DBH Activity Research Articles

Changes in platelet monoamine oxidase and plasma dopamine-beta-hydroxylase activities in lithium-treated bipolar patients

The activity of monoamine oxidase (MAO) and dopamine-β-hydroxylase (DBH), enzymes involved in monoamine metabolism, were studied in 29 bipolar patients (mean age = 33.12years, SD = 7.27) who were treated with lithium carbonate and in 20 healthy volunteers (mean age = 30.05 years, SD = 6.04). Platelet MAO activity was higher after lithium withdrawal, whereas plasma DBH activity was lower in remitted euthymic bipolar patients compared with normal volunteers. During lithium treatment, platelet MAO activity decreased and plasma DBH activity increased compared with the lithium-withdrawal values. It was also observed that the activities of these enzymes in the bipolar patients during lithium treatment did not differ from those in the volunteers. Thus, platelet MAO and plasma DBH activities differed in unmedicated patients with bipolar affective disorder from those of healthy subjects. Treatment with lithium appeared to have a normalizing effect on MAO and DBH activity levels.

Peripheral markers of catecholamine metabolism among workers occupationally exposed to manganese (Mn)

In a preliminary study of 11 men randomly selected in a ferro-alloy plant and of 15 control subjects, platelet monoamine oxidase (MAO) and serum dopamine β-hydroxylase (DBH) activities were measured. A tendency towards lower MAO-B activity in the exposed workers as compared to control subjects ( t = 1.95; P = 0.06) was found whereas DBH activity was similar. In the exposed group, a dose-effect relationship was noted between a manganese (Mn) cumulative exposure index (CEI) and DBH activity ( R 2 = 0.40, P < 0.05). Since DBH is an expression of catecholamine release, the relative increase in such activity could be envisaged as a compensatory mechanism to a reduced turnover rate as reflected by MAO-B activity. Owing to the limited sample size, these findings should be confirmed by further epidemiological and experimental studies.

Changes in Hypothalamic Catecholamines, Dopamine-β-hydroxylase, and Phenylethanolamine- N-methyltransferase in the Catfish Heteropneustes fossilis in Relation to Season, Raised Photoperiod and Temperature, Ovariectomy, and Estradiol-17β Replacement

In Heteropneustes fossilis, contents and turnovers of hypothalamic catecholamines (CA) and activities of dopamine-β-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT) showed significant seasonal variations with significantly high day values. The seasonal pattern of dopamine (DA) on one hand and that of noradrenaline (NA) and adrenaline (A) on the other hand showed an inverse relationship, the former decreasing and the latter increasing during the progress of gonadal recrudescence. The DBH and PNMT levels were low in the resting phase and increased to the peak in the prespawning (DBH) and spawning (PNMT) phases. Maintenance of the fish under long photoperiods (16L:8D) and high temperature (28 ± 2°) stimulated the NA and A, and DBH and PNMT activities, and suppressed the DA mechanism, the changes being maximal in the raised temperature groups. In the resting phase (December), ovariectomy (OVX) or estradiol-17β, (E 2) replacement in 4-week ovariectomized fish did not produce any significant effects on the CA and enzyme activities. On the contrary, in the prespawning phase (May), OVX produced differential and biphasic responses on CA and the enzymes. The contents and turnovers of both NA and A increased significantly at 2-5 weeks and decreased in the sixth week. However, the reverse was true for DA. The DBH and PNMT activities (assayed only 3, 4, and 6 weeks after OVX) were elevated significantly in the third and fourth weeks but decreased in the sixth week. Plasma levels of gonadotropin (GTH) increased significantly at all durations of OVX in a bimodal pattern while the E 2 levels decreased consistently. Supplementation with a low dose (0.1 μg/g BW) or E 2 restored the NA and A and enzyme activities while the higher doses (0.5, 1.0, and 5.0 μg/g BW) depleted them. The reverse was true for DA. The low dose of E 2 restored the GTH level while the higher ones inhibited it significantly. These results indicate that both environmental photoperiod and temperature and E 2-negative feedback act on the CA to modulate GTH secretion.

Homovanillic Acid and Dopamine-β-hydroxylase in Male Youth: Relationships with Paternal Substance Abuse and Antisocial Behavior

Recent research suggests that dopaminergic/noradrenergic system dysfunction may be associated with substance abuse and/or antisocial behavior. In order to determine whether male youth of fathers with these disorders would manifest differences in these systems when compared with youth of nonsubstance-abusing or nonantisocial fathers, levels of homovanillic acid (HVA), the metabolite of dopamine (DA) and dopamine-beta-hydroxylase (DBH), the enzyme facilitating the conversion of dopamine to norepineprhine, were studied in offspring blood samples. The subjects were 65 male youth aged 6-15 years admitted to a residential center because of behavioral disorders. Parental substance abuse and antisocial behavior were assessed through interviews, rating scales, and/or chart review. HVA and DBH were determined from blood samples obtained after admission. The findings indicated that youth of substance-abusing fathers had significantly greater levels of HVA than yough of nonsubstance-abusing fathers. Younger (< 12.0 years) boys of antisocial fathers had significantly lower DBH activity than comparably aged youth of nonantisocial fathers. The results suggest that common generational links in substance abuse and antisocial behavior in males may be associated with detectable biological parameters in susceptible youth.

Functional and high level expression of human dopamine beta-hydroxylase in transgenic mice.

Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. Transgenic mice were generated with multiple copies of a human DBH minigene construct containing the full-length cDNA connected downstream of the 4-kilobase upstream promoter region to achieve overexpression of DBH. Human DBH mRNA and immunoreactivity were detected tissue-specifically in the brain and adrenal gland of these transgenic mice. The transgene products were correctly processed to a glycosylated mature polypeptide with a molecular mass of 72 kDa and existed in the secretory vesicles as both soluble and membrane-bound forms. We detected a marked increase in DBH activity in various catecholamine-containing tissues of the mice that occurred as a consequence of expression of the catalytically active human DBH enzyme. However, in these transgenics the steady-state levels of norepinephrine and epinephrine were normally maintained without the acceleration of the catecholamine turnover rate, suggesting that there are some regulatory mechanisms to preserve a constant rate of norepinephrine synthesis in spite of the increased amount of DBH protein. These transgenic mice with the minigene construct provide one approach to study the mechanisms underlying biogenesis of the DBH polypeptide and regulation of norepinephrine synthesis.

Neural control of dopamine β-hydroxylase in vivo: acute and chronic effects

Reserpine treatment was used to examine whether short- and long-term neural stimulation regulates rat adrenal medullary dopamine β-hydroxylase (DBH, EC 1.14.17.1) through transcriptional activation and to examine the extent of coordinate control of DBH and phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). A single dose of reserpine (10 mg/kg i.p.) elevates DBH mRNA 1.5-fold by 6 h post-injection. Chronic treatment (10 mg/kg i.p., 4 alternate day injections) continues the rise in DBH mRNA, with a peak of 3.4-fold control values after 2 doses of reserpine and a plateau at this level thereafter. Even though DBH mRNA is elevated 6 h after a single injection of reserpine, DBH activity does not change in parallel. A 1.3-fold rise in activity occurs at 24 h post-injection. In contrast, chronic reserpine treatment concommitantly increases DBH activity and mRNA. As observed for DBH mRNA, enzyme activity peaks and plateaus after 2 injections on alternate days. However, the rise in enzymatic activity is less than the rise in mRNA (2.4-fold versus 3.4-fold). Ribosomal loading experiments demonstrate that the DBH mRNA pool is fully utilized for protein synthesis with an apparent decrease in the number of ribosomes loaded per molecule of mRNA. Western analysis and thermal denaturation studies indicate that an altered form of DBH may be expressed. With a single dose of reserpine, the enzyme shows a decline in specific activity while repeated treatment leads to an enzyme with higher specific activity. In both cases, the protein appears to be more stable. Reserpine treatment also markedly elevates adrenal glucocorticoids. A 1.5-fold increment in glucocorticoid receptor mRNA accompanies the corticosteroid rise, with the receptor mRNA peaking at 6 h and remaining at this level thereafter. The up-regulation of glucocorticoid receptor mRNA expression, together with the presence of a putative glucocorticoid response element in the 5′ flanking region of the DBH gene, suggests that neural and hormonal regulatory mechanisms may work in concert to control DBH gene transcription. Finally, by comparison to PNMT, activation of DBH appears to require sustained stimulation of the neural axis, since acute changes in mRNA lead to only minor changes in enzyme expression. Similar to PNMT, continuous neural stimulation increases both DBH mRNA and enzymatic activity. However, the discordance in the magnitude of these indices suggests that other regulatory controls may be important in setting the ultimate limits on DBH expression, glucocorticoids perhaps being one such influence.

Some biological mechanisms of the inborn predisposition to alcoholism.

The children of alcoholism patients have a high biological risk of this illness, mental and emotional disorders, and behavioral disturbances. The offspring of white mongrel rats with chronic alcohol intoxication were investigated in order to study the neurochemical mechanisms of these phenomena. The content of DA in blood and blood plasma, the characteristics of GABA and the opiate receptors of the brain, the activity of DBH, COMT, MAO, the content of cAMP and cGMP in brain tissue, as well as the expression of the gene c-fos were studied. Changes in the brain content of DA and qualitative and quantitative changes in MAO (an increase and solubilization of MAO A and B activity in the liver) were identified in the offspring of alcoholic rats. A tendency was also observed in the brain toward a decrease in the activity of DBH and COMT and an increase in the activity of cAMP and cGMP. The baseline expression of the gene c-fos in the offspring of male alcoholic rats did not differ from the norm; however, a powerful increase in the expression of the gene c-fos did appear in response to the administration of 2 g/kg of ethanol, in the absence of this effect in the control. A view is presented on the significant role of changes in the functions of the DA system in the genesis of pathology in the offspring of parents with chronic alcohol intoxication, as well as on the possible influence of the prolonged consumption of alcohol on the function of the genome.

Relationship between Gene Polymorphism and Plasma Dopanine .BETA.-Hydroxylase Activity in Hypertensive and Normotensive Subjects.

The association between restriction fragment length polymorphism (RFLP) in the 3′-untranslated region of the dopamine β-hydroxlase (DBH) gene and essential hypertension, and the relationship between this RFLP and plasma DBH activity were investigated. A 322bp segment of the 3′-untranslated region of the human DBH gene was amplified by polymerase chain reaction (PCR). The restriction enzyme SphI cleaved the 322bp PCR product into 201 and 121bp fragments for that allele which contained the SphI cutting site. This allele was designated S. The allele that lacked the SphI restriction site was designated L. Plasma DBH activity was determined by a spectrophotometric method. For this polymorphic restriction site, the frequency of the minor allele of the polymorphism was similar in the hypertensive and normotensive groups (0.39 vs. 0.35, respectively). In the normotensive group, there was a significant (p< 0.01) relationship between plasma DBH activities and genotypes: 65±24, 55±20 and 45± 14IU/I for homozygotes (LL), heterozygotes (LS) and homozygotes (SS), respectively. In the hypertensive group, no significant relationship was observed. These results demonstrate that a SphI RFLP in the 3′-untranslated region of the DBH gene is not associated with essential hypertension in the group studied. However, in only normotensive subjects, this RFLP may be responsible in part for the variance of plasma DBH activity. (Hypertens Res 1994; 17: 49-53)

Are gender differences genetically related to catecholamine metabolism in schizophrenia?

Serum homovanillic acid (HVA) and norepinephrine (NE), serum dopamine-β-hydroxylase (DBH), platelet monoamine oxidase (MAO), and erythrocyte catechol-O-methyltransferase (COMT) have been measured in 86 healthy parents of schizophrenic patients and 36 normal control subjects. The t-test showed that serum HVA concentration was significantly higher in mothers of female patients than in mothers of male patients ( p < .05); Kruskal-Wallis analysis revealed a significant difference in erythrocyte COMT activity among the mothers of male patients, mothers of female patients and female control subjects ( H = 8.7, df = 2, p < .02); and the Mann-Whitney test demonstrated that erythrocyte COMT activity was significantly increased in mothers of male patients as compared with female control subjects ( p < .01), but there were no significant differences in the HVA concentration and COMT activity between the fathers of male and female patients, and male control subjects. There were no significant changes in serum NE concentration, serum DBH and platelet MAO activity in these subjects. The present study suggests that catecholamine metabolism in mothers of schizophrenic patients may play a genetic role in the gender differences of schizophrenia.

Studies on concentrations of NA and HVA and activity of DBH in the serum from schizophrenic patients, first-degree relatives and normal subjects

The serum noradrenaline (NA), homovanillic acid (HVA) and dopamine β-hydroxylase (DBH) have been examined in neuroleptic-free and -treated patients, healthy first-degree relatives of the patients and normal subjects. Analysis of variance (ANOVA) revealed significant differences in the concentrations of serum NA( F = 2.91, p < 0.05) and HVA( F = 3.58, p < 0.05), and in the activity of serum DBH( F = 2.77, p < 0.05) among the four groups. The serum NA was significantly higher in neuroleptic-free patients (475±220pg/ml, n = 18), than in healthy first-degree relatives (343±189 pg/ml, n = 37, p < 0.05) or in normal subjects (354±111 pg/ml, n = 17, p < 0.05), and it also was significantly higher in neuroleptic-treated patients (442±223 pg/ml, n = 58) than in healthy first-degree relatives ( p < 0.05) or in normal subjects ( p < 0.05). There was a trend towards high serum HVA in neuroleptic-free patients (11.3±6.3 ng/ml, n = 17) compared with the other three groups. The serum DBH activity was high in neuroleptic-free patients (31.2±15.6 nmol/ min/ml, n = 17), and significantly in comparison with those treated with neuroleptic drugs (21.6±10.9 nmol/ min/ml, n = 56, p < 0.05). There was a significant negative correlation between HVA concentration and DBH activity in the serum from neuroleptic-free patients ( r = −0.64, n = 16, p < 0.01), and there appeared to be three subgroups with alterations of serum DBH activity and HVA concentration. The concentrations of serum HVA or NA, or the activity of serum DBH did not correlate with the severity of illness. These results suggest that disturbances of metabolic pathways of catecholamines may be involved in schizophrenia and that this group of schizophrenic patients may be heterogeneous in neurochemistry.

Biphasic effects of smoking on human serum dopamine-β-hydroxylase activity

To investigate the chronic effects of smoking on sympathetic nerve activity, serum dopamine-β-hydroxylase (DBH) activity was determined in 119 male non-smokers and 183 age-matched male smokers. The smokers were classified into 3 groups: 51 light smokers (1–19 cigarettes/day), 76 moderate smokers ( 20 cigarettes day ), and 56 heavy smokers (more than 20 cigarettes day ). The light smokers had the highest mean DBH activity, and the heavy smokers had the lowest mean DBH activity in the 4 groups. These results suggest that light smoking stimulates the sympathetic nervous system, but that heavy smoking depresses the system. These biphasic changes in DBH activity are similar to the pharmacological effects of nicotine on the peripheral sympathetic nervous system.

Propranolol reduces rat dopamine-β-hydroxylase activity and catecholamine levels

Propranolol treatment (1 mg/kg i.p. twice daily for 8 days) reduced atrial dopamine-β-hydroxylase (DβH) activity by 60.5% and lung DβH activity by 53.5% but did not alter ventricle DβH activity. Propranolol also significantly reduced atrial noradrenaline (NA) by 66.3%, adrenaline (A) by 40%, dopamine (DA) by 72.4% and lung NA by 46.6% but did not change plasma or cardiac ventricle catecholamines. The addition of propranolol (10 −6 M) to cardiac and lung tissue homogenates in vitro did not inhibit tissue DβH activities. The results suggest that chronic propranolol treatment inhibits NA synthesis and support the hypothesis of a centrally induced inhibition of sympathetic activity caused by β-adrenoceptor blockade.

Inhibitory effect of neuropeptide Y (NPY) on the in vitro activity of dopamine-β-hydroxylase

Neuropeptide Y (NPY) is found to be costored with norepinephrine (NE) in vesicles of the nerve terminals. An endogenous inhibitor of dopamine-β-hydroxylase (DBH), the synthetic enzyme of NE, has been mentioned. In an attempt to clarify the effect of NPY on DBH activities, an in vitro assay is carried out using chromatographic analysis of NE formation from dopamine. NPY (20 80 pmol/ml) produced a dose-dependent depression of NE formation catalysed by the purified bovine adrenal DBH. Lineweaver Burke plots ( K m = 1.1 mM, V max = 10 pmol/min/mg protein) showed a non-competitive inhibition in NPY (30 pmol/ml, IC 50)-treated samples. Moreover, failure of denatured NPY even at maximum concentration to influence the DBH activities suggested the essential of natural form of NPY. Participation of sulthydryl compound seems also negligible, because N-ethylmaleimide did not overcome the effect of NPY. These results indicate that NPY has the ability to inhibit the catalytic action of DBH.

Tyrosine hydroxylase and dopamine β-hydroxylase inductions evoked by reserpine in the superior cervical ganglion of developing eu- and hypothyroid rats

This study was designed to determine the effect of neonatally-produced hypothyroidism on reserpine-elicited tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DβH) induction in the superior cervical ganglion (SCG) in rats. Some rats were rendered hypothyroid from birth by daily treatment with propylthiouracil (PTU). Some hypothyroid rats received replacement therapy with triiodothyronine (T 3). Some rats received PTU for 20 days, beginning at 90 days of age. Some rats were not treated and served as controls. TH and DβH activities were assayed at 30, 50 and 110 days of age. Basal TH activity in the SCG for rats made hypothyroid as neonates was significantly lower than for controls at all ages tested; basal DβH activity for these rats was lower than for controls at 30 and 50 days of age, but by 110 days was not different from that for controls. Basal TH activity for rats made hypothyroid as adults was intermediate between that for controls and rats made hypothyroid from infancy. Injecting control rats with reserpine produces a robust TH induction in the SCG at each age tested, and a strong DβH induction at 50 and 110 days of age. Reserpine-evoked TH and DβH inductions in rats made hypothyroid as adults were not different from those seen in controls. In contrast, rats made hypothyroid from infancy showed virtually no evidence of a reserpine-provoked TH or DβH induction at any age tested. TH and DβH inductions for hypothyroid rats given T 3 replacement were completely normal. Thus, although the presence of thyroid hormones per se is not required for either TH or DβH induction in the SCG, thyroid hormones acting during infancy seem to be important for the development of the capacity for TH and DβH induction in this tissue.

Low dopamine-beta-hydroxylase: A biological sequela of abuse and neglect?

Twenty-one psychiatrically hospitalized boys were studied while off psychoactive medication to determine if conduct disorder, solitary type, and abuse or neglect experiences correlated with low levels of dopamine-β-hydroxylase (DBH) activity. Preliminary results supported earlier findings that undersocialized types of conduct disorder in boys were correlated with low DBH activity. Possible or definite neglect or abuse before 36 months of age was correlated with low DBH activity. Abuse or neglect was not correlated with low DBH activity when time of occurrence was not specified. Low serum DBH may be a biological sequela of seriously disrupted attachment.

The activity of dopamine β-hydroxylase of central nervous system in genetically epilepsy prone rats

Abnormality in the central noradrenergic system may be related to the seizure prone state in the genetically epilepsy prone rats (GEPR). The present work deals with the characterization of the deficit in noradrenergic system if susceptitibility and intensity of seizure are dependent on central noradrenregic activities by comparing the activities of dopamine β-hydroxylase (DBH) which hydroxylates dopamine into noradrenaline. DBH activities were measured in 5 areas of brain of normal rats, naive GEPR, and severe GEPR. The results suggest that lower DBH activities in the midbrain of GEPRs may positively be coupled to the susceptibility to seizure, whereas the same characteristics of the naive or severe GEPR are not necessarily in parallel with the intensity of seizure.

No change in serum dopamine-β-hydroxylase activity in workers exposed to trichloroethylene

To determine whether occupational exposure to trichloroethylene (TCE) influences sympathetic nerve activity, serum dopanine-β-hydroxylase (DBH) activities were analyzed in 84 male workers exposed to TCE and 83 male age-matched controls. The workers were exposed to about 22 ppm TCE in air. There were no significant differences between the mean serum DBH activity levels for the exposed workers and the corresponding controls. No significant correlation was found between the serum DBH activities and the urinary TCE-metabolite levels or the duration of employment of the workers. The results suggest that chronic occupational exposure to TCE did not influence sympathetic nerve activity of the workers.

Efferent connections of the A1 noradrenergic cell group: A DBH immunohistochemical and PHA-L anterograde tracing study

Immunohistochemical localization of the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) was employed to reveal the anatomical organization of the A1 noradrenergic cell group in the caudal ventrolateral medulla oblongata of the rat. Subsequently, the supraspinal efferent axonal projections of A1 were investigated with a view to elucidating the anatomical substrates underlying its postulated function in central fluid and cardiovascular homeostasis. Within the caudal medulla, DBH-positive/PNMT-negative (noradrenergic) neurons were observed extending bilaterally through the ventrolateral medullary reticular formation from upper cervical spinal cord levels to the level of the area postrema. At the rostral pole of A1, its neurons intermingled with PNMT-immunoreactive perikarya of the more rostrally situated C1 adrenergic cell group. Discrete injections of the anterogradely transported plant lectin Phaseolus vulgaris leucoagglutinin (PHA-L) into A1 resulted in terminal labeling in a number of presumptive efferent target sites including the nucleus of the solitary tract, rostral ventrolateral medulla, dorsal parabrachial nucleus, Kolliker-Fuse nucleus, central grey, dorsomedial nucleus of the hypothalamus, perifornical region, zona incerta, lateral hypothalamus, paraventricular nucleus of the hypothalamus, supraoptic nucleus, bed nucleus of the stria terminalis, and organum vasculosum of the lamina terminalis. Tissue sections adjacent to those reacted for PHA-L were processed immunohistochemically for DBH to determine if anterogradely labeled terminals were localized in regions that demonstrated appropriate immunoreactivity. The majority of regions in which PHA-L terminal labeling was present also exhibited moderate to intense DBH activity. These experiments provide neuroanatomical evidence for direct efferent pathways from the A1 noradrenergic cell group to a number of supraspinal sites that have been reliably implicated in the neural circuitry underlying the central regulation of fluid and cardiovascular homeostasis. Furthermore, the results suggest a selective anatomical interrelation between A1 and sites in the basal forebrain and hypothalamus in which vasopressinergic neurons have been previously demonstrated. It is postulated that the noradrenergic A1 projections observed in this investigation represent the morphological substrate through which A1 exerts a significant influence on cardiovascular regulatory mechanisms.

Altered relationship of plasma FFA and DBH activity in schizophrenia : Nancy Wolfe, M.D., Peter J. Knott, Ph.D., Michael Davidson, M.D., Neill Runyon, B.A., and Kenneth L. Davis, M.D. Departments of Psychiatry (all authors) and Pharmacology (P.K., K.L.D.), The Mount Sinai School of Medicine, New York, NY 10029

Altered relationship of plasma FFA and DBH activity in schizophrenia : Nancy Wolfe, M.D., Peter J. Knott, Ph.D., Michael Davidson, M.D., Neill Runyon, B.A., and Kenneth L. Davis, M.D. Departments of Psychiatry (all authors) and Pharmacology (P.K., K.L.D.), The Mount Sinai School of Medicine, New York, NY 10029

Plasma dopamine-beta-hydroxylase in familial and sporadic paranoid schizophrenia

This study was designed to check the hypothesis of low DBH activities in paranoid schizophrenia (PS), controlling for the influence of positive family history