Dopamine Beta-hydroxylase Gene Research Articles

The dopamine beta-hydroxylase gene polymorphism rs1611114 is associated with schizophrenia in the Chinese Zhuang but not Chinese Han population.

Schizophrenia (SCZ) is a devastating neurodevelopmental disorder. However, the mechanism underlying this highly heritable disorder remains unclear. The dopamine beta-hydroxylase (DBH) gene encodes a key metabolic enzyme of dopamine. Consequently, DBH is considered a candidate gene for SCZ. However, previous studies on its association with SCZ susceptibility have shown conflicting results. Here, we examined association between the rs1611114 polymorphism of DBH and SCZ susceptibility and related clinical symptoms. A total of 691 SCZ patients and 698 age- and gender-matched healthy controls were examined. mRNA expression levels of DBH were measured by quantitative real-time polymerase chain reaction, and the rs1611114 polymorphism was genotyped using the Sequenom MassARRAY platform. Also, the Positive and Negative Syndrome Scale (PANSS) was used to assess SCZ clinical symptoms. Our results show lower DBH mRNA expression levels in SCZ patients than healthy controls (Zhuang: p=0.000; Han: p=0.037). Interestingly, the rs1611114 polymorphism was significantly associated with SCZ susceptibility (overdominant model: p=0.010) in only the Chinese Zhuang population. Furthermore, the rs1611114 polymorphism was associated with PANSS total score (allele T/C: p=0.015) and general psychopathology score (allele T/C: p=0.027) in Chinese Zhuang SCZ patients. These results suggest that the DBH gene may play an important role in the occurrence of SCZ. Also, rs1611114 may be associated with SCZ susceptibility and related clinical symptoms in the Chinese Zhuang but not Han Chinese population. Further studies with larger samples of different ethnicities are needed to confirm the role of DBH in SCZ.

A Preliminary Study of DBH (Encoding Dopamine Beta-Hydroxylase) Genetic Variation and Neural Correlates of Emotional and Motivational Processing in Individuals With and Without Pathological Gambling.

Background and aimsCorticostriatal-limbic neurocircuitry, emotional and motivational processing, dopaminergic and noradrenergic systems and genetic factors have all been implicated in pathological gambling (PG). However, allelic variants of genes influencing dopaminergic and noradrenergic neurotransmitters have not been investigated with respect to the neural correlates of emotional and motivational states in PG. Dopamine beta-hydroxylase (DBH) converts dopamine to norepinephrine; the T allele of a functional single-nucleotide polymorphism rs1611115 (C-1021T) in the DBH gene is associated with less DBH activity and has been linked to emotional processes and addiction. Here, we investigate the influence of rs1611115 on the neural correlates of emotional and motivational processing in PG and healthy comparison (HC) participants.MethodsWhile undergoing functional magnetic resonance imaging, 18 PG and 25 HC participants, all European Americans, viewed gambling-, sad-, and cocaine-related videotapes. Analyses focused on brain activation differences related to DBH genotype (CC/T-carrier [i.e., CT and TT]) and condition (sad/gambling/cocaine).ResultsCC participants demonstrated greater recruitment of corticostriatal-limbic regions, relative to T-carriers. DBH variants were also associated with altered corticostriatal-limbic activations across the different videotape conditions, and this association appeared to be driven by greater activation in CC participants relative to T-carriers during the sad condition. CC relative to T-carrier subjects also reported greater subjective sadness to the sad videotapes.ConclusionsIndividual differences in genetic composition linked to aminergic function contribute significantly to emotional regulation across diagnostic groups and warrant further investigation in PG.

Analysis of dopamine beta hydroxylase gene polymorphisms in migraine

BackgroundMigraine is a complex neurological disorder characterized by severe recurrent headache, nausea, vomiting, photophobia, and phonophobia. The frequency and duration of these symptoms varies among individuals. Dopaminergic systems are believed to be involved in migraine pathophysiology. We aimed to look for association of polymorphisms in dopaminergic genes in genetic susceptibility to migraine in Turkey population. MethodsThe present study was designed to explore possible association of three polymorphisms, (1021C>T (Rs1611115), +1603C>T (Rs6271; C535R) and +444G>A (rs1108580), of Dopamin Beta Hydroxylase gene in migraine patients.200 migraine patients and 267 healthy controls were included in the study. Genomic DNA was extracted from blood and genotypes were analyzed using polymerase chain reaction–restriction fragment length polymorphism methods (PCR-RFLP). ResultsStatistical evaluation of data results showed a significant association for allelic and genotypic frequency distribution between the Dopamin Beta Hydroxylase gene +1603C>T polymorphism and migraine (p=0.000, OR: 4.36, 95% CI: 2.73–7.16). There was no association observed between the −1021C>T and +444 G>A polymorphisms of the Dopamin Beta Hydroxylase gene and migraine (p=0.8731 and p=0.7584). ConclusionsThis study reflects that Dopamin Beta Hydroxylase gene +1603C>T polymorphism may be one of the many genetic factors for migraine susceptibility in the Turkish population.

Combination of DAT and DBH gene polymorphisms with a family history of alcohol use disorders increases the risk of withdrawal seizures and delirium tremens during alcohol withdrawal in alcohol-dependent men

To explore the genetic influence of a family history of alcohol use disorders and the dopamine transporter SLC6A3 (DAT1) and dopamine beta-hydroxylase (DBH) gene polymorphisms on the risk of severe complications (withdrawal seizures (AWS) and delirium tremens (DT)) during alcohol withdrawal in alcohol-dependent men. We investigated the effects of 3 previously reported candidate genetic variations: 40-bp variable number tandem repeat (VNTR) polymorphism and C/T exon 15 (rs27072) in the 3' untranslated region (3' UTR) of the SLC6A3(DAT1) gene, and -1021 C/T (rs1611115) of DBH gene in 266 alcohol-dependent Russian male inpatients in two groups by presence (SC group: AWS, DT, AWS+DT, n=130) or absence (n=136) of severe complications diagnosed by ICD-10 during current alcohol withdrawal. Clinically important information and a family history of alcohol use disorders (FH) were obtained by semi-structured interview. Patients in SC group more often have positive FH (54.6% vs. 33%, p=0.001) and their age at first alcohol use (FAU) was lower (16±3.53y.o vs. 17±1.66 y.o, p=0.001). Logistic regression revealed that FH predicts severe complications in total (р=0.001) and DT (р=0.003), FAU independently predicts severe complications in total (р=0.008), AWS (р=0.04), DT (р=0.032), AWS+DT (р=0.048) and every year of delay alcohol use decreases the risk by 18-30%. The gene polymorphisms interact with FAU to decrease the FAU influence on the risk of AWS (T variant of DAT (rs27072), р=0.04), (AWS+DT) and DT (T variant of DBH (rs1611115), р=0.023 and р=0.06). The T variant of DAT (rs27072) is associated with FAU (p=0.007) and increases the risk of (AWS+DT) (р=0.036), but decreases the risk of AWS (р=0.038) and of DT (р=0.021) too, but only in interaction with positive FH. The 9 repeat variant (9R) of DAT VNTR is associated with AWS (p=0.009), but the risk of AWS (р=0.004) and of SC in total (р=0.001) are elevated only in 9R carriers with positive FH. The 9R independently increases the risk of DT (р=0.048) and the effect become more robust in 9R carriers with high density of FH (р=0.014). The gene x gene interaction decreases the risk of DT (р=0.055). According to an analysis of total cohort of patients, the T variant of DBH (rs1611115) is associated with any kind of manifestation of delirium in alcohol-dependent men (p=0.039). This study demonstrate the genetic influence of a family history of alcohol use disorders and DAT and DBH gene polymorphisms on the risk of withdrawal seizures and delirium tremens. The interaction of genetic variations with positive family history provides the most robust effect, the interaction of genetic variations with the age at first alcohol use may «protect» their carriers from negative influence of this «behavioral» risk factor. Replication in large cohorts of patients is necessary to verify these findings for subsequent use in prevention programs.

The cortical surface area of the insula mediates the effect of DBH rs7040170 on novelty seeking

Novelty seeking (NS) is a personality trait important for adaptive functioning, but an excessive level of NS has been linked to psychiatric disorders such as ADHD and substance abuse. Previous research has investigated separately the neural and genetic bases of the NS trait, but results were mixed and neural and genetic bases have yet to be examined within the same study. In this study, we examined the interrelationships among the dopamine beta-hydroxylase (DBH) gene, brain structure, and the NS trait in 359 healthy Han Chinese subjects. We focused on the DBH gene because it encodes a key enzyme for dopamine metabolism, NS is believed to be related to the dopaminergic system and has been reported associated with DBH variation. Results showed a significant positive association between the cortical surface area of the left insula and NS score. Furthermore, the DBH genetic polymorphism at the SNP rs7040170 was strongly associated with both the surface area of the left insula and NS score, with G carriers having a larger left insula surface area and a higher NS score than AA homozygotes. Subsequent path analysis suggested that the insula partially mediated the association between the DBH gene and the NS trait. Our data provided the first evidence for the involvement of the insula in the dopamine–NS relationship. Future studies of molecular mechanisms underlying the NS personality trait and related psychiatric disorders should consider the mediation effect of the neural structure.

ABO Blood Type and Personality Traits in Healthy Japanese Subjects.

There is no scientific consensus that a relationship exists between the ABO blood group and personality traits. However, a recent study hypothesized that the dopamine beta-hydroxylase (DBH) gene is in linkage with the ABO gene. The sample population consisted of 1,427 healthy Japanese subjects who completed the Temperament and Character Inventory (TCI). Each subject’s ABO blood type was determined by genotyping the rs8176719 and rs8176746 ABO gene single-nucleotide polymorphisms (SNPs) using a TaqMan genotyping assay. The relationships between the six ABO genotypes or four ABO phenotypes and personality traits were examined using a multivariate analysis of covariance (MANCOVA), controlling for age and sex. The MANCOVA data showed a significant difference in TCI scores among the ABO genotype groups (F [7, 1393] = 3.354, p = 0.001). A subsequent univariate analysis showed a significant difference in the mean scores for Persistence among the genotype groups (F = 2.680, partial η2 = 0.010, p = 0.020). Similarly, dividing the ABO blood type into four phenotypes revealed a significant difference among the phenotype groups (F [7, 1397] = 2.529, p = 0.014). A subsequent univariate analysis showed a significant difference among the phenotype groups in the mean scores for Persistence (F = 2.952, partial η2= 0.006, p = 0.032). We observed a significant association between ABO blood group genotypes and personality traits in a large number of healthy Japanese subjects. However, these results should be regarded as preliminary and should be interpreted with caution because it is possible that the association between ABO blood group genotype and the Persistence trait is relatively weak.

Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder

Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency. Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y. Results. A SNP within the 3′ untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p < 0.001) in luciferase activity. Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.

Congenital central hypoventilation syndrome with hyperinsulinemia in an infant

Congenital central hypoventilation syndrome (CCHS) is a rare disorder that typically presents in the newborn period and is characterized by alveolar hypoventilation and symptoms of autonomic nervous system dysregulation. We describe an infant with CCHS who developed hyperinsulinism, which is an uncommon association. She was born by semi-elective Caesarean section at 37 weeks of gestation after a pregnancy complicated by polyhydramnios. Apgar scores were 7and 9 (at 1 and 5 min) and birth weight was 3550 g. She was intubated and ventilated within 24 hours for frequent apnoea’s and desaturations. Multiple extubation attempts on the following days failed because of progressive respiratory acidosis. She underwent tracheostomy at 2 months of age. CCHS was diagnosed in the first month of life, after a polyalanine repeat expansion of the PHOX2B gene (20/26genotype) was detected. At 7 months of age, she was admitted to hospital with seizures associated with hypoglycaemia. A critical sample (glucose 2.5mmol/L) revealed an inappropriately raised plasma insulin of 3.0 mU/L, growth hormone 7mu/L, cortisol 470 mmol/L, and serum ketones <0.1g/L. Urine and serum metabolic screen was normal, as was an EEG. Diazoxide was commenced at 5 mg/kg/day along with hydrochlorothiazide at 1mg/kg/d. These relatively low doses were used in view of parental concerns of potential drug side effect of hirsutism. The dose had to be increased to 7.5mg/kg/day as hypoglycaemic episodes persisted. Capillary blood glucose testing and continuous glucose monitoring showed no further hypoglycaemia at this dose. Sequence analysis of the KCNJ11 and ABCC8 genes implicated in congenital hyperinsulinism was undertaken and no pathogenic mutation was found. The mechanisms underlying abnormal glycaemia in CCHS are not fully understood. Multiple hypotheses have been postulated including the co-expression of the dopamine beta hydroxylase gene mutation with PHOX 2B mutation. Further, disordered autonomic homeostasis as seen in PHOX2B mutations is thought to impact the regulation of insulin and glucagon secretion. Our case highlights the importance of considering hyperinsulinism in the differential diagnosis of hypoglycaemia in infants with CCHS. Written informed consent was obtained from the patient's parent or guardian for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

The 444G/A and -1021 C/T polymorphisms of the dopamine-beta-hydroxylase gene modulate the trajectory of alcohol dependence development

To study the influence of 444 G/A (rs 1108580) and -1021 C/T (rs 1611115) polymorphisms of the dopamine beta-hydroxylase (DBH) gene on clinical parameters of the trajectory of alcohol dependence. Authors studied 548 male inpatients, of Slavic ethnicity, with ICD-10 diagnosis of «alcohol dependence» (F-10.2). The effects of DBH * 444 G/A on the rate of formation of alcohol withdrawal syndrome (AWS), and DBH *-1021C/T on the age of onset of alcohol abuse with significant role of the age of first alcohol use were identified. In 444 G/A GG carriers, the development of AWS was accelerated since the beginning of alcohol abuse compared with AA carriers (p=0.026), AG carriers occupied an intermediate position. In 22.5% of GG carriers, AWS developed within 2 years (AA: 8.11%, p=0.005; AG: 17.67%, p=0.04). According to the results of linear regression analysis, in AG carriers the alcohol abuse (p=0.037) and the AWS (p=0.049) developed earlier than in AA carriers if the first alcohol use occured at the age of about 15 years. Among -1021C/T genotype carriers who began to abuse alcohol at an early age (before 20 years), there were 23.45% patients with CC genotype and only 11.97% with a T allele (genotypes CT+TT) (p=0.03), but T carriers began to abuse alcohol earlier than others (p=0.05) if the first alcohol use occurred at the age of about 16 years. The results can be used to search for genetic markers for prognosis of alcohol dependence development.

EHMTI-0233. Clinical characteristics of migraine patients with dopaminergic gene polymorphisms RS1611115

The dopaminergic system plays a major role in migraine. Dopamine beta hydroxylase (DBH) is responsible for maintaining dopamine-to-norepinephrine ratio implicated in migraine pathophysiology. We aimed to look for association of polymorphisms in dopaminergic genes in genetic susceptibility to migraine in Russian population. In the present study DBH polymorphisms rs1611115 was selected. The aim of this study was to determine whether the polymorphisms rs1611115 in DBH gene influenced any particular symptoms of the disease.

Association between dopamine beta-hydroxylase 19-bp insertion/deletion polymorphism and major depressive disorder.

Norepinephrine and dopamine mediate important aspects of several psychoses, including major depressive disorder (MDD). Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in central neurons and thus is critically involved in maintaining the transformational homeostasis. Functional polymorphisms have been reported in DBH gene, including a 19-bp insertion/deletion polymorphism (DBH5'-insertion/deletion (Ins/Del)) and a single nucleotide polymorphism (-1021C/T). The purpose of this study was to investigate whether there was an association between the two functional polymorphisms and MDD in a Han Chinese population. DBH5'-Ins/Del and -1021C/T polymorphism in promoter region of DBH gene was analyzed in 313 patients with MDD and 318 healthy subjects by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. The results showed statistically significant associations for genotypic distribution between the DBH5'-Ins/Del polymorphism and MDD (P = 0.007). Individuals with Del/Del genotype demonstrated a 1.72 times increased risk of MDD compared to those with insertion alleles (95% confidence interval (CI) 1.20-2.47, P = 0.003). Moreover, the Del/Del genotype was associated with poorer digital span and language scores than the insertion alleles in healthy subjects (P = 0.041 and P = 0.048, respectively). However, there was no association observed between the genotype and allele frequencies for -1021C/T and depression. Our data suggest that the DBH5'-Ins/Del polymorphism of the DBH gene may be associated with susceptibility to MDD in a Chinese population.

Dopamine beta-hydroxylase gene modulates individuals’ empathic ability

Dopamine beta-hydroxylase (DBH), an enzyme that converts dopamine to norepinephrine, has broad influences on social functions. In this study, we examined to what extent two polymorphisms (-1021C/T and a 19 bp insertion/deletion) in DBH gene modulate individuals' empathic perception and response, which were measured, respectively, by reading the mind in the eyes test and the empathic concern subscale of interpersonal reactivity index. Results showed that polymorphism at -1021C/T, but not the 19 bp insertion/deletion, accounts for 2.3% variance of empathic perception and 1.4% variance of empathic response. Individuals with the CC genotype, which is associated with higher DBH activity, manifested greater empathic ability than those with CT/TT genotypes. These findings demonstrate the importance of DBH -1021C/T as a genetic basis of empathy and in predicting individual differences in social and affective processing.

The Interaction of Polymorphisms of IL10 and DBH Was Associated with General Symptoms of PANSS with TD in Chinese Han Schizophrenic Patients

ObjectiveTardive dyskinesia (TD) is a human hyperkinetic movement disorder as a result of potentially irreversible long-term chronic first-generation antipsychotic medications. Unfortunately, mechanisms involved in the development of TD have been poorly understood. Previous studies have indicated that some genetic polymorphisms of immune system and dopamine beta-hydroxylase (DBH) genes may be involved in the pathogenesis of TD. Rs1800872 and rs72393728 are located on the promoter of interleukin-10 (IL10) and DBH gene, respectively. The genetic association between the rs1800872 and TD is unclear. Previous studies have indicated that genetic variations of IL 10 and DBH are implicated in the positive and negative symptoms in schizophrenia. However, the interaction of two variations with severity of TD and symptoms of schizophrenic patients with TD has not been reported. The present study investigated whether these variations and their interaction were associated with clinical phenotypes of TD with schizophrenia in a genetically homogeneous northern Chinese Han population.MethodsRs1800872 and rs72393728 were genotyped in schizophrenic patients with TD (n = 372) and without TD (NTD; n = 412). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were applied to assess the severity of TD and psychopathology of schizophrenia, respectively.ResultsThe allele and genotype frequencies of rs1800872 and rs72393728 did not significantly differ between TD and NTD patients (p>0.05). No significant difference was found in the AIMS total score among the genotypes of two loci (p>0.05). Interestingly, the interaction of rs1800872 and rs72393728 showed a significant association with the PANSS general score (p = 0.011), and a trend toward to the PANSS total score (p = 0.055).ConclusionThese findings suggest that the interaction of rs1800872 and rs72393728 variants may play a role in psychopathology of the general symptoms on PANSS in schizophrenic patients with TD in a northern Chinese Han population.

Association between DBH 19 bp insertion/deletion polymorphism and cognition in first-episode schizophrenic patients

Many genes associated with dopamine (DA) and norepinephrine (NE) systems influence cognitive deficits of schizophrenia patients, but one key enzyme is dopamine beta-hydroxylase (DBH), which converts DA to NE and whose activity and levels are under strong genetic control. This study examines the association of the 19bp insertion/deletion (Ins/Del) polymorphism in the 5′ flank of the DBH gene with cognitive deficits in first-episode schizophrenic patients (FEP). We assessed the cognitive function in 195 FEP and 304 healthy controls using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The 19bp Ins/Del polymorphism of DBH gene was genotyped. Our results showed that the allelic and genotypic frequencies of the 19bp Ins/Del polymorphism significantly differed between FEP and healthy controls (both p<0.05). Cognitive test scores were significantly lower in FEP than healthy controls on all scales (all p<0.001) except for the visuospatial/constructional index (p>0.05). Immediate memory abilities significantly differed by genotype (p<0.05) but not genotype×diagnosis. Immediate memory score was lower in FEP with DBH5′-Del/Del genotype (61.3±17.2) than those with DBH5′-Ins/Ins genotype (68.6±16.2; p<0.05). The 19bp Del allele was associated with poorer immediate memory performance than the Ins allele in FEP (p<0.05). However, healthy controls did not show any differences in cognitive function indices between the Ins and Del for either the allele or genotype of the 19bp Ins/Del polymorphism. Our findings suggest that the DBH5′-Ins/Del polymorphism may play a role in susceptibility to FEP. The DBH5′-Ins/Del polymorphism may also influence immediate memory in FEP. Moreover, FEP had poorer cognitive function than healthy controls in all examined cognitive domains except for the visuospatial/constructional index.

Association Between Dopamine Beta-Hydroxylase Gene Polymorphisms and Attention-Deficit Hyperactivity Disorder in Korean Children

Attention-deficit hyperactivity disorder (ADHD) is a common disorder of the school-age population. ADHD is familial, and genetic studies estimate heritability at 80%-90%. The aim of the present study was to investigate the association between the genetic type and alleles for the dopamine beta-hydroxylase (DBH) gene in Korean children with ADHD. The sample consisted of 142 ADHD children and 139 control children. We diagnosed ADHD according to DSM-IV. ADHD symptoms were evaluated with the Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 281 subjects; DNA was extracted from blood lymphocytes, and polymerase chain reaction was performed for the DBH polymorphism. The alleles and genotype frequencies were compared using the chi-square test. We compared the allele and genotype frequencies of the DBH gene polymorphism in the ADHD and control groups. This study showed that there was a significant correlation among the frequencies of rs1611115 (odds ratio=0.64, 95% confidence interval=0.42-0.97, p=0.034) of the alleles of DBH, but the final conclusions are not definite. Follow-up studies with larger patient or pure subgroups are expected. These results suggested that DBH might be related to ADHD symptoms.

Subchronic exposure to arsenic disturbed the biogenic amine neurotransmitter level and the mRNA expression of synthetase in mice brains

Little is known about the influence of arsenic (As) exposure on monoamine neurotransmitters and the underlying mechanisms, although arsenic toxicity on the central nervous system has been well documented. In the present study, the levels of norepinephrine (NE), dopamine (DA), and 5-HT were determined by high performance liquid chromatography in the cerebrum and cerebellum of mice exposed to 1, 2 and 4ppm As2O3 through drinking water for 60days. The ultra-structural change of vesicles in the synapses of mice brains was observed by transmission electron microscopy; the mRNA expressions of dopamine beta hydroxylase (DBH), tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) as NE, DA and 5-HT synthetases were quantitatively assessed by real time reverse transcription-polymerase chain reaction. It was shown that the concentrations of NE, DA and 5-HT in the cerebrum or cerebellum of mice exposed to As were significantly lower than those in the control group. The number of synaptic vesicles significantly decreased in the brain of mice exposed to As. Moreover, the expressions of TH, TPH and DBH genes were significantly lower in the brains of mice exposed to As than those in the controls. These results suggested that subchronic exposure to As might decrease the concentrations of the three monoamine neurotransmitters in the mouse brain and downregulate TH, TPH and DBH gene expressions. It was also indicated that the decreased concentrations of the three monoamine neurotransmitters in the brain might be related to the down-regulated gene expressions of these synthetases by As.

Positive association between −1021TT genotype of dopamine beta hydroxylase gene and progressive behavior of injection heroin users

By balancing the ratios of dopamine and norepinephrine, dopamine beta hydroxylase (DBH) plays an important role in brain reward circuit that is involved with behavioral effects of heroin addiction. DBH −1021C/T (rs1611115) is a functional variant with strong correlation with plasma DBH activity and several nerval and psychic disorders. In the present study, we have collected 333 male cases with heroin addiction and 200 male healthy controls to explore the role of −1021C/T in heroin addiction. There is no evidence of association between −1021C/T and heroin addiction on both genotype and allele levels (P>0.05). In the injection subgroup of cases, −1021TT carriers have longer heroin addiction time (P<0.001) and higher dosage of self-administered heroin (P=0.045) than carriers with −1021CC or −1021CT, suggesting that patients with TT genotype are likely to have more progressive style of heroin users with injection route. In conclusion, our results support −1021TT genotype may be implicated with a more progressive nature of heroin addiction, although DBH −1021C/T is unlikely to be involved in the risk of heroin addiction.

Genotype-independent decrease in plasma dopamine beta-hydroxylase activity in Alzheimer's disease

The noradrenergic system is involved in the etiology and progression of Alzheimer's disease (AD) but its role is still unclear. Dopamine beta-hydroxylase (DBH) as a catecholamine-synthesizing enzyme plays a central role in noradrenaline (NA) synthesis and turnover. Plasma DBH (pDBH) activity shows wide inheritable interindividual variability that is under genetic control. The aim of this study was to determine pDBH activity, DBH (C-970T; rs1611115) and DBH (C1603T; rs6271) gene polymorphisms in 207 patients with AD and in 90 healthy age-matched controls. Plasma DBH activity was lower, particularly in the early stage of AD, compared to values in middle and late stages of the disease, as well as to control values. Two-way ANOVA revealed significant effect of both diagnosis and DBH (C-970T) or DBH (C1603T) genotypes on pDBH activity, but without significant diagnosis×genotype interaction. No association was found between AD and DBH C-970T (OR=1.08, 95% CI 1.13-4.37; p=0.779) and C1603T (OR=0.89; 95% CI 0.36-2.20; p=0.814) genotypes controlled for age, gender, and ApoE4 allele. The decrease in pDBH activity, found in early phase of AD suggests that alterations in DBH activity represent a compensatory mechanism for the loss of noradrenergic neurons, and that treatment with selective NA reuptake inhibitors may be indicated in early stages of AD to compensate for loss of noradrenergic activity in the locus coeruleus.

Electroacupuncture Analgesia Is Improved by Adenoviral Gene Transfer of Dopamine Beta-hydroxylase into the Hypothalamus of Rats

Electroacupuncture (EA) is a modified form of acupuncture that utilizes electrical stimulation. We previously showed that EA stimulated rats were divided into responders that were sensitive to EA and non-responders that were insensitive to EA based on the tail flick latency (TFL) test. The dopamine beta-hydroxylase (DBH) gene was more abundantly expressed in the hypothalamus of responder rats than non-responder rats. To determine whether overexpression of DBH gene expression in the hypothalamus modulate EA analgesia, we constructed a DBH encoding adenovirus and which was then injected into the hypothalamus of SD rats. Microinjection of DBH or control GFP virus into the hypothalamus had no changes on the basal pain threshold measured by a TFL test without EA treatment. However, the analgesic effect of EA was significantly enhanced from seven days after microinjection of the DBH virus, but not after injection of the control GFP virus. DBH expression was significantly higher in the hypothalamus of DBH virus injected rat than control GFP virus or PBS injected rats. Moreover, expression of the DBH gene did not affect the body core temperature, body weight, motor function or learning and memory ability. Although the functional role of DBH in the hypothalamus in the analgesic effect of EA remains unclear, our findings suggest that expression of the DBH gene in the hypothalamus promotes EA analgesia without obvious side-effects.

DBH −1021C>T and COMT Val108/158Met genotype are not associated with the P300 ERP in an auditory oddball task

ObjectiveThe amplitude and latency of the P300 may be associated by variations in dopaminergic genes. The current study was conducted to determine whether functional variants of the catechol-O-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) gene were associated with P300 amplitude and latency in an auditory oddball task. MethodsThe P300 ERP was assessed by a two-tone auditory oddball paradigm in a large sample of 320 healthy volunteers. The Val108/158Met polymorphism (rs4680) of the COMT gene and the −1021C>T polymorphism (rs1611115) of the DBH gene were genotyped. P300 amplitude and latency were compared across genotype groups using analysis of variance. ResultsThere were no differences in demographic characteristics in subjects for genotypic subgroups. No genotype associations were observed for the P300 amplitude and latency on frontal, central and parietal electrode positions. ConclusionsCOMT Val108/158Met and DBH −1021C>T polymorphisms do not show evidence of association with characteristics of the P300 ERP in an auditory oddball paradigm in healthy volunteers. SignificanceWe failed to find evidence for the association between dopaminergic enzymatic polymorphisms and the P300 ERP in healthy volunteers, in the largest study undertaken to date.