Low Dopamine-beta-hydroxylase 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.

Dopamine beta hydroxylase genotype identifies individuals less susceptible to bias in computer-assisted decision making.

Computerized aiding systems can assist human decision makers in complex tasks but can impair performance when they provide incorrect advice that humans erroneously follow, a phenomenon known as “automation bias.” The extent to which people exhibit automation bias varies significantly and may reflect inter-individual variation in the capacity of working memory and the efficiency of executive function, both of which are highly heritable and under dopaminergic and noradrenergic control in prefrontal cortex. The dopamine beta hydroxylase (DBH) gene is thought to regulate the differential availability of dopamine and norepinephrine in prefrontal cortex. We therefore examined decision-making performance under imperfect computer aiding in 100 participants performing a simulated command and control task. Based on two single nucleotide polymorphism (SNPs) of the DBH gene, −1041 C/T (rs1611115) and 444 G/A (rs1108580), participants were divided into groups of low and high DBH enzyme activity, where low enzyme activity is associated with greater dopamine relative to norepinephrine levels in cortex. Compared to those in the high DBH enzyme activity group, individuals in the low DBH enzyme activity group were more accurate and speedier in their decisions when incorrect advice was given and verified automation recommendations more frequently. These results indicate that a gene that regulates relative prefrontal cortex dopamine availability, DBH, can identify those individuals who are less susceptible to bias in using computerized decision-aiding systems.

Association between migraine and a functional polymorphism at the dopamine β-hydroxylase locus

Migraine is a common neurological disorder with a significant genetic component. Although a number of linkage and association studies have been undertaken, the number and identity of all migraine susceptibility genes has yet to be defined. The existence of dopaminergic hypersensitivity in migraine has been recognised on a pharmacological basis and some studies have reported genetic association between migraine and dopamine-related gene variants. Our laboratory has previously reported association of migraine with a promoter STR marker in the dopamine beta hydroxylase (DBH) gene. In the present study, we analysed two additional DBH markers in two independent migraine case-control cohorts. These two markers are putative functional SNPs, one within the promoter (-1021C-->T) and another SNP (+1603C-->T) in exon 11 of the DBH gene. The results showed a significant association for allelic and genotypic frequency distribution between the DBH marker in the promoter and migraine in the first (P = 0.004 and P = 0.012, respectively) and the second (P = 0.013 and P = 0.031, respectively) tested cohorts. There was no association observed between either genotype and/or allelic frequencies for the DBH marker located in exon 11 and migraine (P > or = 0.05). The promoter DBH marker, reported associated with migraine in this study, has been shown to affect up to 52% of plasma DBH activity. Varying DBH activity levels have been postulated to be involved in migraine process with an increase of dopamine, resulting from a lower DBH activity shown positively correlated with migraine severity. It is plausible that the functional promoter variant of DBH may play a role in the migraine disorder.

Dopamine beta‐hydroxylase (DBH) activity and ‐1021C/T polymorphism of DBH gene in combat‐related post‐traumatic stress disorder

The roles of dopamine (DA) and norepinephrine (NE) in posttraumatic stress disorder (PTSD) are unclear. The aim of the study was to determine plasma dopamine beta-hydroxylase (DBH) activity and DBH-1021C/T gene polymorphism in combat veterans with (N = 133) or without (N = 34) chronic PTSD. Similar frequencies in genotype or allele distribution were found between veterans with or without PTSD. War veterans with PTSD had lower DBH activity, associated with the DBH-1021C/T variant in DBH genes, than veterans without PTSD. A significantly lower plasma DBH activity was found in combat veterans with PTSD carrying the CC genotype as compared to veterans without PTSD carrying the corresponding genotype. Since both groups were exposed to the same trauma, it is possible that a pre-existing trait difference in regulation of NE function contributed to a differential vulnerability to develop PTSD, or that the regulation of DBH expression was different in response to trauma. The results suggest that that genotype-controlled measurement of plasma DBH activity might be used as a potential biological marker of the response to trauma, and that further studies of DBH and other loci related to DA and NA in PTSD are warranted.

Plasma dopamine and noradrenaline variations in response to stress

Dopamine (DA) the precursor of noradrenaline (NA) has been shown to have many functions such as its influence on endorphins activity and its association with hedonic impact, anxiety and depression. However with regard to the sympathetic nervous system activity, the role of DA has merely been considered as being the precursor of NA. We have shown in a previous study a positive correlation between the resting plasma level of NA and those found during exposure to a physical stress. No explanation was proposed to explain this finding. Enhanced sympathetic nervous system activity has been shown to increase the secretion of NA as well as DA. It is not known however if the secretion of DA during exposure to stress parallels that of NA. What are the interactions between the two amines and also between values at rest and during exposure to stress? For that reason a test was used which consisted of blowing cold wind (4 °C at 60 km/h) on the face of a group of subjects and measuring plasma concentration of the two amines before, during and after the test. For a given individual, the increase of either plasma NA or DA in response to the cold wind stress parallels the resting plasma concentrations of these two amines respectively. Low level of one amine at rest coincides with low increase during the stress. Furthermore the results have shown that when the plasma level of either one of these two amines is high in response to stress, the values of the other amine are small; both amines are not high or low at the same time. The literature suggests that dopamine beta hydroxylase (DBH), the enzyme which catalyzes the synthesis of NA from DA, may provide an explanation to our findings. Lower DBH activity of this enzyme would result in a lower NA and a greater DA storage and secretion. Further investigation is needed to verify this possibility.

Advances in the pharmacotherapy of stimulant dependence: From alcohol antagonists to Xenova vaccines

Several widely varying pharmacotherapies, which help ‘re-normalize’ documented stimulant-induced brain dysfunction in DA, GABA and glutamate receptors and metabolism, are promising for stimulant dependence. Disulfiram has significantly reduced cocaine abuse in six independent clinical trials. It inhibits dopamine beta hydroxylase (DBH), which converts dopamine (DA) to norepinephrine (NE), and thereby reduces NE, which may reduce cocaine withdrawal symptoms, and increases DA, which may ‘re-normalize’ depleted DA and compensate for down-regulated DA receptors that are associated with chronic cocaine dependence. Low DBH activity, which is determined by a functional genetic polymorphism, appears critical to disulfiram's efficacy in cocaine dependence. Amantadine, which is also an indirect DA agonist, is only effective in patients with severe withdrawal symptoms, a subgroup of patients who also respond to the adrenergic blocker propranolol. The GABA enhancers including tiagabine, baclofen and topiramate have shown some efficacy in clinical trials and in reducing cue-induced cocaine craving. Glutamate enhancers like modafinil show efficacy, perhaps by enhancing learning of new relapse prevention behaviors. Finally, a cocaine vaccine, which prevents cocaine from getting out of the blood stream and into the brain, shows a dose-response in reducing cocaine use.

Dopamine beta-hydroxylase (DBH) gene and schizophrenia phenotypic variability: a genetic association study.

Recently, two polymorphisms (DBH5'-Ins/del and DBH 444 g/a) of the Dopamine Beta Hydroxylase (DBH) gene were isolated, and one haplotype (Del-a) was found to be associated with low DBH activity and cocaine-induced paranoia. The purpose of this study is to test for association between these two polymorphisms and schizophrenia or its phenotypic variability with respect to neuroleptic therapeutic response and symptom profile. Allelic and haplotype distributions of these two polymorphisms were compared between two groups of schizophrenic patients (excellent neuroleptic-responders; R, n = 42 and non-responders; NR, n = 64), and one group of healthy volunteers (n = 120). The "Del" and "a" alleles were in positive linkage disequilibrium. No allelic or genotype differences in the distribution of these two polymorphisms were observed between patients and controls. However, The Del-a haplotype was significantly more common in NR patients, and the mean total BPRS score was significantly higher in the group of patients with the Del-a compared to those without the Del-a haplotype. These results suggest that the DBH gene is not a causative factor in schizophrenia but that it may be a modulator of psychotic symptoms, severity of the disorder and therapeutic response to neuroleptic drugs.

Possible control of dopamine beta-hydroxylase via a codominant mechanism associated with the polymorphic (GT)n repeat at its gene locus in healthy individuals.

Six allelic fragments were typed by a PCR-based process with a pair of primers specific for a sequence containing the polymorphic (GT)n repeat at the human dopamine beta-hydroxylase (DBH) locus in 125 unrelated healthy individuals. Their frequencies among these individuals were 0.012 (A1), 0.08 (A2), 0.344 (A3), 0.548 (A4), 0.004 (A5) and 0.012 (A6); the two major alleles, A3 and A4, made up nearly 90% of the alleles. These individuals were divided into four groups according to the genotype they possessed, i.e. A3/A3, A4/A4, A3/A4 and others (mixed group). Kruskal-Wallis analysis revealed a significant difference in serum DBH activity among these four genetic groups (H = 32.7, P < 0.0001). The homozygotic genotypes, A3/A3 and A4/A4, were associated with low and high DBH activity, respectively, and the heterozygotic genotype, A3/A4, seemed to play a role in keeping the DBH activity at a moderate level. The present work suggests that the human DBH is likely to be controlled via a codominant mechanism associated with the dinucleotide repeat polymorphism at its gene locus.

Serum dopamine beta hydroxylase and maltreatment in psychiatrically hospitalized boys

Fifty boys, hospitalized on a school-age and an adolescent unit in an intermediate length psychiatric hospital, were studied while off psychoactive medication to determine how serum dopamine beta hydroxylase (DBH) activity varies with different childhood maltreatment experiences. Childhood maltreatment was categorized according to onset (before 36 months old, between 36–72 months old and over 72 months old). Childhood maltreatment groups were compared with a group of psychiatrically hospitalized boys who had neither been abused nor neglected. Boys who were younger than 72 months at age of onset of maltreatment had significantly lower DBH activity than those who had experienced maltreatment later in childhood and those who had not been subjected to abuse or neglect. This difference appeared attributable to the DBH activity of school age (but not adolescent) boys who had been abused/neglected before 72 months. Boys with a principal diagnosis of conduct disorder solitary aggressive type had lower DBH activity than boys without this diagnosis regardless of whether or not they had been maltreated. Low serum DBH may be a biological sequela of maltreatment early in life that correlates with the development of conduct disorder solitary aggressive type in boys.

Dopamine-beta-hydroxylase in behaviorally disturbed youth: Relationship between teacher and parent ratings

A series of neurotransmitters, metabolites, and enzymes considered relevant to emotional and behavioral disorders was studied in blood samples obtained from boys admitted to a residential setting because of disruptive or unmanageable behavior in their home environments. The youth were categorized into mainly prepubertal (under 12.0 years) and pubertal/post pubertal (12.0 years and over) groups. Behavior ratings of the younger group completed by parents revealed significant inverse correlations between several behavioral factors and dopamine-beta-hydroxylase (DBH) activity levels, notably in the agressive behavior and antisocial domains. Teacher ratings completed after about 1 month of living in the residential setting also showed numerous significant, but positive, correlations between several behavior factors and DBH activity levels. Furthermore, teacher and parent ratings themselves often were significantly and inversely correlated. The findings related to DBH activity levels were strongest in the younger group of boys. The results are discussed in terms of the possibility that low DBH activity in boys reflects a vulnerability towards behavioral disorder, which in certain environments becomes manifested by conduct problems and antisocial behavior.

Developmental change of dopamine ?-hydroxylase activity in cerebrospinal fluid of epileptic and non-epileptic children

The developmental change of dopamine beta-hydroxylase (DBH) activity in cerebrospinal fluid (CSF) of epileptic children was studied. Non-epileptic children showed lower DBH activity in CSF than adult, and its activity increased with age. In contrast, epileptic children showed no increase in DBH activity with age. DBH in CSF may be a good index of noradrenergic function in child brain. The results on developmental change in DBH in CSF suggest that refractory epilepsy with long term medication has decreased activity in central noradrenergic neurons.

Dopamine-beta-hydroxylase activity of the cat carotid body under different arterial O2 and CO2 conditions.

To determine the importance of dopamine and noradrenaline as neurotransmitters during chemoreception in the cat carotid body we investigated the contents of both compounds as well as the activity of dopamine-beta-hydroxylase (DBH) under different arterial PO2 and PCO2 conditions. The superior cervical ganglion was used as a control organ. In the carotid body and the ganglion an inverse relationship exists between the catecholamine content and the DBH activity. The carotid body has a high catecholamine content with a low DBH activity whereas the superior cervical ganglion has a low catecholamine content and high DBH activity. Hypercapnia did not produce any significant change in the catecholamine content or in the DBH content of the carotid body. However, in comparison with hyperoxia, hypoxia produced a significant change (p less than 0.05) in the noradrenaline content without changing the DBH activity. The dopamine content under these conditions did not change significantly. The results may indicate that the high catecholamine content of the carotid body is the result of a high retention and/or low rate of degradation rather than of a high rate of synthesis.

Studies on biogenic amine metabolizing enzymes (DBH, COMT, MAO) and pathogenesis of affective illness. I. Plasma dopamine-beta-hydroxylase activity in endogenous depression.

On the basis of studies carried out with a group of 47 patients with endogenous depressive illness, lower plasma activity of dopamine-beta-hydroxylase (DBH) was found as compared with a control group (31 healthy persons). Lower DBH activity particularly characterized bipolar patients. Lowest DBH activity was found in patients with a family history of psychiatric disorders, in particular, affective illness (in comparison with the control group the difference was statistically significant, P less than 0.05). It was noticed, that in a period of remission or significant improvement the enzymatic activity increases, although in some cases the level of activity is still lower than in the control group. There was a correlation between activity of the enzyme and clinical course of the illness and susceptibility to antidepressive drugs. Most of the observed phenomena are related to male patients. On the basis of these studies and data supplied by corresponding literature, concerning in particular the effects of DBH inhibitors (fusaric acid, disulfiram), the authors consider that changes in DBH activity may play a role in the pathogenesis of depression and that DBH deserves further studies, also of genetic nature.

Enzyme Studies in Tardive Dyskinesia. III. Noradrenergic Hyperactivity in a Subgroup of Dyskinetic Patients

This study was undertaken to test a hypothesis that tardive dyskinesia (TD) patients with high plasma dopamine-beta-hydroxylase (DBH) activity would also have other enzymatic alterations suggestive of noradrenergic hyperactivity. Plasma renin activity was chosen as a peripheral indicator of noradrenergic function. We measured plasma renin activity in three groups of female psychiatric inpatients over the age of 50: a TD group with high plasma DBH activity, a TD group with low plasma DBH activity, and a non-TD group. The high-DBH TD group had significantly greater plasma renin activity than the other two groups. Our results are consistent with the hypothesis that a subgroup of TD patients has relative noradrenergic hyperactivity.

Biochemical differences in children with conduct disorder socialized and undersocialized.

The authors compared plasma dopamine beta-hydroxylase (DBH), platelet monoamine oxidase (MAO), whole blood serotonin, and RBC catechol O-methyltransferase (COMT) in 25 children with conduct disorder and 20 control children. They found that children diagnosed as having conduct disorder undersocialized had significantly lower DBH activity than children diagnosed as having conduct disorder socialized and the control group. The children with conduct disorder socialized had significantly higher COMT activity than the other two groups. When children with a diagnosis of conduct disorder plus a diagnosis of attention deficit disorder were compared with the control group, no significant biochemical differences were found because of the mixing of the two diagnoses.

Cerebrospinal fluid and plasma dopamine-beta-hydroxylase activity in human hypertension.

Cerebrospinal fluid (CSF) and plasma dopamine-beta-hydroxylase (DBH) activity was measured in 22 normotensive (NT), 31 essential hypertensive (EH), and 11 renal hypertensive (RH) patients. Although no differences were observed in their plasma DBH, the mean CSF-DBH activity and specific activity of EH were significantly lower than those of NT and RH patients. Very low CSF-DBH (less than 0.15 units/ml of CFS or less than 0.5 units/mg of CSF protein) was found only in EH (26% of EH). Of the 31 EH patients, 19(60%) had CSF-DHB activities lower than 0.5 units/ml, whereas only 5 of 22 NT (23%) and no RH fell within this range. Nevertheless, 20% of EH, 55% of NT, and 40% of RH patients had CSF-DBH activities above the mean value for NT (less than 0.9 units/ml). NT subjects with very low plasma DBH (less than 50 units/ml) had CSF-DBH activities that fell within normal range. With the exception of these subjects, the specific activity of CSF-DBH was always lower than that of the plasma enzyme. The concentration of albumin, alpha 1, beta, and gamma globulins was measured in plasma and CSF obtained from the last five NT, four EH, and two RH patients. A positive linear relationship was obtained when the log of the plasma/CSF concentration ratio for these proteins was plotted against their molecular weight. Similar slopes and intercepts were obtained for these patients, suggesting that no major differences seem to exist in their blood-brain-barrier permeability to proteins. The results suggest that measurements of CSF-DBH could be of help in the differential diagnosis of human hypertension and in the neurochemical characterization of EH. If CSF-DBH reflects central noradrenergic activity, its reduction might indicate the existence of a central catecholaminergic defect in a subgroup of EH patients.

Plasma dopamine beta-hydroxylase activity in a North Swedish isolate with a high frequency of schizophrenia.

Plasma dopamine beta-hydroxylase (DBH) activity was determined in 115 members of a North Swedish geographical isolate with a high frequency of schizophrenia, of which 30 persons had schizophrenia, and was compared with a Middle Swedish population of 185 apparently healthy persons. There was no significant difference between the schizophrenic group and their healthy relatives or between the North and Middle-Swedish populations. The number of persons with very low plasma DBH activity in the North Swedish population appeared to be less than those in the control population.

Thermal stability and the biochemical genetics of erythrocyte catechol-O-methyl-transferase and plasma dopamine-beta-hydroxylase.

The levels of activity of human erythrocyte (RBC) catechol-O-methyl-transferase (COMT) and human plasma dopamine-beta-hydroxylase (DBH) are inherited in a monogenic fashion. The COMT in erythrocytes of subjects homozygous for the allele for low basal enzyme activity, COMTL, is more thermolabile than that in the erythrocytes of subjects with genetically high basal enzyme activity. This observation suggests that the locus COMT may represent the structural gene for COMT in man. Wide individual variations in the thermal stability of human plasma DBH also occur. There is a significant familial aggregation of the trait of thermolabile plasma DBH. Although subjects with thermolabile plasma DBH have average basal plasma DBH activity only about 55% of that of subjects with thermostable enzyme, the trait of thermolability does not cosegregate with DBHL, the allele for very low basal plasma DBH activity. Studies of thermal stability may help to increase our understanding of the biochemical basis of the genetic regulation of catecholamine enzymes in man.

Dopamine beta-hydroxylase and plasma renin activity in patients with low-, normal-, and high-renin essential hypertension.

The relationship of serum dopamine-beta-hydroxylase (DBH), plasma renin activity (PRA) and urinary catecholamines (IU catechols) in various forms of essential hypertension (EHT) (low, normal and high renin) was evaluated. Eighty-four predominantly white, young (37 +/ 8 years (SD)), mildly hypertensive patients (diastolic pressure 93 +/- 4 mm Hg (SD)) continued their regular diet and received no medications. Thirteen patients had low-renin, 64 had normal-renin, and seven had high-renin EHT. DBH, total IU catechols and urinary norepinephrine were not different between these renin subgroups. DBH was significantly lower in all hypertensives (55.6 +/- 36 IU) and in the low-renin subgroup (46 +/- 30 IU) compared with normal subjects (68 +/- 35 IU) (p less than 0.01). However, the DBH range was so broad that an individual DBH value did not distinguish EHT from normals. After a baseline period, patients were randomly assigned to receive chlorthali done 50 mg q.a.m. or placebo in a double-blind study. In the chlorthalidone group 1 month after therapy, the diastolic pressure decreased, PRA increased, and total IU catechols and urinary norepinephrine increased. Serum DBH did not change during diuretic therapy. A significant correlation could not be shown between pretreatment DBH and the changes in PRA and IU catechols before and after diuretics for all treated EHT patients. However, within the normal PRA EHT subgroup receiving chlorthalidone, the one-third of patients with lowest pretreatment DBH levels (n = 10) were compared with the one-third of patients with the highest pretreatment DBH values (n = 10). The lower DBH patients showed significantly less change in PRA (delta PRA = 2.9 +/- 1.8 ng/ml/hr) compared with the higher DBH patients (delta PRA = 8.2 +/- 1.6; P less than 0.05). In some EHT patients, DBH levels may be related to PRA response to diuretic therapy.

Low serum dopamine beta-hydroxylase activity. A marker of congestive heart failure.

To gain information about the nature of disturbances in sympathetic nervous system control in congestive heart failure, serum dopamine beta-hydroxylase (DBH) activity was measured in 30 patients with heart failure of diverse etiologies and 29 healthy normotensive controls. The heart failure patients had been symptomatic for at least 6 wk and had elevated filling pressures, low cardiac indices, low ejection fractions, and wide arteriovenous oxygen differences. DBH activity was 47.1+/-4.7 (mean+/-SE) for the controls and 14.4+/-2.7 IU for the heart failure patients (P < 0.001). Sera from some patients with heart failure had potent inhibitory effects on DBH activity of normal sera. The inhibitor was heat stable and dialyzable and could be demonstrated despite presence of N-ethylmaleimide or Cu(++) in the reaction mixture. However, some inhibitory activity was also present in sera of normal patients; this inhibitory property was not demonstrable in unheated normal serum, but was unmasked when DBH was heat inactivated. It is proposed that although the inhibitor may have been a factor in low serum DBH activity in some patients with heart failure, the major cause of the low activity in the heart failure group was a reduced rate of synthesis or release of the enzyme by sympathetic nerves. This may reflect a dissociation between rates of neural release of norepinephrine and release of DBH in chronic, severe heart failure. The observation of low serum DBH levels in patients with heart failure suggests that measurement of DBH levels may serve as a useful indicator of cardiac dysfunction.