Monoamine Metabolite Levels Research Articles

Amelioration of metabolic and behavioral defects through base editing in the PahR408W phenylketonuria mouse model

Phenylketonuria (PKU) is a liver metabolic disorders mainly caused by a deficiency of the hepatic phenylalanine hydroxylase (PAH) enzyme activity, often leading to severe brain function impairment in patients if untreated or if treatment is delayed. In this study, we utilized dual-AAV8 vectors to deliver a near PAM-less adenine base editor variant, known as ABE8e-SpRY, to treat the PahR408W PKU mouse model carrying a frequent R408W mutation in the Pah gene. Our findings revealed that a single intravenous injection in adult mice and a single intraperitoneal injection in neonatal mice resulted in 19.1% to 34.6% A-to-G editing efficiency at the pathogenic mutation site with minimal bystander edits. Furthermore, the dual-AAV8 treated mice exhibited reduced blood Phe levels to below the therapeutic threshold of 360 μmol L-1 and restored weight and fur color to normal levels. Importantly, the brain function of the mice was restored after the treatment, particularly when administered during the neonatal stage, as levels of monoamine neurotransmitters and metabolites in the brain returned to normal and near-normal levels. Our study demonstrated that ABE8e-SpRY-based base editing could effectively correct the point mutation in the PahR408W PKU mouse model, indicating potential clinical applications for PKU and other genetic diseases.

Impact of Long-Rope Jumping on Monoamine and Attention in Young Adults.

Previous research has shown that rope jumping improves physical health; however, little is known about its impact on brain-derived monoamine neurotransmitters associated with cognitive regulation. To address these gaps in the literature, the present study compared outcomes between 15 healthy participants (mean age, 23.1 years) after a long-rope jumping exercise and a control condition. Long-rope jumping also requires co-operation between people, attention, spatial cognition, and rhythm sensation. Psychological questionnaires were administered to both conditions, and Stroop task performance and monoamine metabolite levels in the saliva and urine were evaluated. Participants performing the exercise exhibited lower anxiety levels than those in the control condition. Saliva analyses showed higher 3-methoxy-4-hydroxyphenylglycol (a norepinephrine metabolite) levels, and urine analyses revealed higher 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid (a serotonin metabolite) levels in the exercise condition than in the control. Importantly, urinary 5-hydroxyindoleacetic acid level correlated with salivary and urinary 3-methoxy-4-hydroxyphenylglycol levels in the exercise condition. Furthermore, cognitive results revealed higher Stroop performance in the exercise condition than in the control condition; this performance correlated with salivary 3-methoxy-4-hydroxyphenylglycol levels. These results indicate an association between increased 3-methoxy-4-hydroxyphenylglycol and attention in long-rope jumping. We suggest that long-rope jumping predicts central norepinephrinergic activation and related attention maintenance.

Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease.

ABSTRACTBackgroundCerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).ObjectiveThe aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.MethodsAbsolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies.ResultsBaseline levels of homovanillic acid (HVA) and 3,4‐dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single‐photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug‐naive individuals, but some changed on starting levodopa treatment.ConclusionsHVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Combined approaches for evaluation of xenoestrogen neural toxicity and thyroid dysfunction: Screening of oxido-nitrosative markers, DNA fragmentation, and biogenic amine degradation.

Anthropogenic chemicals such as parabens and triclosan are used in personal care products. Duetotheir ability to decrease or prevent bacterial contamination and act as preservatives, these chemicals are used in cosmetic manufacturing processes to increase the shelf life of products. In this study, we assessed the side effects of environmental estrogens (such as the xenoestrogen butylparaben and the antimicrobial agent and preservative triclosan) on thyroid function, brain monoamine levels, and DNA aberration. Forty-two male albino rats were divided into seven groups with six members each: the first group served as control; the second and the third groups were treated with butylparaben 10 and 50 mg/kg body weight, respectively; the fourth and fifth groups were treated with triclosan 10 and 50 mg/kg body weight, respectively; and the sixth and seventh groups were treated with butylparaben plus triclosan 10 and 50 mg/kg body weight, respectively. After 60 days, blood samples were collected and brain specimens were divided into striatum, midbrain, cortex, and thalamus. Thyroid function and levels of monoamines and monoamine metabolites were determined for each brain area. Comet assay was used for brain tissue analysis. The results showed that butylparaben and triclosan and their combinations induced hypothyroidism and disrupted monoamine levels, leading to a decrease in catecholamine and serotonin levels, and accelerated production of 5-hydroxyindoleacetic acid. The obtained data indicate that anthropogenic chemicals such as butylparaben and triclosan have harmful effects on thyroid and brain function and accelerate cell destruction and mutation, as evidenced by single-stranded DNA breaks in the comet assay.

Cerebrospinal fluid monoamine metabolite concentrations in depressive disorder: A meta-analysis of historic evidence

Altered monoaminergic functions have been implicated in the pathophysiology of depressive disorder. However, previously reported cerebrospinal fluid (CSF) monoamine metabolite concentrations in major depression have been inconsistent. We performed a meta-analysis of historic evidence to determine whether CSF monoamine metabolite levels were different between patients with depression and normal controls, and could be used as depression biomarkers. Relevant studies that investigated CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with depression and normal controls were identified in PubMed, Web of Science, PsycINFO, and Embase databases through September 5, 2017, using a synonymous search for depression, CSF, normal, control, and each monoamine metabolite name, and in the reference lists of the acquired articles. Obtained records were individually scrutinized for eligibility. Our search strategy identified 26 studies, including our own. We employed random effects modeling and adopted “Hedges's g” as an index of effect size. In the meta-analyses, no significant difference was observed in CSF 5-HIAA or MHPG levels between patients with depressive disorder and controls. In contrast, CSF HVA was significantly decreased in patients with depression (Hedges's g = −0.30, P = 0.0000025), and these results remained significant after patients with bipolar disorder were excluded (Hedges's g = −0.37, P = 0.000061). In the meta-regression, sex was significantly associated with the Hedges's g of CSF HVA (Q = 4.41, P = 0.036). This meta-analysis revealed that only CSF HVA, and not 5-HIAA or MHPG, levels were decreased in depressive disorder. The reduction in the CSF HVA concentration in patients with depression may guide future studies on depression and serve as a useful biomarker of depressive disorder.

Bacterial Lipopolysaccharide Increases Serotonin Metabolism in Both Medial Prefrontal Cortex and Nucleus Accumbens in Male Wild Type Rats, but Not in Serotonin Transporter Knockout Rats.

It is well known that bacterial lipopolysaccharides (LPS) both increases proinflammatory cytokines and produces sickness behavior, including fatigue and anhedonia (i.e., the inability to experience pleasure). Previously, we have shown that intraperitoneally (i.p.) administered LPS increased extracellular monoamine metabolite levels in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), which was completely, or at least partly, prevented by pretreatment with a triple reuptake inhibitor that also blocks the serotonin (5-HT) transporter (SERT). This suggests indirectly, that LPS may enhance SERT transporter activity, and consequently, increase removal of 5-HT from the synaptic cleft, and increase metabolism of 5-HT. In the present study, we focus more specifically on the role of SERT in this increased metabolism by using rats, that differ in SERT expression. Therefore, the effects of an intraperitoneal LPS injection on extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis in the NAc and mPFC of wild type (SERT+/+), heterozygous (SERT+/−) and knockout (SERT−/−) rats. Here, we show that LPS-induced 5-HIAA formation in male rats, is significantly increased in SERT+/+ rats in both the NAc and mPFC, whereas this increase is partly or totally abolished in SERT+/− and SERT−/− rats, respectively. Thus, the present study supports the hypothesis that systemic LPS in male rats increases SERT function and consequently enhances 5-HT uptake and metabolism in both the NAc and mPFC.

COMT Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia.

IntroductionThe COMT Val 108/158 Met polymorphism (rs4680) may affect treatment response to antipsychotics, as well as metabolism and dynamics of neurotransmitters during the treatment of schizophrenia. We investigated the effects of the COMT Val 108/158 Met polymorphism on treatment response to aripiprazole and plasma monoamine metabolite levels in patients with acute schizophrenia.Materials and methodsForty patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured Positive and Negative Syndrome Scale (PANSS) and plasma levels of homovanillic acid (HVA) and plasma MHPG (3-methoxy-4-hydroxyphenethyleneglycol) at baseline and endpoint. The COMT Val 108/158 Met polymorphism was genotyped with the polymerase chain reaction and restriction fragment length polymorphism.ResultsThere were significant genotype–time interactions on PANSS total and general psychopathology scores, with Met/Met genotype showing greater improvement. The response rate to aripiprazole did not differ between COMT Val 108/158 Met genotype groups. We found a significant time effect on plasma MHPG levels, but no time effect on plasma HVA levels or time–genotype interactions in the plasma levels of HVA and MHPG. Although the responder rate did not differ among the 3 genotype groups.ConclusionOur results suggest that individuals with the Met/Met genotype had greater improvement in PANSS score after the treatment with aripiprazole. On the other hand, the Val 108/158 Met polymorphism may not induce changes in plasma levels of monoamine metabolites during aripiprazole treatment. Because of the small sample size, further studies are needed to confirm and to extend our results.

DNA methylation of ANKK1 and response to aripiprazole in patients with acute schizophrenia: A preliminary study

Epigenetic modification including DNA methylation may affect pathophysiology and the response to antipsychotic drugs in patients with schizophrenia. The objective of the present study was to investigate the effect of the DNA methylation of ANKK1 (ankyrin repeat and kinase domain containing 1) on the response to aripiprazole and plasma levels of monoamine metabolites in antipsychotic-free acute schizophrenia patients. The subjects were 34 Japanese patients with schizophrenia who had been treated with aripiprazole for 6 weeks. Comprehensive DNA methylation of ANKK1 was determined using a next-generation sequencer. DNA methylation levels at CpG site 387 of ANKK1 were higher in responders to treatment with aripiprazole and correlated with the changes in Positive and Negative Syndrome Scale scores, although the associations did not remain significant after Bonferroni correction. In responders, methylation at all CpG sites was significantly correlated with plasma levels of homovanillic acid (r = 0.587, p = 0.035) and 3-methoxy-4hydroxyphenylglycol (r = 0.684, p = 0.010) at baseline. Despite our non-significant results after multiple correction, our preliminary findings suggest that methylation levels at CpG site 387 of ANKK1 may be associated with treatment response to aripiprazole. Furthermore, methylation of ANKK1 may affect dopaminergic neural transmission in the treatment of schizophrenia, and may influence treatment response. Caution is needed in interpreting these findings because of the small sample size, and further studies are needed to confirm and expand our preliminary results.

Relationships of Cerebrospinal Fluid Monoamine Metabolite Levels With Clinical Variables in Major Depressive Disorder.

Many studies have investigated cerebrospinal fluid (CSF) monoamine metabolite levels in depressive disorders. However, their clinical significance is still unclear. We tried to determine whether CSF monoamine metabolite levels could be a state-dependent marker for major depressive disorder (MDD) based on analyses stratified by clinical variables in a relatively large sample. Subjects were 75 patients with MDD according to DSM-IV criteria and 87 healthy controls, matched for age, sex, and ethnicity (Japanese). They were recruited between May 2010 and November 2013. We measured homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in CSF samples by high-performance liquid chromatography. We analyzed the relationships of the metabolite levels with age, sex, diagnosis, psychotropic medication use, and depression severity. There was a weak positive correlation between age and 5-HIAA levels in controls (ρ = 0.26, P < .016) and a similar trend in patients, while sex was unrelated to any metabolite. All monoamine metabolites in moderately to severely depressed patients (17-item Hamilton Depression Rating Scale score > 12) were significantly lower than those in controls (P < .0005 for all 3 metabolites). We found that antidepressants decreased the levels of 5-HIAA (ρ = -0.39, P < .001) and MHPG (ρ = -0.49, P < .0001) and that antipsychotics increased levels of HVA (ρ = 0.24, P < .05). There was a strong correlation between HVA and 5-HIAA levels (controls: ρ = 0.79, P = .000001; MDD: ρ = 0.66, P = .000001). HVA levels (ρ = -0.43, P < .001) and 5-HIAA levels (ρ = -0.23, P < .05), but not MHPG levels (ρ = -0.18, P > .1), were related to depression severity. CSF 5-HIAA and HVA levels could be state-dependent markers in MDD patients. Since 5-HIAA levels greatly decrease with the use of antidepressants, HVA levels might be more useful in the clinical setting.

Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria.

Phenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis. We therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available. Mean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020). These findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

Peripheral blood gene expression profiles linked to monoamine metabolite levels in cerebrospinal fluid.

The blood–brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 × 10−8, β=0.08) and DDX6 (P=2.9 × 10−7, β=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 × 10−52). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain-expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS.

Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity

BackgroundTo examine whether delirium in hip fracture patients was associated with changes in the levels of amino acids and/or monoamine metabolites in cerebrospinal fluid (CSF) and serum.MethodsIn this prospective cohort study, 77 patients admitted with an acute hip fracture to Oslo University Hospital, Norway, were studied. The concentrations of amino acids in CSF and serum were determined by high performance liquid chromatography. The patients were assessed daily for delirium by the Confusion Assessment Method (pre-operatively and post-operative day 1–5 (all) or until discharge (delirious patients)). Pre-fracture dementia status was decided by an expert panel. Serum was collected pre-operatively and CSF immediately before spinal anesthesia.ResultsFifty-three (71 %) hip fracture patients developed delirium. In hip fracture patients without dementia (n = 39), those with delirium had significantly higher CSF levels of tryptophan (40 % higher), tyrosine (60 % higher), phenylalanine (59 % higher) and the monoamine metabolite 5-hydroxyindoleacetate (23 % higher) compared to those without delirium. The same amino acids were also higher in CSF in delirious patients with dementia (n = 38). The correlations between serum and CSF amino acid levels were poor.ConclusionHigher CSF levels of monoamine precursors in hip fracture patients with delirium suggest a higher monoaminergic activity in the central nervous system during delirium in this patient group.

Associations between five-factor model of the Positive and Negative Syndrome Scale and plasma levels of monoamine metabolite in patients with schizophrenia

The five-factor model of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia symptoms is the most common multiple-factor model used in analyses; its use may improve evaluation of symptoms in schizophrenia patients. Plasma monoamine metabolite levels are possible indicators of clinical symptoms or response to antipsychotics in schizophrenia. We investigated the association between five-factor model components and plasma monoamine metabolites levels to explore the model's biological basis. Plasma levels of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography in 65 Japanese patients with schizophrenia. Significant negative correlation between plasma 5-HIAA levels and the depression/anxiety component was found. Furthermore, significant positive correlation was found between plasma MHPG levels and the excitement component. Plasma HVA levels were not correlated with any five-factor model component. These results suggest that the five-factor model of the PANSS may have a biological basis, and may be useful for elucidating the psychopathology of schizophrenia. Assessment using the five-factor model may enable understanding of monoaminergic dysfunction, possibly allowing more appropriate medication selection. Further studies of a larger number of first-episode schizophrenia patients are needed to confirm and extend these results.

Impacts of age on plasma monoamine metabolite concentrations in a large cohort of healthy individuals

The measurement of plasma concentrations of monoamine metabolites is a useful method for inferring the dynamics of monoamine metabolites in the brain. To clarify effects of age and sex on plasma monoamine metabolites levels, we used high-performance liquid chromatography to measure plasma levels of homovanillic acid (HVA), free and total 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in healthy men and women of various ages (n=214). In all plasma monoamine metabolites, there were significant differences across the age groups, and multiple comparisons revealed that older subjects had higher levels than younger subjects. Moreover, significant positive correlations were found between age and plasma levels of HVA, free MHPG, total MHPG, and 5-HIAA. On the other hand, plasma concentrations of monoamine metabolites were not influenced by sex, except for total MHPG for which the plasma levels were significantly higher in men than in women. Age-related changes in monoamine oxidase and renal function might affect our results. This large cohort survey provides further evidence to be cautiously aware of age effects when regarding plasma monoamine metabolites levels as reflections of central activity.

Near-infrared spectroscopy and plasma homovanillic acid levels in bipolar disorder: a case report

Misdiagnosis of bipolar disorder is a serious, but not unusual problem for patients. Nevertheless, there are few biomarkers for distinguishing unipolar and bipolar disorder. Near-infrared spectroscopy (NIRS) is a noninvasive and useful method for the measurement of hemoglobin concentration changes in the cortical surface area, which enables the assessment of brain function. We measured NIRS and plasma monoamine metabolite levels in a patient with bipolar disorder. A 22-year-old man was admitted due to major depression. At admission, NIRS findings showed oxygenated hemoglobin reincrease in the posttask period, which is characteristic of schizophrenia. After treatment with paroxetine, he became manic with psychotic symptoms. His plasma level of homovanillic acid just before the manic switch was ten times higher than that just after paroxetine initiation. Treatment with lithium and antipsychotics was successful, and plasma homovanillic acid decreased after treatment. In this case, the NIRS findings may predict a possible risk of a manic switch, which is likely induced by paroxetine. NIRS may be able to help distinguish unipolar and bipolar disorder in clinical settings.

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.

Lipopolysaccharide increases degradation of central monoamines: An in vivo microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice

Peripheral administration of lipopolysaccharide (LPS) in rodents induces anhedonia, i.e. the inability to experience pleasure. Recently, we reported that serotonin transporter (SERT) function is required for LPS-induced anhedonia. Less is known about the effect of LPS on the biological activity of dopamine transporters (DAT) and norepinephrine transporters (NET). Therefore, in vivo microdialysis was performed in the nucleus accumbens and medial prefrontal cortex of C57BL6/J mice exposed to saline or LPS (133µg/kg i.p.). To investigate the possible involvement of different monoamine transporters, the triple reuptake inhibitor DOV 216,303 or saline was i.p. injected 30min before the saline/LPS injection. The dose of LPS, shown to decrease responding for brain stimulation reward in mice, significantly increased extracellular levels of monoamine metabolites (5-HIAA, DOPAC and HVA) in the nucleus accumbens and medial prefrontal cortex. Remarkably, DOV 216,303 abolished LPS-induced DOPAC and HVA formation in the nucleus accumbens, suggesting that LPS increases DAT activity in this brain area. DOV 216,303 also inhibited LPS-induced DOPAC and HVA formation in the medial prefrontal cortex. Since DAT density is very low in this brain structure, reuptake of DA predominantly takes place via NET, suggesting that LPS increases DAT and NET activity in the medial prefrontal cortex. Furthermore, DOV 216,303 pretreatment prevented LPS-induced 5-HIAA formation only in the medial prefrontal cortex, indicating that LPS increases prefrontal SERT activity. In conclusion, the present findings suggest that peripheral LPS increases DAT activity in the nucleus accumbens and increases NET and SERT activity in the medial prefrontal cortex of mice.

Switching antipsychotics to aripiprazole or blonanserin and plasma monoamine metabolites levels in patients with schizophrenia

Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia. Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography. There were no significant effects for time (p = 0.346) or time × group interaction (p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = -0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia.

EPA-0868 – Genetic determinants of monoamine turnover in human cerebrospinal fluid: associations with 5-HT seasonality and mood symptoms

Although monoamines are thought to be involved in seasonal mood disorders, it is unknown how such concentrations may impact seasonal variation in mood symptoms. Studies of monoaminergic seasonality and a possible influence of the serotonin transporter gene, SLC6A4, on serotonin seasonality have yielded conflicting results. To study this comprehensively, we first performed a genome-wide association study (GWAS) of monoamine metabolites in human cerebrospinal fluid (CSF). We then examined whether the S/L promoter polymorphism of the serotonin transporter gene (5-HTTLPR) affects seasonal changes in CSF serotonin metabolite levels. To translate our findings to the behavioral level, we tested for correlations of 5-HT seasonality values with mood symptoms. The GWAS yielded a locus significantly associated with monoamine metabolite levels 20kb from SSTR1 (P = 4.92 x 10−8), a locus that was shown to control expression of PDE9A, a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. We additionally show evidence for involvement of the S allele with 5-HT seasonality (standardized β = 0.12, P = 0.020). Moreover, 5-HT seasonality correlated positively with depressive symptoms (Spearman's rho = 0.13, P = 0.018). We demonstrate how genetic variation in a range of genes involved with neuronal activity influences monoamine metabolite levels in human CSF. We furthermore highlight a dose-dependent association of the 5-HTTLPR with 5-HT seasonality and a positive correlation between 5-HT seasonality and depressive symptomatology. The presented data provide new insights into the genetic determinants of 5-HT seasonality and its role in affective disorders.

Relationship between Plasma monoamine metabolites levels and clinical response in the treatment of depression

Relationship between Plasma monoamine metabolites levels and clinical response in the treatment of depression