Mutations in human monoamine-related neurotransmitter pathway genes

Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org).     

EFFECT OF ACUPUNCTURE COMBINED WITH EPIDURAL ANESTHESIA ON PLASMA CATECHOLAMINE CONTENT IN CHOLECYSTECTOMY PATIENTS

Ｉｔｉｓｒｅｐｏｒｔｅｄｔｈａｔｃａｔｅｃｈｏｌａｍｉｎｅ (ＣＡ)ｉｎ ｃｌｕｄｉｎｇｎｏｒｅｐｉｎｅｐｈｒｉｎｅ (ＮＥ )ａｎｄｄｏｐａｍｉｎｅ(ＤＡ)ｉｓｉｎｖｏｌｖｅｄｉｎａｃｕｐｕｎｃｔｕｒｅａｎａｌｇｅｓｉａ[1 ,3] .ＣＡｃａｎａｎｔａｇｏｎｉｚｅａｃｕｐｕｎｃｔｕｒｅａｎａｌｇｅｓｉａ.Ｄｕｒ ｉｎｇａｃｕｐｕｎｃｔｕｒｅ,ＮＥｃｏｎｔｅｎｔｄｅｃｒｅａｓｅｓｉｎｔｈｅｂｒａｉｎｗｈｉｌｅｔｈｅａｎａｌｇｅｓｉｃｅｆｆｅｃｔａｐｐｅａｒｓ.Ｂｕｔｔｈｅｓｅｆｉｎｄｉｎｇｓａｒｅａｃｈｉｅｖｅｄｍ…     

Development of dopamine-immunoreactive neurons associated with the antennal lobes of the honey bee, Apis mellifera.

This report examines the development of the dopaminergic system in the primary antennosensory centres (antennal lobes) of the brain of the honey bee, Apis mellifera, and the effects of dopamine on neurite outgrowth of antennal-lobe neurons in vitro. Antibodies raised against dopamine were used to follow the development of a small population of dopamine-immunoreactive neurons that invade the antennal lobes during metamorphic adult development. Immunopositive somata associated with the antennal lobes were first detected at stage 2 of the nine stages of metamorphic adult development, but processes of these neurons within the antennal-lobe neuropil did not exhibit immunostaining until pupal stage 3. Severe depletion of primary sensory input to the right antennal lobe early in metamorphic adult development or removal of the right antenna from newly emerged bees did not alter the expression of dopamine immunoreactivity in the antennal-lobe neuropil. The presence of dopamine in developing antennal lobes was confirmed by using high performance liquid chromatography with electrochemical detection. Levels of dopamine were significantly higher at pupal stage 4 than at all other stages examined. This surge in dopamine levels coincided with rapid growth and compartmentalisation of the antennal-lobe neuropil. Exogenously applied dopamine (50 microM) enhanced the growth of antennal-lobe neurons in vitro, but only in cells derived from pupae at stage 5 of metamorphic adult development. The early appearance of dopamine-immunoreactive neurons and the effects of dopamine on stage 5 antennal-lobe neurons in vitro support the view that dopamine plays a role in the developing brain of the honey bee.     

Localization of the δ‐opioid receptor and dopamine transporter in the nucleus accumbens shell: Implications for opiate and psychostimulant cross‐sensitization

Opiate‐ and psychostimulant‐induced modulation of dopamine transmission in the nucleus accumbens shell (AcbSh) is thought to play a key role in their potent reinforcing and locomotor effects. To investigate the cellular basis for potential functional interactions involving opiates active at the δ‐opioid receptor (DOR) and psychostimulants that bind selectively to the dopamine transporter (DAT), we examined the electron microscopic localization of their respective antisera in rat AcbSh. DOR immunoperoxidase labeling was seen primarily, and DAT immunogold particles exclusively, in axon terminals. In these terminals, DOR immunoreactivity was prominently associated with discrete segments of the plasma membrane and the membranes of nearby small synaptic and large dense core vesicles. DAT immunogold particles were almost exclusively distributed along nonsynaptic axonal plasma membranes. Thirty‐nine percent DOR‐labeled profiles (221/566) either apposed DAT‐immunoreactive terminals or also contained DAT. Of these 221 DOR‐labeled profiles, 13% were axon terminals containing DAT and 15% were dendritic spines apposed to DAT‐immunoreactive terminals. In contrast, 70% were morphologically heterogeneous axon terminals and small axons apposed to DAT‐immunoreactive terminals. Our results indicate that DOR agonists in the AcbSh can directly modulate the release of dopamine, as well as postsynaptic responses in spiny neurons that receive dopaminergic input, but act principally to control the presynaptic secretion of other neurotransmitters whose release may influence or be influenced by extracellular dopamine. Thus, while opiates and psychostimulants mainly have differential sites of action, cross‐sensitization of their addictive properties may occur through common neuronal targets. Synapse 34:1–10, 1999. © 1999 Wiley‐Liss, Inc.     

Noradrenergic input to nociceptive modulatory neurons in the rat rostral ventromedial medulla

Within the rostral ventromedial medulla (RVM), there are two classes of putative pain modulation neurons: ON cells and OFF cells, which respectively burst or pause prior to withdrawal reflexes elicited by noxious stimulation. Alpha-adrenergic agonists injected into the RVM produce changes in the latency of spinal nocifensive reflexes and, when iontophoretically applied, alter the firing of RVM ON but not OFF cells. To provide further information about the contribution of norepinephrine to RVM neuron function, we analyzed the distribution of tyrosine hydroxylase immunoreactive (TH-ir) appositions upon RVM ON and OFF cells. In the lightly anesthetized rat, seven ON and five OFF cells were identified by changes in their discharge rate in relation to nociceptive withdrawal reflexes and were labeled by intracellular injection of neurobiotin. Sections containing labeled cells were visualized by using avidin conjugated to a Texas Red fluorophore. Tissue with labeled cells was subsequently processed for TH-ir by using a Bodipy fluorophore conjugated secondary antibody. The distribution of the Bodipy-labeled fibers and terminals upon the Texas Red-labeled neurons was mapped using a confocal laser-scanning microscope. All the labeled neurons exhibited close TH-ir appositions. Appositions were of two types: swellings and fibers. Although the numbers and density of appositions varied among the cells, there were no consistent differences that correlated with physiological properties. Thus the overall density of appositions for ON cells (29.0 ± 22.2 × 10⁴ μm²) did not differ significantly from that for OFF cells (25.4 ± 22.2 × 10⁴ μm²). Tyrosine hydroxylase immunoreactive (TH-ir) appositions upon ON and OFF cells varied with their location along the dorso-ventral axis with more ventral neurons having a greater density of TH-ir swelling-type appositions. In a separate study, TH-ir and dopamine-β-hydroxylase-like immunoreactivity (DBH-ir) were mapped in the same sections by using confocal microscopy. Nearly 97% of the TH-ir profiles co-localized with DBH-ir. These observations provide evidence that both ON and OFF cells in the RVM are targeted by noradrenergic inputs. J. Comp. Neurol. 377:381–391, 1997. © 1997 Wiley-Liss, Inc.     

Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome

Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploinsufficiency of a gene(s) within 22q11. One candidate that has been mapped to this region is catechol-O-methytransferase (COMT). We recently identified a polymorphism in the COMT gene that leads to a valine → methionine substitution at amino acid 158 of the membrane-bound form of the enzyme. Homozygosity for COMT158^met leads to a 3–4-fold reduction in enzymatic activity, compared with homozygotes for COMT158^val. We now report that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158^met, and the development of bipolar spectrum disorder, and in particular, a rapid-cycling form. © 1996 Wiley-Liss, Inc.     

Regional distribution of cytochrome P450 2D1 in the rat central nervous system

Cytochrome P450s are enzymes involved in the oxidative metabolism of numerous endogenous and exogenous molecules. The enzyme cytochrome debrisoquine/sparteine-type monoxygenase is a specific form of cytochrome P450 and is found in the liver and the brain (in the rat the enzyme is known as CYP2D1). CYP2D1 has no established role in the brain; however, it has been shown to share substrate and inhibitor specificities with the dopamine transporter and the enzyme monoamine oxygenase B. Using CYP2D-specific deoxyoligonucleotide probes and a polyclonal antibody to CYP2D1, we have mapped the distribution of CYP2D mRNA and CYP2D1-like immunoreactivity in the rat central nervous system. CYP2D1 immunoreactivity and the CYP2D mRNA signal were heterogenously distributed between brain areas. There were moderate to high levels of immunoreactivity and mRNA signal in the olfactory bulb, olfactory tubercle, cerebral cortex, hippocampus, dentate gyrus, piriform cortex, caudate putamen, supraoptic nucleus, medial habenula, hypothalamus, thalamus, medial mamilliary nucleus and superior colliculus. In the brainstem, strong CYP2D1 immunoreactivity and CYP2D mRNA signal were observed in the substantia nigra compacta, red nucleus, interpeduncular nucleus, pontine grey, locus coeruleus, cerebellum, and the ventral horn of the spinal cord. This study indicates that CYP2D1 is widely and constitutively expressed in neuronal and some glial populations in the rat brain. The localization of CYP2D1 in several regions known to harbor catecholamines and serotonin may suggest a role for CYP2D1 in the metabolism of monoamines. © 1996 Wiley-Liss, Inc.     

Optimising urinary catecholamine metabolite diagnostics for neuroblastoma

Introduction

The analysis of urinary catecholamine metabolites is a cornerstone of neuroblastoma diagnostics. Currently, there is no consensus regarding the sampling method, and variable combinations of catecholamine metabolites are being used. We investigated if spot urine samples can be reliably used for analysis of a panel of catecholamine metabolites for the diagnosis of neuroblastoma.

Methods

Twenty-four-hour urine or spot urine samples were collected from patients with and without neuroblastoma at diagnosis. Homovanillic acid (HVA), vanillylmandelic acid (VMA), dopamine, 3-methoxytyramine, norepinephrine, normetanephrine, epinephrine and metanephrine were measured by high-performance liquid chromatography coupled with fluorescence detection (HPLC-FD) and/or ultra-performance liquid chromatography coupled with electrospray tandem mass spectrometry (UPLC-MS/MS).

Results

Catecholamine metabolite levels were measured in urine samples of 400 neuroblastoma patients (24-hour urine, n = 234; spot urine, n = 166) and 571 controls (all spot urine). Excretion levels of catecholamine metabolites and the diagnostic sensitivity for each metabolite were similar in 24-hour urine and spot urine samples (p > .08 and >.27 for all metabolites). The area under the receiver-operating-characteristic curve (AUC) of the panel containing all eight catecholamine metabolites was significantly higher compared to that of only HVA and VMA (AUC = 0.952 vs. 0.920, p = .02). No differences were observed in metabolite levels between the two analysis methods.

Conclusion

Catecholamine metabolites in spot urine and 24-hour urine resulted in similar diagnostic sensitivities. The Catecholamine Working Group recommends the implementation of spot urine as standard of care. The panel of eight catecholamine metabolites has superior diagnostic accuracy over VMA and HVA.     

加兰肽及其受体在人嗜铬细胞瘤中的表达及意义

[目的]探讨加兰肽（GAL）及其受体（GALR1、GALR2）在嗜铬细胞瘤中的表达及意义。[方法]分析功能不同嗜铬细胞瘤患者临床特点,ELISA法检测功能组（n=130）、功能隐匿组（n=26）、高血压组（n=30）和健康组（n=30）的血清GAL水平;免疫组化法检测GAL、GALR1和GALR2的表达水平。[结果]功能隐匿组与功能组患者年龄、性别、肿瘤性质、部位、肿瘤数目及多巴胺、尿皮醇水平均无显著性差异,两组24h肾上腺素、去甲肾上腺素水平有显著性差异（P〈0.001）。功能组、功能隐匿组、高血压组和健康组的血清GAL浓度无显著性差异。功能组、功能隐匿组GAL阳性表达率分别为94.6%和23.1%（P〈0.001）,两组GALR1阳性表达率分别为95.4%和96.2%（P〉0.05）,两组GALR2阳性表达率分别为86.9%和34.6%（P〈0.001）。[结论]嗜铬细胞瘤中分泌儿茶酚胺功能与患者血清GAL浓度无关,可能与肿瘤组织中GAL及GALR2的表达有关。