Metabolite 3-methoxy-4-hydroxyphenylethylene Glycol Research Articles

Elevated norepinephrine metabolism is linked to cortical thickness in the context of Alzheimer's disease pathology

Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), Aβ42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of Aβ42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes.

Early life stress and novelty seeking behavior in adolescent monkeys

Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and investigate whether novelty seeking behavior is associated with differences in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the dopamine metabolite homovanillic acid (HVA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the neuropeptide corticotrophin-releasing factor (CRF). Monkeys were randomized early in life to either mild intermittent stress (IS) or no stress (NS) conditions, and subsequently presented with opportunities to interact with a familiar or novel object in a test box that was connected to each monkey's home cage. To further minimize the potentially stressful nature of the test situation, monkeys were acclimated to the test procedures prior to study initiation. Post-test plasma levels of cortisol in IS and NS monkeys did not differ significantly from baseline levels measured in undisturbed conditions. During testing, more IS than NS monkeys voluntarily left the home cage, and IS monkeys spent more time in the test box compared to NS monkeys. More IS than NS monkeys engaged in object exploration in the test box, and IS monkeys preferred to interact with the novel vs. familiar object. Novelty seeking was not associated with differences in 5HIAA, HVA, MHPG, or CRF, but correlated with differences in object exploration observed in a different test situation at an earlier age. These trait-like differences in novelty seeking appear to reflect mild early stress-induced adaptations that enhance curiosity and resilience.

CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson's disease

Background In early disease stages it can be clinically difficult to differentiate idiopathic Parkinson's disease (IPD) from patients with multiple system atrophy predominated by parkinsonism (MSA-P). Methods In CSF of 31 patients with IPD, 19 patients with MSA-P, we analyzed tau, neurofilament light chain (NFL) and heavy chain (NFHp35) and the noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Results CSF levels of NFL, NFHp35, and tau were significantly increased in MSA-P (all p < 0.0001), whereas, MHPG levels were significantly decreased in MSA-P ( p < 0.0001). Optimal discriminative cut-off values for the differentiation between MSA-P and IPD were calculated resulting in high sensitivity (76–94%) and specificity (83–97%) levels. Multivariate logistic regression resulted in the combination of NFL and tau as independent contributors in differentiating between MSA-P and IPD. Discussion Higher CSF levels of axonal biomarkers could reflect advanced axonal degeneration in MSA-P. Differentiating MSA-P from IPD could be accurately possible with CSF analysis of a combination of axonal and neurotransmitter biomarkers.

Biogenic amine metabolites and thiamine in cerebrospinal fluid in heredo-degenerative ataxias.

The aims of the present study were: i) to measure levels of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxindoleacetic acid (5HIAA) and precursor tryptophan, as well as the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and thiamine in the cerebrospinal fluid (CSF) of patients with Friedreich's ataxia (FA), olivopontocerebellar atrophy (OPCA), and the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSAC), as compared with sex- and age-matched control subjects. CSF amine related compound levels and thiamine results were compared in 40 FA, 44 OPCA and nine ARSAC patients with those of 94 sex- and age-matched subjects. Neuroimaging (CT scans and single photon emission computed tomographies i.e. SPECT) were carried out in all patients and controls. Genetic studies were conducted on OPCA patients. CSF amine related compounds were measured by high performance liquid chromatography, whereas CSF thiamine levels were measured by a microbiological method. FA patients had significantly lower CSF HVA, 5HIAA and thiamine values than control patients and a trend for lower MHPG levels. In OPCA patients, CSF HVA, MHPG and thiamine values were markedly lower whereas CSF 5HIAA values showed only a trend towards lower levels; in ARSAC patients only thiamine and HVA CSF values were lower than those in control subjects. After presenting the relationships between neurochemical findings on one side, the degree of ataxia, the degree of cerebellar atrophy and the SPECT findings on the other, the authors concluded that replacement and neuroprotective clinical trials in these patients would have to include two or three drugs because the neurotransmitter deficiencies are multiple.

REGION-SPECIFIC DECREASE OF DOPAMINE AND ITS METABOLITES IN BRAINS OF MICE GIVEN ERGOTAMINE

Ergot alkaloids (EA) such as the ergopeptine alkaloid ergotamine (ET) are adrenergic, dopaminergic, and serotonergic agents. The objective of this experiment was to investigate regional brain neurotransmitter alterations caused by EA. Male BALB/ c mice were treated sc daily with ergotamine tartrate for 10 d at 0 (saline), 0.4, 2, 10, or 50 mg/ kg body weight. Twenty-four hours after the last treatment, animals were sacrificed and brains dissected. Regional concentrations of norepinephrine (NE), dopamine ( DA), serotonin (5-HT), and metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), dihydroxyphenylacetic acid (DOPAC) , homovanillic acid (HVA), and 5-hydroxyindole3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography (HPLC) . Moreover, selected organ weights and plasma prolactin (PRL) were determined. Dopamine concentration was significantly reduced by ET at all doses in the striatal and hypothalamic regions. A reduction of the DA metabolite HVA occurred in striatum at only the highest dose, whereas in the hypothalamus both HVA and DOPAC were markedly reduced. Concentrations of NE, MHPG, 5-HT, and 5-HIAA were not affected by treatment in these regions. In the cerebellum, MHPG was significantly elevated at the 50 mg/ kg dose. No effect of treatment was observed in the cerebrum, medulla, and midbrain. Further, no treatment-related differences in plasma PRL and organ weights other than a significant liver weight decrease at intermediate doses were found. Therefore, the effects of ET were predominantly upon DA metabolism in the corpus striatum and hypothalamus. The reductions in DA, HVA, and DOPAC indicate decreased DA synthesis.

The σ ligand rimcazole activates noradrenergic neurons projecting to the paraventricular nucleus and increases corticosterone secretion in rats

Intraperitoneal injection of rimcazole, a σ ligand, into male rats increased plasma concentrations of corticosterone in a dose- and time-related fashion. Concurrently, rimcazole increased concentrations of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the paraventricular nucleus (PVN) of the hypothalamus, suggesting that the drug activates noradrenergic neurons terminating in this nucleus. This latter suggestion was confirmed by the finding that rimcazole also increased concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) in the PVN. Pentazocine, a σ ligand was without effect per se, but blocked the ability of rimcazole to increase concentrations of MHPG in the PVN and corticosterone in plasma. Taken together, these results suggest that rimcazole activates noradrenergic neurons projecting to the PVN via a mechanism involving σ binding sites, and this action may be responsible for the ability of this drug to increase secretion of corticosterone.

Activation of noradrenergic neurons in the locus coeruleus by corticotropin-releasing factor. A microdialysis study.

In the present study the effects of different doses of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF on locus coeruleus (LC) neurons were studied in anesthetized male Wistar rats. To monitor the release of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), a microdialysis probe was implanted into the parietal cortex, a major projection area of the LC. Saline, 0.17, 0.51 nmol CRF and a combination of 5.1 nmol alpha-helical CRF and 0.51 nmol CRF were applied to the LC via a fused silica capillary. While both doses of CRF augmented NA in parietal cortex dialysates (0.51 nmol CRF: from 0.0206 to 0.0266 pmol/sample; 0.17 nmol CRF: from 0.0147 to 0.0170 pmol/sample), saline did not affect NA concentration. The metabolite MHPG also increased, but in a more prolonged time course. The antagonist alpha-helical CRF attenuated the CRF effects. The increase of extraneuronal NA concentration monitored in the cortical samples indicates an augmented depolarization rate of noradrenergic LC neurons. This clearly demonstrates the activation of these neurons by CRF, suggesting physiological interactions of CRF and noradrenergic neurons.

Noradrenergic response to acute ethanol administration in heathly subjects: comparison with intravenous yohimbine

The effects of oral administration of ethanol [1.1 ml/kg 95% ethanol administered as a 20% (by volume) solution] and intravenous administration of the alpha 2 adrenergic receptor antagonist yohimbine hydrochloride (0.4 mg/kg), alone and in combination, were compared using a double-blind, placebo-controlled design. Twelve healthy subjects completed 4 test days during which drug effects on subjective measures of intoxication and anxiety, plasma levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and cortisol, and cardiovascular indices were assessed. Acutely administered oral ethanol significantly increased the subjective measures of intoxication and anxiety, plasma MHPG, and sitting systolic blood pressure compared with placebo. Intravenous yohimbine significantly increased subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and blood pressure relative to placebo. The ethanol-induced increase in plasma MHPG was significantly greater than that following yohimbine, whereas yohimbine resulted in significantly greater increases in anxiety, plasma cortisol, and blood pressure measurements than ethanol. The combined administration of ethanol and yohimbine had a clear additive effect of increasing the severity of acute intoxication compared with ethanol or yohimbine alone, and resulted in a significantly greater plasma MHPG response compared with either drug given alone. Although the pharmacokinetic effects of ethanol administration on NE metabolism must be considered, these findings suggest that the intoxicating and anxiogenic effects of acute ethanol administration may be associated with increased NE turnover, as measured by plasma MHPG, in healthy human subjects. In addition, these results indicate that ethanol and yohimbine may act additively to increase ethanol intoxication and that they may increase NE turnover through different physiological mechanisms.

Cerebrospinal Fluid Levels of Monoamine Metabolites

The cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the dopamine metabolite homovanillic acid (HVA) were measured in a group of drug-free non-depressed women with premenstrual syndrome (PMS) (late luteal phase dysphoric disorder) (n = 13) and in controls with no premenstrual complaints (n = 13). In six patients and eight controls, CSF samples from both the luteal and the follicular phase were obtained, whereas in the remainder of the subjects, samples from either the follicular phase (patients: 4, controls: 2) or the luteal phase (patients: 3, controls: 3) were taken. The following observations were made: (1) Neither in the follicular phase nor in the luteal phase did the mean concentrations of CSF monoamine metabolites in the PMS group differ from the corresponding values in the control group. (2) Neither in the PMS group nor in the control group did the mean concentrations of monoamine metabolites in CSF samples obtained in the luteal phase differ from the corresponding values obtained in the follicular phase. (3) The intraindividual, intersample variations of CSF HVA and 5-HIAA concentrations were significantly smaller in the PMS group than in the control group. (4) CSF HVA correlated strongly to CSF 5-HIAA in the luteal phase of both patients and controls whereas in the follicular phase, particularly in controls, this correlation was much weaker. (5) In the luteal phase, the CSF HVA/5-HIAA ratio correlated negatively to serum levels of estradiol, progesterone, and testosterone. (6) The CSF HVA/5-HIAA ratio was significantly lower in PMS patients than in controls. (7) A positive correlation between CSF MHPG and serum luteinizing hormone was observed in the follicular phase. (8) A positive correlation between CSF HVA and serum prolactin was observed in the luteal phase. Because the study was comprised of a small number of subjects, the reported findings until replicated should be interpreted with caution.

Histaminergic neurons mediate restraint stress-induced increases in the activity of noradrenergic neurons projecting to the hypothalamus

The role of histamine in mediating restraint stress-induced increases in the activity of noradrenergic neurons projecting to the hypothalamus was evaluated in male rats. Noradrenergic neuronal activity was estimated by measuring concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in the paraventricular and medial preoptic nuclei which contain terminals of these neurons. Placement of rats within restraining tubes rapidly increased MHPG but not norepinephrine concentrations in the paraventricular and medial preoptic nuclei. Depletion of neuronal histamine by α-fluoromethylhistidine and antagonism of H 1 receptors by mepyramine attenuated, whereas blockade of H 2 receptors by zolantidine did not prevent the stress-induced increases in MHPG concentrations. Neither mepyramine nor zolantidine affected MHPG concentrations in hypothalamic regions of nonstressed rats. These results indicate that histaminergic neurons contribute to the stress-induced increase the activity of noradrenergic neurons projecting to the hypothalamus via an action at H 1 receptors.

Reduced brain 5-HT and elevated NE turnover and metabolites in bipolar affective disorder

Levels of norepinephrine (NE), serotonin (5-HT), dopamine (DA), and their major metabolites were determined in postmortem brain obtained from nine subjects with antemortem histories meeting DSM-III-R criteria for bipolar affective disorder. Compared with controls, no statistically significant differences were found in mean levels of NE, 5-HT, or DA in any brain area of bipolar subjects. NE turnover as estimated by the ratio of the major NE metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) to NE was increased in frontal (+ 107%), temporal (+ 103%), and occipital (+ 64%) cortex and thalamus (+ 83%). Significant decreases were found in the major 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA), in frontal (− 54%) and parietal cortex (− 64%), and in 5-HIAA/5-HT ratio in temporal cortex (− 55%), with a trend for decreases in both measures in caudate nucleus. In addition, levels of the major DA metabolite, homovanillic acid (HVA) were significantly decreased (− 46%) in parietal cortex and HVA/DA ratios were significantly reduced (− 66%) in occipital cortex obtained from bipolar compared to control subjects. Our data, taken together with previous findings regarding monoamines in postmortem brain of depressed and suicide subjects, suggest that decreased 5-HT metabolite levels and turnover may be common to all mood disorders. Increased cortical NE turnover, however, may be a more important component in the pathophysiological of bipolar disorder.

Simultaneous Automated Determination of Catecholamines, Serotonin, and Their Metabolites in Brain Tissue by HPLC and Electrochemical Detection

Abstract A robust procedure with minimal tissue sample pretreatment, based on reversed-phase, ion-pair high performance liquid chromatography (HPLC) combined with electrochemical detection has been developed for the automated and simultaneous determination of the biogenic amines norepinephrine (NE), epinephrine (E), dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3,4-dihydroxyacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (H I A A) in as little as 0.5 mg brain tissue. The chromatographic conditions remain stable for at least 8 weeks. In particular small amounts of samples which do not allow reexamination are routinely automatically analysed without close supervision. The sample pretreatment comprises only homogenization of the tissue samples in the HPLC eluent and centrifugation. The supernatant can be directly injected into the HPLC system without further purification. Moreover, optimal concentrations of octane sulfonic acid (230 μM) and methanol (6%; v/v) in the recirculating eluent, a reversed-phase analytical column filled with 3 μm Nucleosil 100 C18 material, constant column temperature (22 ± 1 °C) and an electrochemical detector with a dual electrode permitted baseline resolution without interference with the pharmacological dose of alpha-methyl-p-tyrosine frequently involved in catecholamine turnover studies as well as the determination of catecholamines, serotonin and their metabolites in femtomolar quantities.

The first breaths of air stimulate noradrenaline turnover in the brain of the newborn rat.

The aim of this study was to analyse the noradrenaline (NA)-turnover in the brain around birth and its significance for neonatal adaptation. NA and its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) have been measured by high-pressure liquid chromatography (HPLC) in the pons-medulla and cortex in rat foetuses and pups. The MHPG/NA ratio was used as an index of NA-turnover. Catecholamines were also determined in the adrenals for comparison. The MHPG/NA ratios were found to increase 2.7-fold in the pons-medulla and 2-fold in the cortex during the first day after birth. The surge of NA-turnover occurred after the pups had been breathing air for two hours. The increase of NA-turnover was significantly lower in the cortex of rat pups breathing a hypoxic gas mixture or when they were kept in a cooler environment. The differences were less marked in the pons-medulla. We conclude that breathing air stimulates NA-turnover in the brain of the newborn rat and this stimulatory effect is modulated by environmental factors.

INFLUENCE OF BETA-BLOCKADE ON CIRCULATING PLASMA LEVELS OF 3-METHOXY-4-HYDROXY PHENYLETHYLENE GLYCOL (MHPG) DURING EXERCISE IN MODERATE HYPERTENSION

1. The effect of exercise testing and beta-blockade on plasma norepinephrine (PNE), and secretion of its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), was assessed in 28 mild-to-moderate hypertensives before and after the administration of dilevalol, a new beta-blocker with beta 2-agonism. 2. This double blind, placebo-controlled study consisted of two successive submaximal exercise tests before and after the administration of a single oral dose of dilevalol (200 mg, 400 mg or 600 mg). Plasma norepinephrine levels were determined at rest, at 100 watts step of exercise and at maximal effort (Emax). 3. During the control test, mean PNE levels increased from 1.73 +/- 0.52 nmol/L (resting value) to 8.01 +/- 4.01 nmol/L at Emax (P less than 0.01) as MHPG levels increased from 11.18 +/- 1.33 nmol/L (rest) to 17.50 +/- 1.15 nmol/L (Emax, P less than 0.01). After dilevalol, PNE increased significantly as compared to controls (P less than 0.05), from 2.32 +/- 0.99 to 12.42 +/- 5.97 nmol/L (P less than 0.01). PNE and MHPG levels were correlated, both at rest and during exercise. PNE levels after beta-blockade were linearly related to the dose of beta-blocker administered. MHPG levels were unaltered by the administration of dilevalol, both before and after exercise. 4. The increase in MHPG that occurs during bicycle exercise is largely generated from an increase in central nervous system noradrenergic activity. While dilevalol increases the peripheral sympathetic nervous system, both at rest and during exercise (which is reflected by increases in PNE levels) the drug does not alter resting central nervous system noradrenergic activity nor amplify the increase in central noradrenergic activity that occurs during exercise.

Urinary excretion of metabolites of norepinephrine in Tourette’s syndrome

Urinary excretion of the norepinephrine metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NMR) was measured in Tourette's Syndrome (TS) patients and in control subjects matched for age and education. The 24-h excretion (expressed per gram of creatinine) of total MHPG and of free and total (free + conjugated) NME was significantly lower in TS patients than in the normal subjects.

Amniotic Fluid Catecholamine Metabolites in Maternal Smoking

The concentration of dopamine (DA), norepinephrine (NE), and its metabolites 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG) and vanillyl mandelic acid (VMA), and prostaglandins E2, and F2a in amniotic fluid were measured at labor (1-3 cm of cervical dilatation), in uncomplicated and complicated pregnancies. The amniotic fluid concentration (mean +/- SD) of MHPG in maternal smoking (S) (30.6 +/- 11.9 nmol.mg creatinine-1) and intrauterine growth retardation (IUGR) (36.7 +/- 15.2 nmol.mg creatinine-1) groups is significantly higher than in uncomplicated pregnancies (C) (22.9 +/- 8.8 nmol.mg creatinine-1), or diabetes mellitus groups (D) (26.1 +/- 10.9 nmol.mg creatinine-1) groups; VMA presents similar differences between groups S (145.8 +/- 84.4 nmol.mg creatinine-1) and IUGR (173.0 +/- 135.4 nmol.mg creatinine-1) higher than C (58.3 +/- 26.1 nmol.mg creatinine-1) and D (76.8 +/- 49.0 nmol.mg creatinine-1) groups. NE levels differ between groups in a similar way, but DA does not present significant differences between groups. Prostaglandin levels are higher in the S than in the C group. Nicotine action and/or hypoxia are proposed as a possible cause of NE, MHPG, and VMA rise in amniotic fluid of S, and IUGR versus C or D groups.

Raised plasma concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol in cirrhotic patients with or without hepatic encephalopathy.

We measured the plasma concentration of a centrally derived noradrenaline (NA) metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), in 20 cirrhotic patients (eight with (group A) and 12 without (group B) hepatic encephalopathy (HE] and in 14 age matched healthy subjects to study if the central NA metabolism would be altered in liver cirrhosis patients, particularly in those with HE. The mean (SEM) plasma MHPG concentrations in the patient groups, group A (74.9 (8.6) pmol/l) and B (54.8 (7.2) pmol/l), were significantly (p less than 0.01) greater than in the control group (22.3 (2.0) pmol/l), and that in group A was significantly (p less than 0.05) greater than in group B. The plasma concentration of MHPG observed in these study subjects (n = 34) correlated (rs = 0.77, p less than 0.01) more strongly with the ratio of plasma catecholamine precursor amino acids (tyrosine and phenylalanine) to other neutral amino acids (tryptophan, leucine, isoleucine, and valine) known to compete with catecholamine precursor amino acids for uptake into the brain than with plasma concentration of tyrosine plus phenylalanine alone (rs = 0.63, p less than 0.01). In addition, the mean plasma MHPG concentrations measured in another group of eight cirrhotic patients (group C) during HE (79.3 (10.6) pmol/l) was significantly (p less than 0.01) greater than that measured after the recovery from HE (47.2 (5.2) pmol/l). The results suggest that the central NA metabolism may be altered in patients with liver cirrhosis, particularly in those with HE, and that the derangement in the central NA metabolism may be associated not only with an increase in plasma catecholamine precursor amino acids but also with a decrease in branched chain amino acids.

Catecholamine depletion produces irrepressible saccadic eye movements in normal humans

To determine the effect of catecholamine depletion on ocular motor pathways in humans, we studied the eye movements of 3 normal subjects who received the drug metyrosine (alpha-methylparatyrosine). This drug temporarily depleted dopamine and norepinephrine, as measured by a reduction in the metabolite, 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG). Saccadic, pursuit, and vestibulo-ocular eye movements were recorded using infrared oculography with subjects both on placebo and on metyrosine. The most consistent effect observed with metyrosine was an increase in the amplitude and frequency of saccadic intrusions during fixation and pursuit. Two of the 3 subjects also had shortened time constants for the vestibulo-ocular reflex, attributable in part to the sedative effect of catecholamine depletion. The increase in saccadic intrusions implies that catecholamines modulate the activity of a subpopulation of suppressor motor neurons in the human brainstem.

Determination of urinary 3-methoxy-4-hydroxyphenylethylene glycol and its conjugates by high-performance liquid chromatography with electrochemical and ultraviolet absorbance detection.

A simple method for the determination in urine of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and its conjugated derivatives is described. After an extraction procedure similar to that described by Gaertner and Wiatr [J. Clin. Chem. Clin. Biochem., 18 (1980) 579] isocratic high-performance liquid chromatographic separation is performed. MHPG can be detected by either electrochemical or absorbance detection (278 nm). Free MHPG is determined directly, whereas MHPG sulphate and MHPG glucuronide are determined after enzymic hydrolysis. Since total MHPG, which represents the sum of these substances, is determined separately, a comparison of the results allows the effectiveness of the hydrolysis of the MHPG derivatives for each urine sample to be determined. For quantitation, the method of adding standard amounts of MHPG is used.

Increase in norepinephrine turnover after tyrosine or DL-threo-3, 4-dihydroxyphenylserine (DL-threo-DOPS)

The amino acids tyrosine and DL-threo-3, 4-dihydroxyphenylserine (DL-threo-DOPS) were compared for their effectiveness in increasing central nervous system norepinephrine (NE) turnover in both saline and DSP-4 pretreated mice. NE was decreased significantly in cortex, hippocampus and cerebellum, and only slightly in hypothalamus and brainstem two weeks after a single intraperitoneal injection of the neurotoxin DSP-4. Levels of the major NE metabolite, 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), decreased in parallel in these five brain regions. Neither administration of tyrosine (250 mg/kg, as the ethyl ester, i.p.) nor DL-threo-DOPS (200 mg/kg, i.p.) affected regional NE concentration. However, after tyrosine administration, MHPG levels increased significantly in cortex in control mice and in cortex and hippocampus of DSP-4 pretreated mice. In all five brain noradrenergic regions MHPG level increased after DL-threo-DOPS administration and this increase was enhanced (approximately doubled) in DSP-4 pretreated mice. Thus, both amino acids may be useful as precursors of central NE when its level is depleted (e.g. following administration of DSP-4); DL-threo-DOPS producing a generalized increase in brain NE turnover, while increases following tyrosine are specific to those areas in which neuronal activity is increased i.e. cortex and hippocampus.