Immunocytochemical localization of dopamine-β-hydroxylase in neurons of the human brain stem

doi:10.1016/0306-4522(87)90173-4

Neuroscience

Volume 23, Issue 3, December 1987, Pages 981-989

https://doi.org/10.1016/0306-4522(87)90173-4 Get rights and content

Abstract

The distribution of catecholaminergic cells in the human pons and medulla was illustrated by immunocytochemistry using a polyclonal antibody directed against the catecholamine synthetic enzyme, dopamine-β-hydroxylase. The antibody specifically recognizes dopamine-β-hydroxylase in putative adrenergic and noradrenergic neurons. The adrenergic and noradrenergic neurons are found in the brain stem from caudal levels of the medulla through the caudalmost levels of the midbrain. Large numbers of dopamine-β-hydroxylase-positive cells were observed in cell groups of the medulla. Additionally, dopamine-β-hydroxylase-positive cells were concentrated in the nucleus locus coeruleus and the nucleus subcoeruleus in the pons.

These studies confirm that immunocytochemical localization of dopamine-β-hydroxylase can be used to identify noradrenergic and adrenergic neurons and their terminal varicosities in the pons and medulla in routine autopsy material. These studies have also illustrated that the distribution of dopamine-β-hydroxylase in the adult human brain is comparable to the distribution in other species.

Reference (18)

FrigonR.P. et al.
Human plasma dopamine-β-hydroxylase: purification and properties
J. biol. Chem.
(1978)
IversenL.L. et al.
Loss of pigmented dopamine-β-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer's type
Neurosci. Lett.
(1983)
KitahamaK. et al.
Adrenergic neurons in human brain demonstrated by immunohistochemistry with antibodies to phenylethanolamine-N-methyl-transferase (PNMT): Discovery of a new group in the nucleus tractus solitarius
Neurosci. Lett.
(1985)
MorrisonJ.H. et al.
Laminar, tangential, and regional organization of the noradrenergic innervation of monkey cortex: Dopamine-β-hydroxylase immunohistochemistry
Brain Res. Bull.
(1982)
PearsonJ. et al.
Tyrosine hydroxylase immunocytochemistry in human brain
Brain Res.
(1979)
WestlundK.N. et al.
Noradrenergic projections to the spinal cord of the rat
Brain Res.
(1983)
WestlundK.N. et al.
Origins and terminations of descending noradrenergic projections to the spinal cord of monkey
Brain Res.
(1984)
BermanA.L.
The Brain Stem of the Cat
(1968)
BogertsB.
A brainstem atlas of catecholaminergic neurons in man, using melanin as a natural marker
J. comp. Neurol.
(1981)

There are more references available in the full text version of this article.

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Citation Excerpt :
AKT is a serine/threonine protein kinase, identified as a key signaling intermediary downstream of dopamine D2 receptor (Zheng et al., 2012). DBH catalyses the conversion of dopamine to noradrenaline (Kemper et al., 1987). DBH knockout mice show a lack of noradrenaline and also of dopamine in several brains areas, due to interaction between noradrenergic and dopaminergic systems (Schank et al., 2006).
Cannabis is one of the most widely-used drugs in industrialized countries. It is now well established that cannabis use impacts neurocognition. In the intoxication period time episodic memory, working memory and attention are impacted and impulsivity is increased. The long-term effects of cannabis use tend to be similar. Various internal factors, such as sex differences, modulate this impact. It is unclear whether genetic variations can also influence the impact of cannabis on neurocognition. We set out to examine the impact of genetic variations on neurocognition in cannabis users.
We conducted a search via the PubMed, Web of Science, and ScienceDirect databases to identify studies measuring neurocognition and assessing genotypes in the context of cannabis use.
We included 13 articles. We found that working memory, verbal and visual memory and sustained attention are more impacted during intoxication in subjects with the Val COMT allele. COMT gene could also modulate sustained attention in regular use. The CNR1, AKT1, DBH and 5-HTT/SLC6A4 genes may also modulate effects.
Most of these genes are linked to schizophrenia. A fuller understanding of their impact on the effects of cannabis on neurocognition would thus help elucidate the mechanisms linking cannabis and psychosis. However, evidence is still scant, and more research is needed.
The dopamine b-hydroxylase 19 bp insertion/deletion polymorphism was associated with first-episode but not medicated chronic schizophrenia
2012, Journal of Psychiatric Research
Citation Excerpt :
Dysfunction in the dopaminergic system has been reported to be a key component to the pathophysiology of schizophrenia (Davis et al., 1991) as well as disturbances in central noradrenergic neurotransmission (Klimek et al., 1999; Gu, 2002). Dopamine beta-hydroxylase (DBH) is a key enzyme catalyzing the conversion of dopamine to noradrenaline within these neurons (Cimarusti et al., 1979; Kemper et al., 1987). The level of DBH protein is under strong genetic control and has a significant correlation between its activity in plasma and cerebrospinal fluid (CSF) (Dunnette and Weinshilboum, 1976; Wilson et al., 1988; Cubells et al., 2011).
Numerous studies report dysfunctional dopaminergic and noradrenergic neurotransmission in the pathogenesis of schizophrenia. Dopamine beta-hydroxylase (DBH) is an intracellular enzyme catalyzing the conversion of dopamine to noradrenaline. Functional polymorphisms have been reported in the promoter region of DBH gene, including a 19 bp insertion/deletion polymorphism. The purpose of this study was to investigate whether there was an association between the functional polymorphism (DBH5′-Ins/Del) and schizophrenia in a Han Chinese population.
This polymorphism was genotyped in 221 first-episode schizophrenics, 360 chronic schizophrenics and 318 healthy controls using a case-control design. We assessed their psychopathology using the Positive and Negative Syndrome Scale (PANSS).
We showed that the DBH5′-Ins/Del deletion (Del) allelic and genotypic frequencies were significantly lower in controls than first-episode of schizophrenics (FES) (both p < 0.001), but controls were not different from chronic schizophrenics. Furthermore, the PANSS positive symptom and total scores were significantly higher in FES with the Del/Del genotype than those with Ins/Del and Ins/Ins genotypes (all p < 0.05).
The DBH5′-Ins/Del polymorphism may play a role in susceptibility to the positive symptoms of FES and to these FES not progressing on to chronic schizophrenia.
Lack of association between genetic polymorphisms affecting sympathetic activity and tilt-induced vasovagal syncope
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Although the pathophysiology of vasovagal syncope is not completely understood, the involvement of sympathetic nervous system alterations has been suggested.
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We genotyped 129 subjects with recurrent unexplained syncope who underwent tilt testing, and investigated the recurrence of syncope.
The analysed polymorphisms were Arg492Cys (ADRA1A gene), Ser49Gly and Arg389Gly (ADRB1), Arg16Gly and Gln27Glu (ADRB2), 825C/T (GNB3), –1021C/T (DBH) and S/L (SLC6A4). No association of the aforementioned genetic variants with both tilt test outcomes and new syncopal episodes during follow-up was found.
None of the considered polymorphisms influencing sympathetic activity is a major risk factor for vasovagal syncope in Italian patients.
Heterogeneous dopamine populations project to specific subregions of the primate amygdala
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Citation Excerpt :
Double-labeled cells were only seen in the main locus coeruleus (A7) and A5 group. Retrograde injections into all of the amygdaloid nuclei, except for the amygdalostriatal area, resulted in bilaterally double-labeled cells in the A5 and A7 groups, which are noradrengeric (Kemper et al., 1987). Anterogradely labeled terminal fiber patterns were similar for injections in the medial A9-SNpc (J15FR) and the A8-RRF (J16FS, J19FS), consistent with retrograde results.
Amygdala dysfunction has been reported among patients with various psychiatric disorders, and dopamine is critical to the amygdala's ability to mediate fear conditioning. Recent work indicates that the midbrain dopaminergic neurons have heterogeneous receptor and membrane channel profiles, as well as differential physiologic responses to discrete stimuli. To begin understanding how dopamine affects amygdala physiology and pathology in higher primates, we mapped the inputs from the midbrain dopaminergic neurons to various amygdala nuclei in the monkey using retrograde and anterograde tracing techniques, and single and double immunofluorescence histochemistry for tracer and tyrosine hydroxylase, a dopamine marker. Our results show that the primate amygdala as a whole receives broad input, mostly from the dorsal tier of the substantia nigra, pars compacta, and the A8-retrorubral field. Input from the A10-ventral tegmental area, while present, was less prominent. These results differ from data in the rat, where the midline A10-ventral tegmental area is a major source of dopamine to the amygdala “mesolimbic” pathway. Both the “amygdala proper” and the “extended amygdala” receive the majority of their input from the dorsal tier of the substantia nigra and A8-retrorubral field, but the extended amygdala receives additional modest input from the ventral tier. In addition, the “extended amygdala” structures have a denser input than the “amygdala proper,” with the exception of the lateral core of the central nucleus, which receives no input. Our anterograde studies confirm these findings, and revealed fine, diffuse terminal fibers in the amygdala proper, but a denser network of fibers in the extended amygdala outside the lateral core of the central nucleus. These results indicate that the entire extent of the dorsal tier beyond the A10-ventral tegmental area may regulate the amygdala in primates, and subsequently serve as a source of dysfunction in primate psychopathology.
Aromatic l-amino acid decarboxylase-immunoreactive structures in human midbrain, pons, and medulla
2009, Journal of Chemical Neuroanatomy
The objective of the present study was to determine with precision the localization of neurons and fibers immunoreactive (ir) for aromatic l-amino acid decarboxylase (AADC), the second-step enzyme responsible for conversion of l-dihydroxyphenylalanine (l-DOPA) to dopamine (DA) and 5-hydroxytryptophan (5-HTP) to serotonin (5-hydroxytryptamine: 5-HT) in the midbrain, pons, and medulla oblongata of the adult human brain. Intense AADC immunoreactivity was observed in a large number of presumptive 5-HT neuronal cell bodies distributed in all of the raphe nuclei, as well as in regions outside the raphe nuclei such as the ventral portions of the pons and medulla. Moderate to strong immunoreaction was observable in presumptive DA cells in the mesencephalic reticular formation, substantia nigra, and ventral tegmental area of Tsai, as well as in presumptive noradrenergic (NA) cells, which were aggregated in the locus coeruleus and dispersed in the subcoeruleus nuclei. In the medulla oblongata, immunoreaction of moderate intensity was distributed in the mid and ventrolateral portions of the intermediate reticular nucleus, which constitutes the oblique plate of A1/C1 presumptive adrenergic and/or NA neurons. The dorsal vagal AADC-ir neurons were fewer in number and stained more weakly than cells immunoreactive for tyrosine hydroxylase (TH). AADC immunoreactivity was not identified in an aggregate of TH-ir neurons lying in the gelatinous subnucleus of the solitary nucleus, a restricted region just rostroventral to the area postrema. Nonaminergic AADC-positive neurons (D neurons), which are abundant in the rat and cat midbrain, pons, and medulla, were hardly detectable in homologous regions in the human brain, although they were clearly distinguishable in the forebrain.
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2006, Journal of the Neurological Sciences
Migraine is a debilitating neurological disorder, affecting 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is unclear. Our previous work has investigated dopamine related migraine candidate genes and has reported a significant allelic association with migraine of a microsatellite localised to the promoter region of the dopamine beta-hydroxylase (DBH) gene.
The present study performed an association analysis in a larger population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls) examining two different genetic DBH polymorphisms (a functional insertion/deletion promoter and a coding SNP A444G polymorphism). Although no significant association was found for the SNP polymorphism, the results showed a significant association between the insertion/deletion variant and disease (χ² = 8.92, P = 0.011), in particular in migraine with aura (χ² = 11.53, P = 0.003) compared to the control group. Furthermore, the analysis of this polymorphism stratified by gender, revealed that male individuals with the homozygote deletion genotype had three times the risk of developing migraine, compared to females. The DBH insertion/deletion polymorphism is in linkage disequilibrium with the previously reported migraine associated DBH microsatellite and this insertion/deletion polymorphism is functional, which may explain a potential role in susceptibility to migraine.

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Abstract

Reference (18)

Human plasma dopamine-β-hydroxylase: purification and properties

J. biol. Chem.

Loss of pigmented dopamine-β-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer's type

Neurosci. Lett.

Adrenergic neurons in human brain demonstrated by immunohistochemistry with antibodies to phenylethanolamine-N-methyl-transferase (PNMT): Discovery of a new group in the nucleus tractus solitarius

Neurosci. Lett.

Laminar, tangential, and regional organization of the noradrenergic innervation of monkey cortex: Dopamine-β-hydroxylase immunohistochemistry

Brain Res. Bull.

Tyrosine hydroxylase immunocytochemistry in human brain

Brain Res.

Noradrenergic projections to the spinal cord of the rat

Brain Res.

Origins and terminations of descending noradrenergic projections to the spinal cord of monkey

Brain Res.

The Brain Stem of the Cat

A brainstem atlas of catecholaminergic neurons in man, using melanin as a natural marker

J. comp. Neurol.

Cited by (37)

The effect of interactions between genetics and cannabis use on neurocognition. A review

The dopamine b-hydroxylase 19 bp insertion/deletion polymorphism was associated with first-episode but not medicated chronic schizophrenia

Lack of association between genetic polymorphisms affecting sympathetic activity and tilt-induced vasovagal syncope

Heterogeneous dopamine populations project to specific subregions of the primate amygdala

Aromatic l-amino acid decarboxylase-immunoreactive structures in human midbrain, pons, and medulla

Association between a 19 bp deletion polymorphism at the dopamine beta-hydroxylase (DBH) locus and migraine with aura