Dopamine-beta-hydroxylase Activity Research Articles

Clostridioides difficile Infection Dysregulates Brain Dopamine Metabolism.

ABSTRACTGastrointestinal illnesses and dysbiosis are among the most common comorbidities reported in patients with neurodevelopmental disorders. The manuscript reports that C. difficile infection (CDI), predisposed by antibiotic-induced gut dysbiosis, causes significant alterations in dopamine metabolism in major dopaminergic brain regions in mice (P < 0.05). In addition, C. difficile infected mice exhibited significantly reduced dopamine beta-hydroxylase (DBH) activity compared to controls (P < 0.01). Moreover, a significantly increased serum concentration of p-cresol, a DBH inhibiting gut metabolite produced by C. difficile, was also observed in C. difficile infected mice (P < 0.05). Therefore, this study suggests a potential mechanistic link between CDI and alterations in the brain dopaminergic axis. Such alterations may plausibly influence the precipitation and aggravation of dopamine dysmetabolism-associated neurologic diseases in infected patients.IMPORTANCE The gut-brain axis is thought to play a significant role in the development and manifestation of neurologic diseases. This study reports significant alterations in the brain dopamine metabolism in mice infected with C. difficile, an important pathogen that overgrows in the gut after prolonged antibiotic therapy. Such alterations in specific brain regions may have an effect on the precipitation or manifestation of neurodevelopmental disorders in humans.

L–arginine alleviates postmenopausal complications in female rats by stimulating ovarian dopamine beta hydroxylase

Objective: To evaluate the levels of estrogen, albumin and gonadotropins (luteinizing hormone, follicle-stimulating hormone) as well as the activity of dopamine beta hydroxylase (DAß H) in aged female rats treated with nitric oxide precursor L-arginine and neuronal nitric oxide synthase antagonist L-NAME.Methods: A total of 224 Wistar rats (36 weeks old, weighing 250 g) based on a random sampling were divided into the control and experimental groups after Pap smear test. The control group received only saline (1 mL/kg) intraperitoneally (i.p.). The experiential groups were treated with L-arginine (5, 25 and 50 mg/kg, i.p.) and L-NAME (5 and 25 mg/kg, i.p.) for 3 to 21 days, once a day. Blood samples were taken from the rats and the levels of estrogen and albumin and gonadotropins in the serum were monitored by enzyme-linked immunosorbent assay kit, and the ovaries were examined immunohistopathologically for DAßH activity.Results: L-arginine (5 mg/kg) significantly increased estrogen level (P<0.05), which was associated with DAßH activation in the ovaries. L-NAME reduced this effect when administered prior to L-arginine dose. L-arginine caused no significant change in the levels of luteinizing hormone and follicle-stimulating hormone. Except for the lowest dose of L-arginine in the shortest period, albumin levels significantly decreased in other treatments compared to the control group (P<0.05).Conclusions: L-arginine is likely to reduce postmenopausal problems due to an increased nitric oxide level.

Tyrosine hydroxylase in the ventral tegmental area of rams with high or low libido—A role for dopamine

Dopamine synthesis in the ventral tegmental area (VTA) is necessary for the reinforcement of sexual behavior. The objective of this study determined if sexual stimuli initiates reward, and whether reward is attenuated in sexually inactive rams. Sexually active rams were exposed to urine from estrous (n=4) or ovariectomized (n=3) ewes with inactive rams (n=3) exposed to urine from estrous ewes. Following exposure, rams were exsanguinated and brains perfused. Alternating sections of the VTA were stained for Fos related antigens (FRA), tyrosine hydroxylase, and dopamine beta-hydroxylase activity. Forebrain tissue, mid-sagittal ventral to the anterior corpus callosum, was stained for dopamine D2 receptors. Concentrations of cortisol was determined prior to and following exposure. Exposure to ovariectomized-ewe urine in sexually active rams did not influence (P=0.6) FRA expression, but fewer (P<0.05) neurons were positive for tyrosine hydroxylase in the VTA. Sexually inactive rams had fewer (P<0.05) FRA and tyrosine hydroxylase positive neurons in the VTA than sexually active rams following exposure to estrous ewe urine. VTA neurons staining positive for dopamine beta-hydroxylase did not differ by sexual activity (P=0.44) or urine exposure (P=0.07). Exposure to stimulus did not influence (P=0.46) numbers of forebrain neurons staining positive for dopamine D2 receptors in sexually active rams, but fewer (P=0.04) neurons stain positive in inactive rams. Serum concentrations of cortisol did not differ (P≥0.52) among rams prior to or following stimulus. In conclusion sexual inactivity is unlikely due to stress, but may be partially a result of decreased tyrosine hydroxylase and/or the response to dopamine.

Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice.

The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG -/- , PTPRZ -/- , and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry. The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ -/- mice demonstrated marked social alteration with increased aggressivity, reminiscent of some positive symptoms of schizophrenia. Both knockouts showed elevated dopamine levels in prefrontal cortex, hippocampus, and most particularly amygdala, but not striatum, accompanied by reduced dopamine beta hydroxylase activity only in amygdala. In addition, PTPRG KO elicited a distinct increase in hippocampal serotonin level not observed in PTPRZ KO. PTPRG and PTPRZ gene loss therefore induces distinct patterns of behavioral change and region-specific alterations in neurotransmitters, highlighting their usefulness as models for neuropsychiatric disorder mechanisms and making these receptors attractive targets for therapy.

Association between DBH 19 bp insertion/deletion polymorphism and cognition in schizophrenia with and without tardive dyskinesia

Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5′-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5′-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5′-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5′-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5′-Ins/Del genotype groups in those without TD (p<0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p<0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p<0.05). This study indicated that DBH5′-Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention.

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.

The catecholamine biosynthetic enzyme dopamine β-hydroxylase (DBH): first genome-wide search positions trait-determining variants acting additively in the proximal promoter.

Dopamine beta-hydroxylase (DBH) is the biosynthetic enzyme catalyzing formation of norepinephrine. Changes in DBH expression or activity have been implicated in the pathogenesis of cardiovascular and neuropsychiatric disorders. Genetic determination of DBH enzymatic activity and its secretion are only incompletely understood. We began with a genome-wide association search for loci contributing to DBH activity in human plasma. Initially, in a population sample of European ancestry, we identified the proximal DBH promoter as a region harboring three common trait-determining variants (top hit rs1611115, P = 7.2 × 10(-51)). We confirmed their effects on transcription and showed that the three variants each acted additively on gene expression. Results were replicated in a population sample of Native American descent (top hit rs1611115, P = 4.1 × 10(-15)). Jointly, DBH variants accounted for 57% of DBH trait variation. We further identified a genome-wide significant SNP at the LOC338797 locus on chromosome 12 as trans-quantitative trait locus (QTL) (rs4255618, P = 4.62 × 10(-8)). Conditional analyses on DBH identified a third genomic region contributing to DBH variation: a likely cis-QTL adjacent to DBH in SARDH (rs7040170, P = 1.31 × 10(-14)) on chromosome 9q. We conclude that three common SNPs in the DBH promoter act additively to control phenotypic variation in DBH levels, and that two additional novel loci (SARDH and LOC338797) may also contribute to the expression of this catecholamine biosynthetic trait. Identification of DBH variants with strong effects makes it possible to take advantage of Mendelian randomization approaches to test causal effects of this intermediate trait on disease.

Nicotine dependence as a moderator of genetic influences on smoking cessation treatment outcome

BackgroundGenetic influences on smoking cessation treatment outcome may be affected by pretreatment patient characteristics. Nicotine dependence is arguably the most salient clinical factor in smoking cessation. Methods: In this secondary analysis of clinical trial data (N=793), we examined nicotine dependence severity as a moderator of the effects of 1198 single nucleotide polymorphisms (SNPs) in 53 biologically-relevant gene regions on smoking cessation outcomes. P-values were adjusted to account for multiple correlated SNPs within a gene region; corrected system-wide significance was 5×10−4. Results: SNP×nicotine dependence interactions reached region-wide significance for several SNPs in the Dopamine Beta Hydroxylase (DBH) locus (0.0005<Adjusted-P<0.05), including rs1541333, which reached system-wide significance for predicting end of treatment (EOT) abstinence (Adjusted-P=0.0004). A haplotype including 6 DBH SNPs predicted abstinence at EOT (OR=1.7, P=0.001) and 6-month follow-up (OR=1.6, P=0.008) in those with high nicotine dependence (n=526) but not in those with low dependence (n=227). The DBH signal observed here may be distinct from a previously reported genome-wide significant signal for former smoking status and from the principal haplotype associated with plasma dopamine beta-hydroxylase activity. A haplotype within the Chromosome 15 Nicotinic Acetylcholine Receptor gene region predicted abstinence at EOT in those with high (OR=2.0, P=0.0004) but not low (P=0.6) dependence in post hoc analyses. Conclusions: Considering pre-treatment nicotine dependence level may optimize the prediction of genetic influences on cessation outcomes. If replicated, results like these may inform prognosticative genomic screening panels designed to identify smokers at high risk of relapse when coupled with severe nicotine dependence.

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.

Association of the dopamine β‐hydroxylase 19 bp insertion/deletion polymorphism with positive symptoms but not tardive dyskinesia in schizophrenia

Overactivity of dopaminergic neurotransmission is a putative mechanism of tardive dyskinesia (TD). Dopamine beta-hydroxylase (DBH) is a key enzyme in the conversion of dopamine to norepinephrine, and plasma DBH activity is altered in TD patients. This study examined whether the functional DBH 5'-Ins/Del polymorphism was associated with TD severity in Chinese patients with schizophrenia. We compared the rate of this polymorphism in patients with (n = 312) and without TD (n = 435), and healthy controls (n = 625). The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) and psychopathology using the Positive and Negative Syndrome Scale (PANSS). There were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls, or between the patients with and without TD. Also, there was no significant difference in the AIMS total score between the three genotype groups. However, the PANSS positive symptom subscore was significantly higher in patients with Del/Del genotype (13.2 ± 5.2) than those with Ins/Del (11.2 ± 4.9) and Ins/Ins (11.1 ± 3.1) genotypes (both p < 0.05). These results suggest that although the DBH 5'-Ins/Del polymorphism was not associated with susceptibility to TD in patients with schizophrenia, it might be related to positive symptoms of schizophrenia.

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.

Personality traits of aggression-submissiveness and perfectionism associate with ABO blood groups through catecholamine activities

Personality trait research has shown associations with many genes, prominently those of the catecholamine metabolism such as dopamine beta hydroxylase (DBH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). Because DBH gene is in linkage disequilibrium with ABO gene, there is reason to think that other catecholamine genes using the same substrate as DBH may also have associations with ABO blood groups, and this paper demonstrates how this may be so. Reasons include similarities in hapmap population frequency distributions, similarities in illness risks between ABO blood groups and DBH activities as well as between ABO blood groups and COMT activities and between ABO blood groups and MAOA activities. If ABO blood groups can be demonstrated to associate with all these catecholamine genes, then the catecholamine personality trait research can be applied to ABO blood groups and tested for confirmation. ABO blood typing is widely available and affords ability to test this hypothesis and thus confirm the possible joint association of personality traits of aggression-submissiveness and perfectionism to catecholamine genes and to ABO blood groups. Clinical applications and implications are discussed.

The effects of cadmium ions on blood pressure, dopamine-beta-hydroxylase activity and on the responsiveness of in vivo preparations to sympathetic nerve stimulation, noradrenaline and tyramine.

Changes in sympathetic nervous function of the rat caused by acute and chronic treatment with cadmium ((Cd2+) have been studied in vivo by measurement of changes in blood pressure and plasma dopamine-beta-hydroxylase (DBH) activity. In anaesthetized animals, acute injection of Cd2+ (0.1-1 microM) caused an initial fall followed by a rise in both diastolic and systolic blood pressure, plasma DBH activity increased in a dose-dependent manner. Animals subjected to repeated treatment with Cd2+ (0.5, 1 microM) daily for 12 days became markedly hypertensive, the increases in the systolic pressure being greater than those seen in the diastolic pressure. In pithed animals the blood pressure responses of the treated animals to electrical stimulation of the lower sympathetic outflow (T10-L1) and tyramine injection (35, 70, 140 nmol kg-1) were markedly decreased, whilst responses to low doses of noradrenaline (NA) (7, 15, 30 nmol kg-1) were potentiated compared with untreated animals. In addition, plasma DBH activities following sympathetic outflow stimulation and tyramine administration were markedly increased and decreased respectively compared with untreated controls. The data suggest that a correlation exists between changes in sympathetic nervous function and the induction of hypertension caused by Cd2+.

Psychose et traumatisme psychique. Pour une articulation théorique des symptômes psycho-traumatiques et psychotiques chroniques

The co-occurrence between post-traumatic symptoms and psychotic symptoms is well described in the immediate suites of a trauma but can also be chronic. This symptomatic co-occurrence, rarely studied in the literature, is often approached under the sole angle of a primary post-traumatic stress disorder (PTSD) or of a primary psychosis, without federative will to unify the psychotic and post-traumatic symptoms within the same nosological framework. Individuals with schizophrenia or schizoaffective disorder report higher rates of trauma and assault than the general population. High rates of PTSD have been noted in severe mental illness cohorts. Psychotic phenomena may be a relatively common manifestation in patients with chronic PTSD. The purpose of this paper is to expose the various theorical psychopathological aspects between the symptoms of psychosis and PTSD. In populations of veterans, positive and negative symptoms of psychosis in PTSD are described as delusional thoughts and hallucinations often combat-specific. When a PTSD becomes established at a subject to the personality of neurotic structure, the intensity of the PTSD's symptoms lead to a psychotic expression which constitutes a factor of seriousness. Besides, PTSD often induces a risk of substance use disorder supplying psychotic symptoms. Cannabis increases the hallucinations, cocaine strengthens an underlying paranoid tone, and alcohol implies withdrawal hallucinosis. Moreover, such consumption could be a risk factor for the future development of chronic psychosis. From another point of view, by basing themselves on the plasma dopamine beta-hydroxylase activity, some authors made the analogy between psychotic major depression and PTSD with psychotic features (also characterized as a distinct psychotic subtype of PTSD). However, other studies found no correlation between PTSD with psychotic features and family predisposition for schizophrenia or schizoaffective disorder. The determination of the structure of personality seems fundamental in the understanding of the symptoms. A personality of psychotic structure increases the risk of traumatization and PTSD. At the same time, the fragility of this structure causes an increased sensitivity to the trauma, which takes on a particular echo. Moreover, a trauma can test a latent psychotic structure to reveal its existence. The experience of psychosis may be traumatic in itself for patients with, notably, seclusion and sedation during hospitalization. Lastly, the symptoms of this post-traumatic psychosis will be differentiated from neurological confusion caused by a traumatic brain injury. Clinicians often fail to screen routinely for trauma and PTSD symptoms in patients with severe mental illness because few systematic guidelines exist for the identification and treatment of this comorbidity. The links between psychotic and psycho-traumatic symptoms are complex and multidirectional; this co-occurrence is a factor of seriousness. The clinician, while paying attention to these symptoms, has to distinguish the structure of the personality of the subject to articulate the psychotherapy and the pharmacological treatment. Further investigational studies may determine whether antipsychotics will enhance treatment response in PTSD patients with psychotic features.

Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure.

Dopamine beta-hydroxylase (DBH) plays an essential role in catecholamine synthesis by converting dopamine into norepinephrine. Here we systematically investigated DBH polymorphisms associated with enzymatic activity as well as autonomic and blood pressure (BP)/disease phenotypes in vivo. Seventy genetic variants were discovered at the locus; across ethnicities, much of the promoter was spanned by a 5' haplotype block, with a larger block spanning the promoter in whites than blacks. DBH secretion was predicted by genetic variants in the DBH promoter, rather than the amino acid coding region. The C allele of common promoter variant C-970T increased plasma DBH activity, epinephrine excretion, the heritable change in BP during environmental stress in twin pairs, and also predicted higher basal BP in three independent populations. Mutagenesis and expression studies with isolated/transfected DBH promoter/luciferase reporters in chromaffin cells indicated that variant C-970T was functional. C-970T partially disrupted consensus transcriptional motifs for n-MYC and MEF-2, and this variant affected not only basal expression, but also the response to exogenous/co-transfected n-MYC or MEF-2; during chromatin immunoprecipitation, these two endogenous factors interacted with the motif. These results suggest that common DBH promoter variant C-970T plays a role in the pathogenesis of human essential hypertension: common genetic variation in the DBH promoter region seems to initiate a cascade of biochemical and physiological changes eventuating in alterations of basal BP. These observations suggest new molecular strategies for probing the pathophysiology, risk, and rational treatment of systemic hypertension.

Relative Efficiencies of Plasma Catechol Levels and Ratios for Neonatal Diagnosis of Menkes Disease

Menkes disease is an X-linked recessive neurodevelopmental disorder resulting from mutation in a copper-transporting ATPase gene. Menkes disease can be detected by relatively high concentrations of dopamine (DA) and its metabolites compared to norepinephrine (NE) and its metabolites, presumably because dopamine-beta-hydroxylase (DBH) requires copper as a co-factor. The relative diagnostic efficiencies of levels of catechol analytes, alone or in combination, in neonates at genetic risk of Menkes disease have been unknown. Plasma from 44 at-risk neonates less than 30 days old were assayed for DA, NE, and other catechols. Of the 44, 19 were diagnosed subsequently with Menkes disease, and 25 were unaffected. Compared to unaffected at-risk infants, those with Menkes disease had high plasma DA (P < 10(-6)) and low NE (P < 10(-6)) levels. Considered alone, neither DA nor NE levels had perfect sensitivity, whereas the ratio of DA:NE was higher in all affected than in all unaffected subjects (P = 2 x 10(-8)). Analogously, levels of the DA metabolite, dihydroxyphenylacetic acid (DOPAC), and the NE metabolite, dihydroxyphenylglycol (DHPG), were imperfectly sensitive, whereas the DOPAC:DHPG ratio was higher in all affected than in all unaffected subjects (P = 2 x 10(-4)). Plasma dihydroxyphenylalanine (DOPA) and the ratio of epinephrine (EPI):NE levels were higher in affected than in unaffected neonates (P = 0.0015; P = 0.013). Plasma DA:NE and DOPAC:DHPG ratios are remarkably sensitive and specific for diagnosing Menkes disease in at-risk newborns. Affected newborns also have elevated DOPA and EPI:NE ratios, which decreased DBH activity alone cannot explain.

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.

Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone.

C57BL/6 mice were given 0.2% cuprizone (CPZ) for 2 to 6 weeks while controls ate the same diet without CPZ. At various time points the animals were subjected to behavioral tests and their brains were analyzed. Mice exposed to CPZ for 2 and 3 weeks displayed more climbing behavior and lower prepulse inhibition, suggesting an increase in central nervous system activity and impaired sensorimotor gating. In addition, they showed lower activities of monoamine oxidase and dopamine beta hydroxylase in the hippocampus and prefrontal cortex, and had higher dopamine but lower norepinephrine levels in the prefrontal cortex. Mice exposed to CPZ for 4 to 6 weeks had less social interaction, which is an animal correlate of social withdrawal of patients with schizophrenia. Also, these CPZ-exposed mice showed evident brain demyelination, myelin break down, and loss of oligodendrocytes. At all time points the CPZ-exposed mice spent more time in the open arms of an elevated plus maze and exhibited spatial working memory impairment. These data are in line with evidence from human studies suggesting a putative role of white matter abnormality in the pathophysiology of schizophrenia.

Polymorphisms in the DBH gene promoter region and affective temperaments in healthy volunteers

Event Abstract Back to Event Polymorphisms in the DBH gene promoter region and affective temperaments in healthy volunteers Gabriella Eördegh1*, Tibor Rudisch1, Anna Juhasz1, Agnes Rimanoczy1, Ambrus Z. Kovacs1, Edina Papp1 and Zoltan Janka1 1 Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, University of Szeg, Hungary Dopamine-beta-hydroxylase (DBH) is an enzyme that converts dopamine to noradrenaline. The plasma DBH activity seems to be correlated with human behaviour and psychological traits. Many types of DBH polymorphisms were investigated and the DBH-1021CT polymorphism was found to be associated with the plasma DBH activity. The association between the plasma DBH activity and alcoholism, smoking, attention deficit hyperactivity disorder (ADHD), antisocial behaviour, and the scores on Minnesota Multiphasic Personality Inventory (MMPI), Eysenck Personality Questionnaire (EPQ) and Cloninger’s temperament scales was investigated in several studies. In order to examine whether there is any association between the temperament types and the DBH-1021CT polymorphism we applied in our study a temperament personality inventory, the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A). The investigation was carried out in a sample of 140 unrelated Caucasian healthy, young adult volunteers in both genders (107 females and 33 males). Four of the five temperament scales indicated significant difference between the persons with at least one DBH-1021 T allel and the CC homozygotes. The results of the T-carrier individuals were significant lower in the depressive, the cyclothymic and the anxious temperament scales, while in the hyperthymic scale the CC homozygotes had significant lower mean score. However, the irritable temperament scale demonstrated no difference between the two investigated groups. Our findings support the previous suggestion that the DBH-1021CT polymorphism correlates with personality traits. This work was supported by grants from the Hungarian Ministry of Health (ETT 198 04/ 2006) and the Hungarian Scientific Research Fund (OTKA T 046152/2004). Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Behavioural neuroscience Citation: Eördegh G, Rudisch T, Juhasz A, Rimanoczy A, Kovacs AZ, Papp E and Janka Z (2009). Polymorphisms in the DBH gene promoter region and affective temperaments in healthy volunteers. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.229 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 09 Mar 2009; Published Online: 09 Mar 2009. * Correspondence: Gabriella Eördegh, Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, University of Szeg, Szeged, Hungary, nagyneegabi@freemail.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Gabriella Eördegh Tibor Rudisch Anna Juhasz Agnes Rimanoczy Ambrus Z Kovacs Edina Papp Zoltan Janka Google Gabriella Eördegh Tibor Rudisch Anna Juhasz Agnes Rimanoczy Ambrus Z Kovacs Edina Papp Zoltan Janka Google Scholar Gabriella Eördegh Tibor Rudisch Anna Juhasz Agnes Rimanoczy Ambrus Z Kovacs Edina Papp Zoltan Janka PubMed Gabriella Eördegh Tibor Rudisch Anna Juhasz Agnes Rimanoczy Ambrus Z Kovacs Edina Papp Zoltan Janka Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.