Metabolite 3-methoxy-4-hydroxyphenylglycol Research Articles

The comparison of sex differences in depression-like behaviors and neuroinflammatory changes in a rat model of depression induced by chronic stress.

Clinical prevalence of major depression is higher in women than men, while the psychoneuroimmunological mechanisms underlying the differences between the two sexes are not fully understood. The present study explored sex differences in the behaviors and depressive pathological mechanisms induced by chronic unpredictable mild stress (CUMS). Depression- and anxiety-like behaviors were assessed by the sucrose preference test (SPT), force swimming test (FST), open field test (OFT), and elevated plus-maze (EPM). The enzyme-linked immunosorbent assay (ELISA) was used to measure cytokine concentrations, high-performance liquid chromatography (HPLC) was used to measure monoamine neurotransmitters and metabolite contents, and real-time quantitative PCR (qPCR) and western blotting (WB) were used to measure glial parameters in the hippocampus. Under control conditions, female rats exhibited shorter immobility times in the FST, lower interferon (IFN)-γ, and interleukin (IL)-4 levels in the hippocampus, lower norepinephrine (NE) and homovanillic acid (HVA), and higher p75 and glial-derived neurotrophic factor (GDNF) expression than male rats. CUMS markedly reduced rat body weight gain, sucrose preference, locomotor activity, number of entries into the central zone and rearing in the OFT, as well as the number of entries into and time spent in open arms of the EPM; however, CUMS increased the immobility times of the rats of both sexes in the FST. Interestingly, more pronounced changes in sucrose preference and locomotor activity were observed in female rats than in males. Consistently, CUMS-increased glucocorticoid concentration, M1 microglial marker CD11b, and peripheral IL-1β and IL-4, while decreased hippocampal IL-10, serotonin (5-HT), dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were more significant in females than in males. These data revealed possible mechanisms by which females suffer more depression than males at least in a stressful environment.

Dysfunction of norepinephrine and its metabolites in Alzheimer's dementia - A review with meta-analysis.

Some studies point locus coeruleus cell loss, the central nervous system main source of norepinephrine, to be one of the earliest neuropathological events of Alzheimer's disease (AD). However, there are conflicting reports regarding the level of norepinephrine and its metabolites (3-Methoxy-4-hydroxyphenylglycol (MHPG), 3,5-dihydroxyphenylglycine (DHPG) and 3,4 -dihydroxyphenylglycolaldehyde (DOPEGAL)) in AD patients. Uncover these alterations may be a key factor for understanding cognitive deficits and AD pathology. We review the literature that compare norepinephrine and its metabolites between AD patients and non-demented controls. A meta-analysis did not reveal significant statistical differences, but there was a trend towards a lower level of norepinephrine of AD, with almost no difference in MHPG in the cerebrospinal fluid. Regarding MHPG in plasma, DHPG and DOPEGAL we only performed a qualitative analyse due to the small or absent number of studies. These findings point to a decrease in norepinephrine, what is in line with locus coeluleus cell loss in AD. The absence of statistical difference and an equal level of MHGP could indicate a compensatory mechanism.

CSF and PET biomarkers for noradrenergic dysfunction in neurodegenerative disease: A systematic review and meta‐analysis

AbstractBackgroundAlterations to the noradrenergic system may occur in the early stages of Alzheimer’s disease (AD) and Parkinson’s disease (PD) and could contribute to clinical symptoms. The aim of this study was to conduct a meta‐analysis of noradrenergic differences in AD and PD assessed using cerebrospinal fluid (CSF) and positron emission tomography (PET) measuresMethodCSF noradrenaline (NA) and its metabolite 3‐Methoxy‐4‐hydroxyphenylglycol (MHPG) as well as NA transporter availability (PET MeNER) levels in controls, AD and PD patients were pooled across studies. Differences between controls and patients were calculated with Hedge’s g and combined using a random‐effects model meta‐analysis. A random‐effect meta‐regression was conducted using the volume of the CSF samples, the sample sizes, the years post diagnosis, the severity of the diseases as covariates using laboratory analysis technique as a between‐study factor.ResultTwenty‐seven studies met the inclusion criteria. Seven studies with extreme effect sizes influencing between‐study heterogeneity were identified as outliers and subsequently removed from further analyses. In PD patients, significant reductions in CSF NA (n= 132, g= ‐0.26, p=0.01) and MHPG (n=257, g = ‐0.27, p<0.01), in addition to reduced PET MeNER binding in the hypothalamus (n=29, g = ‐0.87, p<0.05), were observed compared with control subjects (n=166 for NA, n=227 for MHPG respectively). In AD patients, no significant difference in CSF NA levels (n=194, g= ‐0.06, p= 0.78) and only a trend for increased MHPG levels (n=208, g= 0.24, p= 0.07) were observed compared with controls (n=196 for NA, n=218 for MHPG respectively), see Figure 1. The number of articles addressing PET MeNER in AD was not sufficient to conduct a meta‐analysis. The hypothesized explanatory variables, namely the volume of CSF samples, the sample size, the years post diagnosis and the severity of the disease, were not significant (p>0.05) in any of the investigated groups.ConclusionOur results indicate that noradrenergic dysfunction in neurodegenerative diseases can be detected using CSF or PET measures and may be more pronounced in PD compared to AD. Further studies using longitudinal CSF and PET measures are required to elucidate the relationship between noradrenergic dysfunction and the progression of neurodegenerative diseases.

Juvenile social defeat stress exposure favors in later onset of irritable bowel syndrome-like symptoms in male mice

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. Traumatic stress during adolescence increases the risk of IBS in adults. The aim of this study was to characterize the juvenile social defeat stress (SDS)-associated IBS model in mice. Juvenile mice were exposed to an aggressor mouse for 10 min once daily for 10 consecutive days. Behavioral tests, visceral sensitivity, immune responses, and fecal bacteria in the colon were evaluated in 5 weeks after SDS exposure. Social avoidance, anxiety- and depression-like behavior, and visceral hypersensitivity were observed. Juvenile SDS exposure significantly increased the number of 5-HT-containing cells and calcitonin gene-related peptide-positive neurons in the colon. The gut microbiota was largely similar between the control and juvenile SDS groups. The alterations in fecal pellet output, bead expulsion time, plasma corticosterone concentration, and colonic 5-HT content in response to restraint stress were exacerbated in the juvenile SDS group compared with the control group. The combination of juvenile SDS and restraint stress increased the noradrenaline metabolite 3-Methoxy-4-hydroxyphenylglycol (MHPG) content and MHPG/noradrenaline ratio in the amygdala when compared with restraint stress in control mice. These results suggest that juvenile SDS exposure results in later onset of IBS-like symptoms.

Early Rearing Conditions Affect Monoamine Metabolite Levels During Baseline and Periods of Social Separation Stress: A Non-human Primate Model (Macaca mulatta).

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the “experience-expectant brain,” with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study, N = 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR; n = 269) or without adults with 24-h access to same-aged peers (PR; n = 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with the s allele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for the L allele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype.

A Convenient Method for Extraction and Analysis with High-Pressure Liquid Chromatography of Catecholamine Neurotransmitters and Their Metabolites.

The extraction and analysis of catecholamine neurotransmitters in biological fluids is of great importance in assessing nervous system function and related diseases, but their precise measurement is still a challenge. Many protocols have been described for neurotransmitter measurement by a variety of instruments, including high-pressure liquid chromatography (HPLC). However, there are shortcomings, such as complicated operation or hard-to-detect multiple targets, which cannot be avoided, and presently, the dominant analysis technique is still HPLC coupled with sensitive electrochemical or fluorimetric detection, due to its high sensitivity and good selectivity. Here, a detailed protocol is described for the pretreatment and detection of catecholamines with high pressure liquid chromatography with electrochemical detection (HPLC-ECD) in real urine samples of infants, using electrospun composite nanofibers composed of polymeric crown ether with polystyrene as adsorbent, also known as the packed-fiber solid phase extraction (PFSPE) method. We show how urine samples can be easily precleaned by a nanofiber-packed solid phase column, and how the analytes in the sample can be rapidly enriched, desorbed, and detected on an ECD system. PFSPE greatly simplifies the pretreatment procedures for biological samples, allowing for decreased time, expense, and reduction of the loss of targets. Overall, this work illustrates a simple and convenient protocol for solid-phase extraction coupled to an HPLC-ECD system for simultaneous determination of three monoamine neurotransmitters (norepinephrine (NE), epinephrine (E), dopamine (DA)) and two of their metabolites (3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxy-phenylacetic acid (DOPAC)) in infants' urine. The established protocol was applied to assess the differences of urinary catecholamines and their metabolites between high-risk infants with perinatal brain damage and healthy controls. Comparative analysis revealed a significant difference in urinary MHPG between the two groups, indicating that the catecholamine metabolites may be an important candidate marker for early diagnosis of cases at risk for brain damage in infants.

Monoaminergic impairment in Down syndrome with Alzheimer's disease compared to early-onset Alzheimer's disease

IntroductionPeople with Down syndrome (DS) are at high risk for Alzheimer's disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS. MethodsNoradrenaline, adrenaline, and their metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid; and serotonin and its metabolite 5-hydroxyindoleacetic acid were quantified in 15 brain regions of DS without AD (DS, n = 4), DS with AD (DS+AD, n = 17), early-onset AD (EOAD, n = 11) patients, and healthy non-DS controls (n = 10) in the general population. Moreover, monoaminergic concentrations were determined in cerebrospinal fluid (CSF)/plasma samples of DS (n = 37/149), DS with prodromal AD (DS+pAD, n = 13/36), and DS+AD (n = 18/40). ResultsIn brain, noradrenergic and serotonergic compounds were overall reduced in DS+AD versus EOAD, while the dopaminergic system showed a bidirectional change. For DS versus non-DS controls, significantly decreased MHPG levels were noted in various brain regions, though to a lesser extent than for DS+AD versus EOAD. Apart from DOPAC, CSF/plasma concentrations were not altered between groups. DiscussionMonoamine neurotransmitters and metabolites were evidently impacted in DS, DS+AD, and EOAD. DS and DS+AD presented a remarkably similar monoaminergic profile, possibly related to early deposition of amyloid pathology in DS. To confirm whether monoaminergic alterations are indeed due to early amyloid β accumulation, future avenues include positron emission tomography studies of monoaminergic neurotransmission in relation to amyloid deposition, as well as relating monoaminergic concentrations to CSF/plasma levels of amyloid β and tau within individuals.

Need for medication to complement catecholamines in smoking cessation of hardcore smokers.

Many smokers find it difficult to stop smoking without assistance. The antidepressants bupropion and nortriptyline can aid smoking cessation. The main aim of this study was to understand the pathophysiology of smoking cessation better based on biological backgrounds. We investigated the following biological markers for any alterations during smoking cessation in the absence of pharmacotherapy: the dopamine metabolite homovanillic acid (HVA), the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and brain-derived neurotrophic factor (BDNF). Assessment and blood sampling were performed at a baseline (the start) time point and at a critical time point during smoking cessation. Seven of 30 smokers quit during a 16-week follow-up period; these smokers were defined as remission group from tobacco dependence. The remaining 23 smokers were categorized as hardcore smokers. The smoking group was compared with 23 non-smokers matched for age and gender. We compared blood levels of biological markers in each of the three groups. The hardcore smoker group showed significant decreases in HVA and MHPG levels between baseline and the critical time point (p=0.018 and p=0.033, respectively). However, the remission from tobacco dependence group exhibited no significant changes in any of the biomarkers examined. They had lower scores on the Minnesota nicotine withdrawal scale than the hardcore smoker group (p=0.002). The hardcore smoker group had higher MHPG and BDNF levels than the non-smoker group (p=0.002 and p<0.001, respectively). Hardcore smokers experience severe nicotine withdrawal symptoms. Nicotine withdrawal is associated with catecholamine deficiency. The resulting withdrawal symptoms make quitting difficult for hardcore smokers. These hardcore smokers may require medication to compensate for the catecholamine deficit. Non-nicotinic medications such as bupropion, nortriptyline, or varenicline may be required to bolster the catecholamine deficit in hardcore smokers.

The effects of tramadol on norepinephrine and MHPG releasing in locus coeruleus in formalin test in rats: a brain stereotaxic study.

The relationship between tramadol, as an antinociceptive drug, and locus coeruleus (LC), the main noradrenergic nucleus of the brain that affects regulation and modulation of pain through descending noradrenergic pathways was investigated. Male Sprague-Dawley rats were divided into four groups of 10 rats. The rats were fixed in stereotaxic instrument and then a probe was inserted into LC. Pain was induced by subcutaneous injection of 50 μl of 2.5% formalin 40 minutes after initiation of microdialysis in right hind paw, and nociceptive pain scores were calculated every 5 minutes. Subsequently noradrenaline (NA) and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were collected and measured by microdialysis of locus coeruleus in freely moving rats every 15 minutes during formalin injection. Nociceptive pain scores observed in formalin test had the highest nociceptive sensation 5 minutes after injection. Significant rises in concentrations of NA and MHPG, in samples taken between 30 and 45 min after initiation of the locus coeruleus microdialysis, coincided with the peak of the pain after injection of formalin. According to concurrency of the highest nociceptive sensation and peak of NE and MHPG concentrations, tramadol can indirectly affect the LC by blocking the pain signals from different parts of the brain such as periaqueductal gray mater, central nucleus of amygdale or the spinal cord.

N-acetyl cysteine reverses social isolation rearing induced changes in cortico-striatal monoamines in rats

Schizophrenia is causally associated with early-life environmental stress, implicating oxidative stress in its pathophysiology. N-acetyl cysteine (NAC), a glutathione precursor and antioxidant, is emerging as a useful agent in the adjunctive treatment of schizophrenia and other psychiatric illnesses. However, its actions on brain monoamine metabolism are unknown. Social isolation rearing (SIR) in rats presents with face, predictive and construct validity for schizophrenia. This study evaluated the dose-dependent effects of NAC (50, 150 and 250mg/kg/day × 14days) on SIR- vs. socially reared induced changes in cortico-striatal levels of dopamine (DA), serotonin (5-HT) noradrenaline (NA) and their associated metabolites. SIR induced significant deficits in frontal cortical DA and its metabolites, 3,4-dihydroxyphenylacetic acid (Dopac) and homovanillic acid (HVA), reduced 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and reduced levels of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). In addition, significant elevations in frontal cortical NA and striatal DA, Dopac, HVA, 5-HT, 5-HIAA, NA and MHPG were also observed in SIR rats. NAC at 150 and 250mg/kg reversed all cortico-striatal DA, Dopac, HVA, 5-HT, 5-HIAA and striatal NA alterations in SIR animals, with 250mg/kg of NAC also reversing alterations in cortico-striatal MHPG. In conclusion, SIR profoundly alters cortico-striatal DA, 5-HT and NA pathways that parallel observations in schizophrenia, while these changes are dose-dependently reversed or abrogated by sub-chronic NAC treatment. A modulatory action on cortico-striatal monoamines may explain NACs' therapeutic use in schizophrenia and possibly other psychiatric disorders, where redox dysfunction or oxidative stress is a causal factor.

Monoamine Neurotransmitter Metabolites in the Cerebrospinal Fluid of a Group of Hybrid Baboons (Papio hamadryas × P. anubis)

Comparatively little is known about the pathways of proximate causation that link divergent genotypes, via neurophysiological differences, to distinct, species-specific social behaviors and systems. One approach to the problem compares gross activity levels of monoamine neurotransmitters (norepinephrine, dopamine, and serotonin), evidenced by their metabolites —3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), respectively— in cerebrospinal fluid (CSF). We have applied this method to Papio hamadryas and P. anubis, closely related baboon species with divergent social behavior, living in the Awash National Park (ANP), Ethiopia. We had previously shown that adult males of the two species differ in the ratio of HVA to 5-HIAA, and in concentrations of MHPG and HVA, but not 5-HIAA. Here, we compare monoamine metabolite levels of the parental species with those of 49 members of a naturally formed, multigenerational hamadryas × anubis hybrid group. We cage-trapped the baboons in July 1998, sampled their CSF by cisternal puncture, and assayed monoamine metabolites by high-performance liquid chromatography. Previous findings suggested, anomalously, that hybrid males showed the high 5-HIAA levels predicted by the low-serotonin–early-dispersal hypothesis (originally based on observation of rhesus macaques, Macaca mulatta), while hamadryas did not. The present study failed to find higher 5-HIAA levels in hybrids, resolving the anomaly, but leaving the previous result unexplained. Among adult females (underrepresented in our sample) and juveniles, metabolite levels of the hybrids did not differ significantly from either parental species. Overall, adult male hybrids resembled anubis in HVA and HVA/5-HIAA ratio, but did not show the low MHPG levels characteristic of that species. Consistent with a significant genetic influence on species differences in these metabolites, the adult hybrids showed intermediate means and greater intra-population diversity than the parental species for most variables, but showed no indication of hybrid dysgenesis in the form of low intermetabolite correlation. To the contrary, an enhanced HVA–MHPG correlation in the hybrids suggested a species-associated factor (not necessarily genetic) influencing both of these monoamine neurotransmitter systems.

Elevated CSF serotonin and dopamine metabolite levels in overweight subjects

Neurotransmitter systems participate in the regulation of food intake, and their activities are expected to influence eating behavior. We investigated possible associations between body mass index (BMI) and central noradrenaline, serotonin, and dopamine activities, as reflected by the cerebrospinal fluid levels of their main metabolites methoxyhydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), respectively. We studied 192 subjects (111 males, 81 females) admitted to neurologic clinic for diagnostic investigations that included CSF analysis, and were found not to suffer from any major neurological disease. Subjects were categorized in three groups, namely in lower, in the two middle, and in upper BMI quartiles, the limits calculated separately for males and females. No differences were found in MHPG levels between groups, while subjects in the upper BMI quartile showed significantly elevated levels of 5-HIAA and HVA compared to the levels of subjects in lower and middle quartiles. The results provide evidence that in overweight subjects there are enhanced demands in serotoninergic and dopaminergic signaling for their reward system that may lead to increased motivation for food consumption. The implication of reward centers in eating behavior supports the hypothesis of common mechanisms in obesity and drug addiction.

Nocturnal Blood Pressure, 3-Methoxy-4-hydroxyphenylglycol and Carotid Intima-media Thickness: The SABPA Study

Research demonstrated a significant relationship between elevated nocturnal blood pressure and sympathetic hyperactivity. The study aimed to investigate possible associations between norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), nocturnal BP and carotid intima-media thickness (CIMT) in urban African and Caucasian men. The study included 82 African and 100 Caucasian male teachers, aged 33-56 years, recruited in the North-West Province, South Africa. Ambulatory BP and fasting saliva and blood samples were collected. B-mode ultrasound images were obtained to determine CIMT. Despite higher usage of anti-hypertensive medication usage (p=0.039), a large number of the African men were nocturnal hypertensives (75, 61%). The nocturnal systolic blood pressure (SBP) (p<0.001), diastolic blood pressure (DBP) (p<0.001) and heart rate (p<0.001) of the African men were higher. After stratifying groups into only nocturnal hypertensives the trend was the same (SBP p<0.001; DBP p<0.001; heart rate p=0.058). In the African and Caucasian men, CIMT was linearly predicted by SBP (β=0.33, p<0.001) and DBP (β=0.24, p=0.016) respectively, but not MHPG. No associations were firstly demonstrated between MHPG as sympathetic activity marker and CIMT or secondly, between MHPG and nocturnal blood pressure. Novel findings of elevated nocturnal BP evidently seem to promote structural vascular disease in urban African and Caucasian men.

Reconsidering the Use of Propranolol in the Treatment of Cosmetic Infantile Hemangiomas

Reconsidering the Use of Propranolol in the Treatment of Cosmetic Infantile Hemangiomas

D-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians

The d-amino acid oxidase activator (DAOA) protein regulates the function of d-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of d-3,4-dihydroxyphenylalanine (D-DOPA) and d-serine. D-DOPA is converted to l-3,4-DOPA, a precursor of dopamine, whereas d-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.

Neurochemical and Neurobehavioral Effects of Low Lead Exposure on the Developing Brain

Lead is found in small but appreciable quantities in air, soil drinking water and food. Exposure to such amounts of lead does not cause acute lead toxicity, but produces subtle effects, particularly in children. The CDC advocates "safe" or "acceptable" levels of blood lead up to 10μg/dl, while OSHA declares blood lead levels up to 40μg/dl as "safe" or "acceptable" in the occupationally exposed. The objective of the study was to see if blood levels considered "safe" can cause changes in the biogenic neurotransmitters in the developing brain which may cause neurobehavioral defects like hyperactivity and other cognitive disorders. Albino Wistar rats were divided into the control and lead-treated groups. The control group was given unleaded water, while the lead-treated group was fed with 50ppm lead acetate in drinking water. On day 45 the animals were subjected to a passive avoidance test, their blood analysed for ZPP and lead. They were then sacrificed and the neurotransmitters-Norepinephrine (NE) and its metabolite-methoxyhydroxyphenylglycol (MHPG) estimated in the brain areas associated with learning and memory-the frontal cortex, hippocampus and the striatum by HPLC-ECD. Our results showed significant increases in blood lead, NE and MHPG, while ZPP increase was insignificant. The rats showed neurobehavioral abnormalities as assessed by the passive avoidance test. We concluded that low blood levels of lead cannot be considered "safe" or "acceptable" as it causes neurotransmitter alterations. Increased NE turnover is implicated in hyperactivity disorders such as ADHD and Tourette syndrome.

Oral administration of Cimicifuga racemosa extract affects immobilization stress-induced changes in murine cerebral monoamine metabolism

We investigated the effects of Cimicifuga racemosa (CR) plant extracts on the changes in levels of the cerebral monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT), the respective metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA), and plasma corticosterone in mice subjected to acute immobilization stress. Single oral administration of the CR extract (1,000 mg/kg) significantly attenuated plasma corticosterone levels that had been increased as a result of enforced immobilization. Acute immobilization stress caused significant changes in the corresponding amine-to-metabolite ratios in the hypothalamus, hippocampus, and cortex; however, CR-extract treatment significantly attenuated the MHPG/NE change in the hypothalamus, and the 5-HIAA/5- HT changes in each region of the brain. Our results suggest that the CR extract interacts not only with the hypothalamic-pituitary-adrenal (HPA) axis but also with the sympathetic adrenomedullary (SAM) system under stress conditions. Thus the CR extract can alleviate acute stress responses by suppressing the changes of amine-to-metabolite ratio in brain.

Environmental enrichment in male CD-1 mice promotes aggressive behaviors and elevated corticosterone and brain norepinephrine activity in response to a mild stressor

Housing rodents in an enriched environment (EE) has been typically considered to have positive effects on well-being and cognitive functioning of the animals. However, in some strains of mice, EEs have also been reported to elicit aggression and to promote stress-related outcomes. In the current investigation, we examined whether environmental enrichment would elicit aggression among CD-1 male mice and thus sensitize responses to a subsequent mild stressor. It was first observed that mice housed in an EE for 2 weeks displayed more aggressive behaviors than did mice that had been housed in a standard environment (SE). In the second experiment, it was noted that after 4 weeks of EE or SE housing, mice exhibited comparable plasma corticosterone concentrations as well as levels of brain norepinephrine and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in the absence of a challenge. However, upon exposure to mild stressor (placement in a novel cage), relative to their SE counterparts, EE mice were more active and displayed higher plasma corticosterone concentrations and enhanced MHPG accumulation in the prefrontal cortex and hippocampus. It seems that enrichment in male CD-1 mice promotes aggression, and may sensitize biological processes, possibly increasing vulnerability to stressor-related outcomes.

Co-involvement of psychological and neurological abnormalities in infertility with polycystic ovarian syndrome

To investigate psychological distress, serum levels of monoamine neurotransmitters and their metabolites, as well as their correlation with polycystic ovarian syndrome (PCOS). Thirty infertility patients with PCOS were assigned as the experimental group and 30 infertility patients without PCOS were assigned as the control group. Psychological distress was self-evaluated in all patients with Symptom Checklist 90 (SCL-90). Serum concentrations of norepinephrine (NE) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA) and its metabolites homovanillic acid (HVA) and dihydroxy-phenyl acetic acid (DOPAC) were measured by high-performance liquid chromatography. The anxious and depressive subscales of SCL-90 were significantly higher in infertility patients with PCOS than those without PCOS (p < 0.05). The serum concentrations of 5-HT, 5-HIAA and HVA were significantly lower in infertility patients with PCOS than those without PCOS (p < 0.05). Importantly, the phobia subscale scores of SCL-90 positively correlated with serum MHPG level (p < 0.05), while the hostility subscale's scores negatively correlated with serum DOPAC level (p < 0.05). Psychological and neurological factors play a crucial role in PCOS.

Dystrobrevin-binding protein 1 gene ( DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers

The dystrobrevin binding protein-1 ( DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects ( n = 132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.