MHPG Concentrations Research Articles

Dose-Ranging Effects of the Intracerebral Administration of Atsttrin in Experimental Model of Parkinson’s Disease Induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Mice

Parkinson’s disease is one of the most common neurodegenerative disorders characterized by a multitude of motor and non-motor clinical symptoms resulting from the progressive and long-lasting abnormal loss of nigrostriatal dopaminergic neurons. Currently, the available treatments for patients with Parkinson’s disease are limited and exert only symptomatic effects, without adequate signs of delaying or stopping the progression of the disease. Atsttrin constitutes the bioengineered protein which ultrastructure is based on the polypeptide chain frame of the progranulin (PGRN), which exerts anti-inflammatory effects through the inhibition of TNFα. The conducted preclinical studies suggest that the therapeutic implementation of Atsttrin may be potentially effective in the treatment of neurodegenerative diseases that are associated with the occurrence of neuroinflammatory processes. The aim of the proposed study was to investigate the effect of direct bilateral intracerebral administration of Atsttrin using stereotactic methods in the preclinical C57BL/6 mouse model of Parkinson’s disease inducted by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. The analysis of the dose dependency effects of the increasing doses of Atsttrin has covered a number of parameters and markers regarding neurodegenerative processes and inflammatory responses including IL-1α, TNFα, IL-6, TH, and TG2 mRNA expressions. Accordingly, the evaluation of the changes in the neurochemical profile included DA, DOPAC, 3-MT, HVA, NA, MHPG, 5-HT, and 5-HIAA concentration levels. The intracerebral administration of Atsttrin into the striatum effectively attenuated the neuroinflammatory reaction in evaluated neuroanatomical structures. Furthermore, the partial restoration of monoamine content and its metabolic turnover were observed. In this case, taking into account the previously described pharmacokinetic profile and extrapolated bioavailability as well as the stability characteristics of Atsttrin, an attempt was made to describe as precisely as possible the quantitative and qualitative effects of increasing doses of the compound within the brain tissue microenvironment in the presented preclinical model of the disease. Collectively, this findings demonstrated that the intracerebral administration of Atsttrin may represent a potential novel therapeutic method for the treatment of Parkinson’s disease.

Relationship between norepinephrine metabolism and plasma markers of tau pathology

AbstractBackgroundThe brainstem locus coeruleus (LC) constitutes the primary source of norepinephrine (NE) in the central nervous system and has been reported as one of the earliest accumulation sites of hyperphosphorylated tau protein in Alzheimer’s disease (AD). Autopsy and animal studies suggested that this aggregation of hyperphosphorylated tau in the LC is associated with hyperactivity in LC neurons and elevated concentrations of NE metabolites. Here, we investigated whether elevated concentrations of 3‐methoxy‐4‐hydrophenylglycol (MHPG), a NE metabolite measured in the plasma, is associated with plasma phosphorylated tau, a biomarker of AD pathology.MethodNinety‐eight cognitively unimpaired participants (age = 59.82 ± 13.13 [30‐84] y, 52 females, Table 1) underwent a blood draw. Plasma MHPG concentrations were measured and adjusted for NE. Levels of total tau, phosphorylated tau at threonine 181 (pTau181) and threonine 231 (pTau231) were quantified by single molecule array (Simoa), while phosphorylated tau at threonine 217 (pTau217) was quantified by the Meso Scale Discovery (MSD) platform. Multiple linear regression models tested for the relationship between MHPG concentrations and plasma levels of tau‐related measures, while controlling for age and sex.ResultPTau231 and MHPG concentrations were positively correlated (t = 2.26, p = .03, Figure 1). No significant relationships were found between MHPG and other phosphorylated tau biomarkers (all p > .23), but we observed a trend for a positive association with plasma total tau levels (t = 1.88, p = .06).ConclusionConsistent with previous CSF studies as well as animal studies, we found that elevated NE metabolism co‐occurs with the earliest events in the phosphorylation cascade of tau proteins, suggesting an important role of a dysregulated NE system early in the AD pathophysiologic cascade. Future work will need to determine the evolution of theses associations as the disease progresses, potential effect modifications by beta‐amyloid and the downstream effects of these processes on cognition and behavior.

Oral Administration of L-Citrulline Changes Brain Free Amino Acid and Monoamine Metabolism in Heat-Exposed Broiler Chickens

High ambient temperatures (HT) in summer are becoming more severe due to global warming, leading to severe adverse effects on poultry production. Recently, we have reported that oral administration of L-citrulline (L-Cit) can minimize hyperthermia in chickens under HT. However, whether oral L-Cit can enter the brain, the center for thermoregulation, has not been studied. We investigated the effects of oral administration of L-Cit on free amino acids and monoamines in the diencephalon region of the brain of heat-exposed broilers. Broilers were treated with L-Cit (40 mmol/20 ml/bird), then moved to a chamber at HT (30 ± 1°C) or to a thermoneutral temperature (CT: 22 ± 1°C) chamber for 2 h. Control groups were given methyl cellulose solution and placed in the CT or HT chambers. After 2 h of exposure to HT, there were increased brain concentrations of Cit in comparison with concentrations in broilers exposed to CT, whereas brain ornithine (Orn) concentrations were decreased, and arginine (Arg) concentrations were not changed. Interestingly, oral administration of L-Cit increased brain concentration of Cit, Arg, and Orn under both CT and HT. Tryptophan and its metabolite, serotonin (5-HT) concentrations were lower in the brain under HT than under CT. HT did not change brain concentrations of tyrosine, but dopamine (DA, a metabolite of tyrosine) concentrations decreased, and methoxyhydroxyphenylglycol (MHPG, a metabolite of DA) concentrations increased in comparison with CT. Oral administration of L-Cit decreased brain concentrations of both tryptophan and tyrosine under CT and HT without changing 5-HT; however, DA levels declined under HT. Moreover, MHPG concentrations increased. In conclusion, these results suggest that metabolism of amino acids and metabolism of DA can be enhanced in the brain by oral administration of L-Cit. Metabolic changes in the brain in response to oral administration of L-Cit may influence the thermoregulatory center in the brain, leading to a reduction in body temperature and conferring thermotolerance in heat-exposed broiler chickens.

5-HT7 receptors in Alzheimer's disease

Even though the involvement of serotonin (5-hydroxytryptamine; 5-HT) and its receptors in Alzheimer's disease (AD) is widely accepted, data on the expression and the role of 5-HT7 receptors in AD is relatively limited. Therefore, the objective of the present work was to study the expression of serotonergic 5-HT7 receptors in postmortem samples of AD brains and correlate it with neurotransmitter levels, cognition and behavior. The study population consisted of clinically well-characterized and neuropathologically confirmed AD patients (n = 42) and age-matched control subjects (n = 18). Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and high-performance liquid chromatography were performed on Brodmann area (BA) 7, BA10, BA22, BA24, hippocampus, amygdala, thalamus and cerebellum to measure mRNA levels of 5-HT7 receptors (HTR7), as well as the concentrations of various monoamine neurotransmitters and their metabolites.Decreased levels of HTR7 mRNA were observed in BA10. A significant association was observed between HTR7 levels in BA10 and BEHAVE-AD cluster B (hallucinations) (rs(28) = 0.444, P < 0.05). In addition, a negative correlation was observed between HTR7 levels in BA10 and both MHPG concentrations in this brain region (rs(45) = -0.311; P < 0.05), and DOPAC levels in the amygdala (rs(42) = -0.311; P < 0.05). Quite surprisingly, no association was found between HTR7 levels and cognitive status. Altogether, this study supports the notion of the involvement of 5-HT7 receptors in psychotic symptoms in AD, suggesting the interest of testing antagonist acting at this receptor to specifically treat psychotic symptoms in this illness.

No major influence of regular tobacco smoking on cerebrospinal fluid monoamine metabolite concentrations in patients with psychotic disorder and healthy individuals

Metabolism of the monoamines dopamine, serotonin and noradrenaline, is altered in the central nervous system of people with schizophrenia, and their major metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively, have been intensively studied as indirect measures of these neurotransmitters in cerebrospinal fluid (CSF). Regular tobacco smoking has been shown to alter neurotransmitter metabolism in the brain and studies have found CSF monoamine metabolite concentrations to be substantially lower in smokers. However, few studies investigating these monoamines in CSF have controlled for regular tobacco smoking. We investigated if regular tobacco smoking influences CSF HVA, 5-HIAA and MHPG concentrations in patients treated for psychotic disorders (n = 69) and healthy non-psychotic human volunteers (n = 200). After lumbar puncture CSF samples were analyzed with mass fragmentography. CSF HVA, 5-HIAA and MHPG concentrations did not significantly differ between smokers and non-smokers neither in patients, nor in healthy subjects, whereas back-length predicted HVA and 5-HIAA and antipsychotic medication MHPG concentrations. The results indicate that regular tobacco smoking has no significant effect on monoamine metabolite concentrations in CSF. This suggests that lack of controlling for regular tobacco smoking should not substantially violate the results in studies of the major monoamine metabolites in CSF.

BIOLOGICAL FLUID MONOAMINE LEVELS TO EXPLORE THE NEUROCHEMICAL CONTINUUM BETWEEN FRONTOTEMPORAL DEMENTIA AND AMYOTROPHIC LATERAL SCLEROSIS

Behavioral variant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are early-onset debilitating diseases with genetic and clinicopathological commonalities, and are hypothesized to be part of a disease continuum alongside FTD-ALS. Although serotonergic and dopaminergic disturbances were recently identified in brain and spinal cord of ALS patients, information about neurochemical status of these disorders in body fluids remains scarce. Furthermore, few studies have compared neurochemical parameters directly between FTD and ALS. No FDA-approved disease-modifying drug therapies are available for FTD, nor ALS, with the sole exception of riluzole. An unmet medical need thus exists for both conditions, necessitating the identification of new pharmacological targets or the establishment of biomarkers for early disease detection. We retrospectively analyzed paired cerebrospinal fluid (CSF) – serum samples from 40 FTD, 26 ALS, 4 FTD-ALS and 40 age-matched control subjects using reversed-phase ultra-high-performance liquid chromatography with electrochemical detection. Levels of serotonergic, dopaminergic and (nor) adrenergic compounds were measured for all samples. Statistically significant differences in monoamine concentrations were predominantly present between FTD and age-matched control subjects, with significantly increased CSF (P<0.001) and serum (P<0.001) dopamine (DA) concentrations in FTD subjects. In contrast, levels of 3,4-dihydroxyphenylacetic acid (DOPAC) (P=0.008 for CSF; P=0.003 for serum) and DOPAC/DA ratios (P<0.001 for CSF; P<0.001 for serum), indicative for dopaminergic turnover, were lowered in latter patients. A similar pattern was observed between the ALS and age-matched control group, despite insignificant differences for DOPAC/DA ratios and DOPAC levels in CSF and serum, respectively. Concerning the (nor)adrenergic system, a significant increase in CSF MHPG concentrations was identified in FTD compared to age-matched control subjects (P=0.006). No dissimilarities could be detected in any of the monoaminergic compounds between FTD and ALS patients. Given the dopaminergic differences in CSF and serum samples in the age-matched control group compared to FTD and ALS groups, we hypothesize that both may be characterized by a dopaminergic disturbance. Furthermore, since no monoaminergic differences could be identified between patients, such neurodegenerative disorders do not only seem to belong to a genetic and clinicopathological continuum, but are likely to share a similar neurochemical pathophysiology as well.

Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia

Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the <smlcap>L</smlcap>-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.

Simultaneous measurement of monoamine metabolites and 5-methyltetrahydrofolate in the cerebrospinal fluid of children

BackgroundWe describe a new method for simultaneous measurement of monoamine metabolites (3-O-methyldopa [3-OMD], 3-methoxy-4-hydroxyphenylethyleneglycol [MHPG], 5-hydroxyindoleacetic acid [5-HIAA], and homovanillic acid [HVA]) and 5-methyltetrahydrofolate (5-MTHF) and its use on cerebrospinal fluid (CSF) samples from pediatric patients. MethodsMonoamine metabolites and 5-MTHF were measured by high-performance liquid chromatography with fluorescence detection. CSF samples were prospectively collected from children according to a standardized collection protocol in which the first 1-ml fraction was used for analysis. ResultsMonoamine metabolites and 5-MTHF were separated within 10min. They showed linearity from the limit of detection to 1024nmol/l. The limit of quantification of each metabolite was sufficiently low for the CSF sample assay. In 42 CSF samples after excluding cases with possibly altered neurotransmitter profiles, the concentrations of 3-OMD, MHPG, 5-HIAA, HVA, and 5-MTHF showed significant age dependence and their ranges were comparable with the reference values in the literature. The metabolite profiles of aromatic l-amino acid decarboxylase deficiency, Segawa disease, and folate receptor α defect by this method were compatible with those in the literature. ConclusionsThis method is a simple means of measuring CSF monoamine metabolites and 5-MTHF, and is especially useful for laboratories not equipped with electrochemical detectors.

COMT haplotypes, catecholamine metabolites in plasma and clinical response in schizophrenic and bipolar patients.

We examined the association of COMT haplotypes and plasma metabolites of catecholamines in relation to the clinical response to antipsychotics in schizophrenic and bipolar patients. We studied 165 patients before and after four weeks of treatment, and 163 healthy controls. We assessed four COMT haplotypes and the plasma concentrations of HVA, DOPAC and MHPG. Bipolar patients: haplotypes are associated with age at onset and clinical evolution. In schizophrenic patients, an haplotype previously associated with increased risk, is related to better response of negative symptoms. Haplotypes would be good indicators of the clinical status and the treatment response in bipolar and schizophrenic patients. Larger studies are required to elucidate the clinical usefulness of these findings.

Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis

Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.

Monoamine metabolites in ventricular CSF of children with posterior fossa tumors: correlation with tumor histology and cognitive functioning

The biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin) are involved in the regulation of multiple neuronal functions, and changes in monoamine concentrations in the CSF have been detected in several disorders. The aim of the present study was to investigate the role of biogenic amines in the ventricular CSF of children suffering from posterior fossa tumors and their possible correlation with tumor histology and cognitive functioning. Twenty-two children with posterior fossa tumors who were treated surgically at Children's Hospital "Agia Sofia" were studied. Patients ranged in age from 5.5 to 15 years. The study population included patients who suffered from hydrocephalus and were treated by ventriculoperitoneal shunt placement. During the operation for shunt placement, a CSF sample was obtained for the assessment of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Simultaneously, a blood sample was also obtained for assessment of the same metabolites in the serum. The concentration of vanillylmandelic acid (VMA) was evaluated in 24-hour urine samples in 11 patients. Cerebrospinal fluid from a control group of children was also studied. Executive functions were assessed using the short form of the Wechsler Intelligence Scale for Children (WISC). Twelve patients suffered from astrocytomas, 9 from medulloblastomas, and 1 from an ependymoma. The MHPG concentration in CSF was significantly higher in patients with astrocytomas compared with patients with medulloblastomas. Twenty-four-hour urine samples of VMA were significantly higher in patients with astrocytomas compared with patients with medulloblastomas. The MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC and there was a trend toward a significant negative correlation with the total WISC score. Homovanillic acid in CSF was positively correlated with the performance scale of the WISC. There was a significant correlation between HVA and MHPG levels in CSF. The CSF concentration of 5-HIAA was significantly correlated with the HVA concentration in serum. Twenty-four-hour urine VMA samples were statistically significantly correlated with HVA concentration in both CSF and serum, with MHPG in CSF, and with 5-HIAA in serum. This study showed that children with posterior fossa tumors have differences in the levels of monoamine metabolites in CSF. Further studies with a larger number of patients are obviously needed to verify these observations as well as studies to correlate the monoamine metabolite levels with the neuropsychological and behavioral findings in children with posterior fossa tumors.

Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis.

BackgroundHomovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis.MethodsWe have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder.ResultsThere were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls.ConclusionsThe present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.

Addition of MHPG to Alzheimer's disease biomarkers improves differentiation of dementia with Lewy bodies from Alzheimer's disease but not other dementias

BackgroundOverlapping clinical features make it difficult to distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and other dementia types. In this study we aimed to determine whether the combination of cerebrospinal fluid (CSF) biomarkers, amyloid-β42 (Aβ42), total tau protein (t-tau), and phosphorylated tau protein (p-tau), in combination with 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), could be useful in discriminating DLB from vascular dementia (VaD) and frontotemporal dementia (FTD), as we previously demonstrated for differentiation of DLB from AD. MethodsWe retrospectively analyzed concentrations of MHPG, Aβ42, t-tau, and p-tau in CSF in patients with DLB, AD, VaD, and FTD. Using previously developed multivariate logistic regression models we assessed the diagnostic value of these CSF parameters. ResultsThe currently used combination of Aβ42, t-tau, and p-tau yielded a sensitivity of 61.9% and a specificity of 91.7% for the discrimination between DLB and AD, but could not discriminate between DLB and VaD or FTD. The addition of MHPG to Aβ42, t-tau, and p-tau improves the discrimination of DLB from AD, yielding a sensitivity of 65.1% and specificity of 100%, but could not distinguish DLB from other forms of dementia. ConclusionsOur results confirm in a separate patient cohort that addition of MHPG to Aβ42, t-tau, and p-tau improves the discrimination of DLB from AD but not the differentiation of DLB from VaD or FTD.

Event-Related Potentials and Plasma Levels of Monoamine Metabolites in Normal Subjects

We examined the relationships between the ERP measurements and concentrations of plasma monoamine metabolites in 20 healthy volunteers. Event-related potentials were recorded within the framework of two auditory paradigms, a standard oddball task and a novelty oddball task. The plasma concentrations of homovanillic acid (HVA, a metabolite of dopamine) and 3-methoxy-4-hydroxyphenylglycol (MHPG, a metabolite of noradrenaline) were analyzed. Some of the N100 measurements correlated with the MHPG concentration and the severity of anxiety. No significant correlations were found between the P300 measurements and concentrations of monoamine metabolites. The P300 latency and plasma HVA concentration were associated with the psychoticism estimate of EPQ. These findings indicate that modulation of the N100 component might be associated with the activity of the noradrenergic system, and that P300 latency and the HVA concentration might be associated with a tendency toward psychosis.

Influence of saliva flow rate stimulated by gum-chewing on salivary concentrations of catecholamine metabolites

BackgroundThe measurement of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) in saliva is useful for diagnosis of some psychiatric disorders. Gum-chewing increases salivation and is sometimes used to collect an adequate sample volume of saliva within a shorter time. However, the rate of saliva production may affect the salivary concentrations of these catecholamine metabolites. We clarified whether the salivary concentrations of HVA and MHPG are dependent on the rate of salivation. MethodsStimulated saliva was collected from healthy volunteers chewing a tasteless and flavorless chewing gum after unstimulated saliva was collected without gum-chewing. The salivary HVA and MHPG concentrations were measured using newly developed LC/ESI-MS/MS methods. ResultsThe salivary HVA and MHPG concentrations were reproducibly measured when saliva was collected without gum-chewing (unstimulated saliva). In contrast, their salivary concentrations significantly decreased when salivation was stimulated by gum-chewing (p<0.05, Wilcoxon signed-rank test). ConclusionsStimulated saliva by gum-chewing should be used with caution in the measurement of the catecholamine metabolites. LogD is a useful indicator, when predicting whether the salivary concentration of a compound is dependent on the rate of salivation.

The effect of oral presentation on salivary 3-methoxy-4-hydroxy-phenylglycol (MHPG) and cortisol concentrations in training doctors: a preliminary study

Exposure to a stress task activates the sympathetic nervous system. Salivary 3-methoxy-4-hydroxy-phenylglycol (MHPG; the major metabolite of norepinephrine) concentrations closely reflect the plasma MHPG levels and are used as indices of noradrenergic activity. On the contrary, exposure to a stress task also activates the hypothalamic– pituitary–adrenal (HPA) axis resulting in the secretion of cortisol from the adrenal cortex. The level of salivary cortisol elevates in response to a stress task including oral presentations. We examined concentrations of salivary MHPG (sMHPG) and cortisol levels in a sample of doctors in training (6 males: mean age = 29.6 ± 3.0 years; 6 females: 26.8 ± 0.2 years) exposed to oral presentations. All the participants gave written informed consent, and this study was approved by the ethic committee of the Faculty of Medicine, Saga University. Each subject gave an oral presentation in a training course. In brief, each participant gave an oral presentation about the same theme: ‘‘How to treat patients who suffered from diabetes mellitus’’ to the audience who were invited. All the presentations were started in the afternoon at 2 p.m. and lasted for 1 h. After the presentation, the performance of each trainee was evaluated by the audience. Salivary sample was collected three times (just before the beginning of the presentation, immediately, and at 10 min after the presentation) for each participant. The concentration of sMHPG was measured by the gas chromatography-mass spectrometry. Salivary cortisol was measured using a commercially available enzyme immunoassay kit [1, 2]. The mean concentration of sMHPG did not change in both male (pre, 11.7 ± 2.1; post, 12.2 ± 1.3; 10 min, 11.7 ± 2.0 in ng/mL) and female (pre, 10.8 ± 1.7; post, 10.7 ± 2.1; 10 min, 10.5 ± 2.0) participants after the oral presentation. In contrast, the mean concentration of salivary cortisol was significantly increased in males (pre, 0.16 ± 0.03; post, 0.43 ± 0.09; 10 min, 0.31 ± 0.06 in lg/dL) but not in females (pre, 0.21 ± 0.05; post, 0.29 ± 0.07; 10 min, 0.24 ± 0.07) immediately and at 10 min after the oral presentation. Two-way analysis of variance with repeated measures revealed that the cortisol 9 sex interaction was significant (F = 5.64, P = 0.039). Male subjects are reported to show greater cortisol responses compared with females in response to public speaking. In contrast, female subjects show greater increase in cortisol levels in response to social rejection challenges [3]. Situations involving interpersonal concerns are perceived as more stressful for females, while the intellectual inferiority or failures of performance are perceived as more stressful for males. Our study supports recent findings suggesting that oral presentations might be more stressful for males. There are few reports on how stress tasks affect sMHPG and cortisol concentrations in a same population. Challenging behavioral tasks including simulated public speaking elevate sMHPG but not cortisol concentrations in volunteers who were injected with typhoid vaccine [4]. This suggests that a psychological stress could affect sMHPG but not cortisol concentrations. Our preliminary report suggests that a psychological stress could affect salivary cortisol but not MHPG concentrations. Y. Mizoguchi (&) A. Sakami Y. Imamura T. Tsuruta M. Egami S. Yamada Department of Neuropsychiatry, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: ymizo@pk2.so-net.ne.jp

The interface between inhibition of descending noradrenergic pain control pathways and negative affects in post-traumatic pain patients

Background. Animal studies have shown that surgical trauma activates the descending noradrenergic pathway. However, perioperative patients have decreased concentrations of noradrenaline (NA) in the cerebrospinal fluid (CSF). We proposed that the descending monoaminergic pathway is altered in post-traumatic pain patients and that CSF monoamine neurotransmitters may be more closely related to affective symptoms. We investigated the levels of monoamine neurotransmitters and assessed pain in these patients.Methods. Patients were divided into a post-traumatic pain group, a pain-free group, a painful labor group, and a pain-free labor group. CSF was collected from all patients, and concentrations of NA, 3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine, homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA) were measured by high-performance liquid chromatography.Results. In the post-traumatic pain group, lumbar CSF concentrations of NA and MHPG were significantly decreased (P < 0.01) compared to the control group. The post-traumatic pain group displayed a significant negative correlation between NA and the respective total value of the short form of the McGill pain questionnaire (SF-MPQ), SF-MPQ (affective), and visual analog scale (r = –0.388, r = –0.433, and r = –0.367; P < 0.05).Conclusions. Post-traumatic pain patients demonstrated decreased concentrations of NAin CSF, indicating that descending noradrenergic pain control pathways may be inhibited. NA is more closely related to negative affects in post-traumatic pain patients.

Sympathetic nervous activity, depressive symptoms, and metabolic syndrome in black Africans: The sympathetic activity and ambulatory blood pressure in Africans study

The aim of this study was to examine the association between sympathetic nervous activity, depressive symptoms, and metabolic syndrome in a sample of black and Caucasian Africans. The sample consisted of healthy men and women: 194 blacks (aged, mean ± SD, 44.1 ± 7.9 years) and 206 Caucasians (aged, mean ± SD, 44.7 ± 10.8 years). Salivary 3-methoxy-phenylglycol (MHPG) concentration, the major metabolite of norepinephrine, was measured during the Stroop mental challenge. Depressive symptoms were assessed from the 9-item Patient Health Questionnaire. Metabolic syndrome (defined as central obesity plus any other two risk factors including raised serum triglycerides, reduced serum high-density lipoprotein- cholesterol, raised blood pressure, and raised fasting plasma glucose) was prevalent in 43.0% and 36.4% of blacks and Caucasians, respectively. In blacks there was, on average, a 16.4% increase in salivary MHPG concentration following mental stress, although no significant response was observed in Caucasians. The salivary MHPG response in blacks was associated with risk of metabolic syndrome (odds ratio [OR] = 1.11, 95% CI, 1.00–1.24) after adjusting for age, sex, and baseline salivary MHPG concentration. This association was mainly driven by the central obesity component of the metabolic syndrome. The salivary MHPG response was also related to moderate-severe depressive symptoms (OR = 1.16, 95% CI, 1.04–1.30), and further adjustment for depressive symptoms attenuated the association between salivary MHPG response and metabolic syndrome (OR = 1.07, 95% CI, 0.96–1.20). These data indicate an association between sympathetic activity, depressive symptoms, and metabolic syndrome in a sample of black Africans.

Quetiapine and Norquetiapine in Plasma and Cerebrospinal Fluid of Schizophrenic Patients Treated With Quetiapine

This study investigated concentrations of quetiapine and norquetiapine in plasma and cerebrospinal fluid (CSF) in 22 schizophrenic patients after 4-week treatment with quetiapine (600 mg/d), which was preceded by a 3-week washout period. Blood and CSF samples were obtained on days 1 and 28, and CSF levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were measured at baseline and after 4 weeks of quetiapine, allowing calculations of differences in HVA (ΔHVA), 5-HIAA (Δ5-HIAA), and MHPG (ΔMHPG) concentrations. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Scale at baseline and then at weekly intervals. Plasma levels of quetiapine and norquetiapine were 1110 ± 608 and 444 ± 226 ng/mL, and the corresponding CSF levels were 29 ± 18 and 5 ± 2 ng/mL, respectively. After the treatment, the levels of HVA, 5-HIAA, and MHPG were increased by 33%, 35%, and 33%, respectively (P < 0.001). A negative correlation was found between the decrease in PANSS positive subscale scores and CSF ΔHVA (r(rho) = -0.690, P < 0.01), and the decrease in PANSS negative subscale scores both with CSF Δ5-HIAA (r(rho) = -0.619, P = 0.02) and ΔMHPG (r(rho) = -0.484, P = 0.038). Because, unfortunately, schizophrenic patients experience relapses even with the best available treatments, monitoring of CSF drug and metabolite levels might prove to be useful in tailoring individually adjusted treatments.

Effects of cognitive-behavioral therapy on Eating Disorders: Neurotransmitter secretory response to treatment

The effects of cognitive-behavioral therapy (CBT) on central dopamine (DA), noradrenaline (NE) and serotonin (5-HT) secretion were studied in a group of 50 female inpatients, of which 14 suffered from anorexia nervosa restricted type (AN-R), 14 from anorexia nervosa bingeing-purging type (AN-BP), and 22 from bulimia nervosa (BN). The aim of the study was to see whether or not CBT modifies the secretion of central DA (blood homovanillic acid=HVA), NE (blood 3-methoxy-4-hydroxy-phenylglycol=MHPG) and the 5-HT transporter (as evaluated by the platelet paroxetine binding=[(3)H]-Par-binding), if the physical and psychological effects of CBT correlate with changes of the neurotransmitter secretion; and if the biological effects of CBT are linked to specific psychopathological aspect of the disorders. The treatment lasted 20 weeks. Body-mass Index, bingeing and purging, specific AN-BN psychopathological (EDE 12-OD), depression (Beck Inventory), anxiety (STAY Form-Y-1), impulsiveness (Barratt Impulsiveness Scale), self-esteem (Rosenberg Self-Biochemical Scale) and temperament (Temperament and Character Inventory, Cloninger Scale) were assessed at baseline and at the end of the treatment. CBT significantly improved the psychophysical aspects of the diseases. HVA and MHPG concentrations did not change. The [(3)H]-Par-binding parameters, the maximum binding capacity (B(max)) and dissociation constant (K(d)) values did not change in either AN-R or AN-BP patients, while the [(3)H]-Par B(max) (and not the K(d)) increased significantly in BN patients. Correlations emerged between basal and final [(3)H]-Par B(max) values and psychopathological scores, but not between CBT-induced differences between basal and final values. Our data suggest that only in BN CBT may act through changes in 5-HT system function.