland of rats. Results: Compared with the control group, the levels of serum PRL, P, and E2 were significantly decreased in the model group as well as the mRNA expression of the pituitary PRL cells. But the mRNA expression of the pituitary DRD2 in the model group was significantly increased compared with the control group. Compared with the model group, the malt total alkaloid significantly increased the volume of mammary lobule and dilated the duct. There was a lot of milk in the duct and acinar in the malt total alkaloid group. Besides, the total alkaloids increased the concentration of serum PRL, P, and E2 and the mRNA expression of the pituitary PRL cells, and decreased the mRNA expression of the pituitary DRD2. Conclusion: The primary the active fraction of malt for galactogogue action is total alkaloids, and its mechanism may be related to promoting PRL secretion, increasing serum PRL receptor level and decreasing the mRNA expression of dopamine D2 receptor.

Effects of DRD2 and 5-HTR2A gene polymorphisms and their interaction on olanzapine in the treatment of schizophrenia / 中国临床药理学与治疗学

AIM: To investigate the association of dopamine D2 receptor (DRD2) and 5-hydroxytryptamine 2A receptor (5-HTR2A) gene polymorphisms and their interactions with efficacy of olanzapine in treatment of schizophrenic patients. METHODS: A total of 147 schizophrenic patients who treated with olanzapine alone were recruited. The positive and negative symptom scale (PANSS) was used to evaluate the efficacy of drugs. According to PANSS reduction rate ≥50% and <50%, patients were divided into the effective group and the ineffective group. The gene polymorphisms of DRD2 (rs1799978, rs1800497) and 5-HTR2A (rs6311, rs6313) were detected by improved multiple ligase detection reaction (iMLDR). Multivariate Logistic regression analysis was used to analyze the correlation between genotypes and olanzapine efficacy, and multifactor dimensionality reduction (MDR) was used to analyze gene-gene interactions. RESULTS: There were significant differences in genotype and allele frequencies of rs1799978 and rs6313 between the effective group and the ineffective group (P<0.05), while there was no difference in genotype and allele frequencies of rs1800497 and rs6311 (P<0.05). Patients with GA and GG of rs1799978 locus were more effective than those with wild type AA when treated with olanzapine, and the ORs (95%CI) were 5.101 (1.118-23.267) and 6.051 (2.454-14.925), respectively. Patients with CT and CC of rs6313 locus were more effective than those with wild type TT when treated with olanzapine, and the ORs (95%CI) were 2.623 (1.054-6.528) and 3.412 (1.180-9.869), respectively. There was a interaction between the gene polymorphisms of rs1799978, rs1800497 and rs6313. The interaction model was the optimal gene-gene interaction model (P<0.05) with the verify sample accuracy rate of 0.727 3 and a cross-validation consistency of 10/10. CONCLUSION: The gene polymorphisms of DRD2 (rs1799978) and 5-HTR2A (rs6313) may be associated with efficacy of olanzapine in treatment of schizophrenic patients, and there is a interaction between DRD2 (rs1799978, rs1800497) and 5-HTR2A (rs6313) on the efficacy of olanzapine.

Association between DRD2 gene polymorphisms and the dosage used on methadone maintenance treatment program / 中华流行病学杂志

Objective To investigate the association between three single nucleotide polymorphism (SNP) genes DRD2 (rs1800497,rs6275,and rs1799978) and the dosage used on methadone maintenance treatment (MMT).Methods From the methadone maintenance treatment centers,257 MMT patients were recruited to participate in a case-control study and divided into two groups—control groups under low dosage (n=89) and case (n=168) group with high dosage.Quanto software was used to estimate the sample size as 180.Information related to social-demographic status,history on drug use and medication were collected.And DRD2 SNPs were genotyped to explore the relationship between polymorphism of DRD2 gene and the dosage of methadone maintenance treatment.Results Distributions of DRD2 rs6275 between different groups were significantly different.Patients carrying TC genotype needed lower dose of methadone when compared to the patients that carrying CC genotype counterparts (OR=0.338,95％ CI:0.115-0.986).Patients that carrying C allele at rs6275 needed lower methadone dose than those that carrying genotype TT (OR=0.352,95％CI:0.127-0.975).Distributions of genotypes,alles in the other two SNPs (rs1800497,rs1799978) were not significantly different between groups under different dosages.Conclusion DRD2 rs6275 was associated with dosage of methadone used for the MMT patients.However,no significant associations were found between rs 1800497,rs 1799978 and the dosage of methadone.

Association between DRD2 gene polymorphisms and the dosage used on methadone maintenance treatment program / 中华流行病学杂志

Objective To investigate the association between three single nucleotide polymorphism (SNP) genes DRD2 (rs1800497,rs6275,and rs1799978) and the dosage used on methadone maintenance treatment (MMT).Methods From the methadone maintenance treatment centers,257 MMT patients were recruited to participate in a case-control study and divided into two groups—control groups under low dosage (n=89) and case (n=168) group with high dosage.Quanto software was used to estimate the sample size as 180.Information related to social-demographic status,history on drug use and medication were collected.And DRD2 SNPs were genotyped to explore the relationship between polymorphism of DRD2 gene and the dosage of methadone maintenance treatment.Results Distributions of DRD2 rs6275 between different groups were significantly different.Patients carrying TC genotype needed lower dose of methadone when compared to the patients that carrying CC genotype counterparts (OR=0.338,95％ CI:0.115-0.986).Patients that carrying C allele at rs6275 needed lower methadone dose than those that carrying genotype TT (OR=0.352,95％CI:0.127-0.975).Distributions of genotypes,alles in the other two SNPs (rs1800497,rs1799978) were not significantly different between groups under different dosages.Conclusion DRD2 rs6275 was associated with dosage of methadone used for the MMT patients.However,no significant associations were found between rs 1800497,rs 1799978 and the dosage of methadone.

The fMRI study of brain inhibitory control function difference between DRD2 gene subtype of heroin addicts / 实用放射学杂志

Objective To explore the difference in inhibitory control ability between DRD2 gene subtype of heroin addicts with fMRI.Methods Thirty-seven heroin-dependent patients were divided into DRD2 Taq IA+ group (A+,22)and matched DRD2 Taq IA-group (A-,15).Functional MRI was performed in all patients while they were executing an event-related go/nogo task at 3.0T MR scanner.The differences of brain activated images and behavioral data between the two groups were analyzed with SPM8 and SPSS1 6.0 software,respectively.Results There were no significant differences in reaction time,accuracy and false alarm rates between the two groups (P>0.05).Compared with A-group,weaker activation in the medial prefrontal cortex,dorsal anterior cingulate,middle cingulate,supplementary motor area,temporal lobe,fusiform gyrus,lingual gyrus,hippocampus and parahippocampal gyrus in response inhibition condition were demonstrated in A+ group (voxel number>228,t=2.11,Alphasim correction,P<0.05).There was no corrlation between the intensity within the activated brain regions and the usage of heroin,morphine urine test positive number(P>0.05).Conclusion DRD2 Taq IA+ group exist deactivation of the brain area on memory,inhibitory control,visual spatial attention. It may be the neural basis that contribute to easy addiction and relapse for A+ carriers.

Polimorfismos del receptor D2 / D2 receptor polymorphisms

Los prolactinomas son tumores bien diferenciados que se originan en las células lactotropas pituitarias, una línea celular que secreta fisiológicamente prolactina (PRL). A nivel hipofisario, la dopamina está implicada en la regulación de la secreción de PRL por las células lactotropas y este efecto inhibitorio está mediado por la activación del receptor de prolactina tipo 2 (DRD2). Hay varios polimorfismos del DRD2, el primero y más estudiado es TaqI A1; está demostrado que este alelo se encuentra asociado a una reducción de la actividad cerebral dopaminérgica, además de observarse una reducción en su capacidad de unión de aproximadamente un 30%. Este alelo se ha vinculado con una menor densidad de DRD2 en el cuerpo estriado, especialmente en el putamen y caudado ventral, y la cantidad de DRD2 en portadores del alelo A1 fue un 30-40% más bajo que en los no portadores (es decir, TaqI A2 homocigotos). En la literatura, hay evidencia que apoya la posible participación de los polimorfismos DRD2 en la regulación de la secreción hormonal.

Prolactinomas are well differentiated tumours that originate in the pituitary lactotrope cells, a cell line that physiologically secretes prolactin (PRL). At pituitary level, dopamine is involved in the regulation of PRL secretion by lactotropes, and this inhibitory effect is mediated by activation of prolactin type 2 receptor (DRD2). Of the several DRD2 polymorphisms, the first and most studied is TaqI A1. It has been demonstrated that this allele is associated with a reduced dopaminergic brain activity, and a reduction in its binding capacity of approximately 30% also being observed. This allele was associated with a lower density of DRD2 in the striatum, especially in the putamen and ventral caudate. The amount of DRD2 in A1 allele carriers was 30 - 40% lower than in non-carriers (this is, TaqI A2 Homozygotes). There is evidence in the literature, that supports the possible involvement of DRD2 polymorphisms in the regulation of hormonal secretion.

The Relationship between the Amisulpride-Induced Hyperprolactinemia and Taq1A Polymorphism of the Dopamine D2 Receptor Gene in Schizophrenia Patients

OBJECTIVES: This study was aimed to investigate the association between amisulpride-induced hyperprolactinemia and the Taq1A polymorphism in the D2 dopamine receptor gene (DRD2) in schizophrenic patients. METHODS: The plasma concentrations of prolactin were measured before and after treatment with amisulpride in one hundred and twenty-five schizophrenic patients. The effect of the Taq1A variants of the DRD2 on the risk of amisulpride-induced hyperprolac-tinemia was the main the outcome measure. The genotyping for Taq1A (rs1800497) polymorphism was performed using TaqMan single nucleotide polymorphism (SNP) genotyping assay. RESULTS: There was a significant difference between the prolactin level at baseline and the 6th week after treatment with amisulpride in all the subjects. However, there were no significant correlations between ΔProlactin (the difference between prolactin level at baseline and the 6th week after treatment) and the Taq1A genotypes. CONCLUSIONS: This is the first study to investigate the-correlations between the Taq1A polymorphism and the amisulpride-induced hyperprolactinemia in Korean schizophrenic patients. The current results suggested the further large-scale researches on various SNPs in the DRD2 gene will establish clear goals and provide answers to the unanswered questions described in this study.

Genome-Wide Supported Risk Variants in MIR137, CACNA1C, CSMD1, DRD2, and GRM3 Contribute to Schizophrenia Susceptibility in Pakistani Population

OBJECTIVE: Schizophrenia is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide. Recently, MIR137, CACNA1C, CSMD1, DRD2, and GRM3 have been reported as the most robustly emerging candidates involved in the etiology of schizophrenia. In this case control study, we performed an association analysis of rs1625579 (MIR137), rs1006737, rs4765905 (CACNA1C), rs10503253 (CSMD1), rs1076560 (DRD2), rs12704290, rs6465084, and rs148754219 (GRM3) in Pakistani population. METHODS: Schizophrenia was diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders 4th ed (DSM-IV). Detailed clinical information, family history of all patients and healthy controls were collected. RFLP based case control association study was performed in a Pakistani cohort of 508 schizophrenia patients and 300 healthy control subjects. Alleles and genotype frequencies were calculated using SPSS. RESULTS: A significant difference in the genotype and allele frequencies for rs4765905, rs1076560 and rs6465084 were found between the patients and controls (p=0.000). CONCLUSION: This study provides substantial evidence supporting the role of CACNA1C, GRM3 and DRD2 as schizophrenia susceptibility genes in Pakistani population.

Association Study between DRD2 Genetic Polymorphisms and Schizophrenia in a Korean Population

OBJECTIVES: This study was designed to investigate the association between the dopamine D2 receptor (DRD2) genetic polymorphism [TaqIB (rs17294542) and TaqID (rs1800498)] and patients with schizophrenia. METHODS: TaqIB (rs17294542) and TaqID (rs1800498) polymorphism of the DRD2 gene were typed in 100 patients with schizophrenia and 109 normal controls. RESULTS: There were no statistical differences in genotype and allele distribution of TaqIB (rs17294542) and TaqID (rs1800498) genetic polymorphism between patients with schizophrenia and normal controls. CONCLUSIONS: These results suggest that the TaqIB (rs17294542) and TaqID (rs1800498) polymorphisms of the DRD2 gene may not be associated with schizophrenia in the Korean population.

Right Caudate Volumetric Differences in Young Healthy Adults with Different Dopamine DRD2/ANKK1 Taq 1a Polymorphisms

OBJECTIVES: The aim of this study was to assess variations in caudate volume according to dopamin receptor D2/ankyin repeat and kinase domain containing 1 (DRD2/ANKK1) Taq 1a polymorphisms in young healthy adults and to evaluate the relationship between caudate volumes and psychiatric symptoms as measured by the Brief Psychiatric Rating Scale. METHODS: Genetic information regarding DRD2/ANKK1 Taq 1a and T1-weighted brain magnetic resonance images were acquired from 30 young healthy adults. Automatic segmentation of caudate was performed using the FreeSurfer program. RESULTS: Individuals with A2 homozygotes of DRD2/ANKK1 Taq 1a polymorphisms (n = 10) had greater right caudate volumes compared to those with A1 allele (s)(18.4% greater ; p = 0.019). Right caudate volumes were negatively associated with total scores of the Brief Psychiatric Rating Scale (beta=-0.50 ; p = 0.016). CONCLUSIONS: Our findings suggest the possibility that DRD2/ANKK1 Taq 1a polymorphisms may underlie the psychiatric symptoms by influencing the structure of the right caudate.

Advance in Genetic Studies for Posttraumatic Stress Disorder (review) / 中国康复理论与实践

@# Posttraumatic stress disorder (PTSD) which is also moderately heritable is unique among the mental disorders in that it requires exposure to a potentially-traumatic life even. Many advances have been made in the genetics of PTSD. This paper reviewed 5-HTTLPR, DRD2 and some others gene which associated with PTSD.

Dopamine D2 Receptor Gene TaqI A Polymorphism in Korean Social Phobia Patients: Preliminary Study

OBJECTIVE: It is suggested that disturbance of dopaminergic system might be related to the possible mechanism of social phobia. The aim of this study was to investigate the possible association of DRD2 TaqI polymorphism and social phobia. METHOD: Fifty-one patients with social phobia and 200 comparison subjects were tested for DRD2 TaqI A polymorphism. The severity of social phobic symptoms was measured by self-report version of the Liebowitz Social Anxiety Scale(LSAS-SR) and Hamilton anxiety scale(HAM-A). RESULTS: There was no signigicant difference in the genotype, allele frequency, A1 carrier frequency, and heterozygote frequency DRD2 TaqI A polymorphism between the social phobia patients and the control groups. However, we found significant decrease in somatic anxiety of the HAM-A in the patients having A2A2 homozygotes(p=0.014). In addition, patients having A1A2 heterozygotes showed more anxiety in two subscales(p=0.042 in anxiety, p=0.019 in performance) of the LSAS-SR. CONCLUSION: These results suggest that DRD2 A2 homozygote might have a protective role against somatic anxiety, and molecular heterosis of DRD2 TaqI A polymorphism might be related with more severe anxiety in social phobia.

Association Study of Dopamine D2, D4 Receptor Gene, GABA(A) Receptor beta Subunit Gene, and Serotonin Transporter Gene Polymorphism with Children of Alcoholics in Korea: Preliminary Study / 신경정신의학

OBJECTIVES: The studies on the genetic risk factors of the children of alcoholics (COAs) are still in an early stage. The A 1 allele of the dopamine receptor 2 gene (DRD2) may be associated with the negative affect and positive alcohol expectancy of the COAs. In addition, several researchers reported that COAs might be associated with the GABAA receptor beta subunit gene (GABRB3) and serotonin transporter gene (5-HTTLPR). In this study, we investigated the association of polymorphism of the DRD2, Dopamine D4 receptor gene (DRD4), GABRB3, 5-HTTLPR with COAs to examine the genetic risk factors of COAs. METHODS: Twenty-two COAs and 23 control children (children of non-Alcoholics ; Non-COAs) were included for the genetic study. All COAs aged 6 to 18 were recruited and selected from families of alcoholic patients in alcohol clinics of three university and mental hospital. Alcoholism of parents was classified as type I (non-antisocial, late onset) and type II (antisocial, early onset) by Cloninger's classification. The genotyping of the DRD2, DRD4, GABRB3, 5-HTTLPR was carried out. Chi-square method was used for evaluating the associations between genetic polymorphism and the COAs. RESULTS: The frequency of A1+ allele of DRD2 in COAs were significantly higher than Non-COAs (Chi-square=4.45, df=1, p=0.035). Significant association between the genotype of DRD4 and COAs was found (Chi-square=8.32, df=1, p=0.004). G1- alleles of GABRB3 in COAs were significantly higher than in Non-COAs (Chi-square=6.622, df=1, p=0.022). We found no association of the polymorphic alleles of 5-HTTLPR with the COAs (Chi-square=0.021, df=1, p=0.884). There were significant associations between the type of parental alcoholism and depression of COAs. CONCLUSION: We found that the children of alcoholics had significantly increased genetic risk of alcohol drinking expectancy. This study provides some preliminary information on the risk and protective factors associated with the COAs, which can be used as a foundation for prevention and intervention of future psychopathology.

Association between D2 Dopamine Receptor Gene Polymorphisms and Reward Dependence Personality Traits

BACKGROUND: The dopaminergic genes have been implicated with some personality traits. Many recent studies indicated that there is a correlation between D2 dopamine receptor gene(DRD2) polymorphisms and the personality traits. The purpose of this study is to investigate a possible association between DRD2 gene (TaqI A, TaqI B) polymorphism and personality traits. METHODS: The subjects were consisted of 173 blood-unrelated young female Koreans with a mean age(+/-SD) of 13.88(+/-0.29) years. These volunteers were recruited from one of the junior high schools in Seoul and were tested by the Korean version of the Temperament and Character Inventory(TCI). Genotyping of the DRD2 polymorphisms by PCR methods were carried out. Two DRD2 gene polymorphisms were classified and individually assessed as follows: TaqI A1+ vs A1-, TaqI B1+ vs B-. The associations between the TCI scores and TaqI A, TaqI B polymorphisms were assessed by Student's t-test. RESULTS: In the 173 subjects, the allele frequencies of the DRD2 TaqI A1, TaqI B1 alleles ranged from 0.42 to 0.43, and these results are quite different from the ranges of 0.15-0.20 in the case of a Caucasian population. The genotype frequencies of DRD2(TaqI A1, TaqI B1) variants showed no significant deviation from the Hardy-Weinberg equilibrium. RD4(dependence vs. independence) of Cloninger's TCI, a sub-dimension of Reward Dependence, was significantly higher in the subjects having DRD2 less frequent alleles than those without these alleles. CONCLUSION: This study suggests that the female subjects carrying the less frequent DRD2 alleles exhibited higher reward-dependent personality trait compared to those without these alleles.

No Association between DRD2 polymorphism Ser311/Cys311 and Bipolar Disorder in Korean Population / 신경정신의학

OBJECTIVES: This study was designed to investigate the association between Ser311/Cys311 polymorphism in the dopamine D2 receptor gene and bipolar disorder in korean population. METHOD: Ser311/Cys311 polymorphism in the dopamine D2 receptor gene was typed with PCR in 86 bipolar disorders and 100 normal controls. RESULTS: Genotype of Ser/Ser, Ser/Cys, Cys/Cys were 82 (95.3%), 4 (4.7%), 0 (0.0%) respectively in the bipolar disorders, 96 (96.0%), 4 (4.0%), 0 (0.0%) respectively in the controls. Allele frequencies of Ser and Cys were 168 (97.7%), 4 (2.3%) in the bipolar disorders, 196 (98.0%), 4 (2.0%) in the controls. There were no differencies in genotype distribution and allele frequencies of dopamine D2 receptor gene polymorphism Ser311/Cys311 between in the bipolar disorders and in the controls. CONCLUSION: These result suggests dopamine D2 receptor gene polymorphism Ser311/Cys311 is not causally related to the development of bipolar disorder in korean population.