Serotonin In Cerebrospinal Fluid Research Articles

Effect of Raha syrup on the motivational effects of morphine and CSF serotonin levels in rats

Opiates may influence motivational processes by a dysregulation of brain reward pathways that play a role in context-induced reinstatement of drug seeking. Raha syrup as herbal bioactive compounds with anti-anxiety/depressant effects may be prevented morphine-induced reward and motivation effects. Therefore, the aim of this study was to investigate the effect of Raha syrup on the rewarding effects of morphine and motivational aspects of morphine-seeking behavior in morphine-induced conditioned place preference (CPP) model and also the cerebrospinal fluid (CSF) serotonin levels following the extinction and reinstatement in rats. In this study, adult male Wistar rats received Raha syrup via oral gavage to assess of the acquisition, extinction and reinstatement of the morphine-induced CPP and as well as measurement of the CSF serotonin levels. Administration of Raha syrup during the conditioning period significantly attenuated the acquisition of morphine-induced CPP, and increased the CSF serotonin level, 6 days after cessation of treatment during extinction, while did not affect the duration of the extinction period. Also, Raha syrup during the extinction period did not affect the reinstatement of morphine-induced CPP and the CSF serotonin levels in rats. We conclude that Raha syrup attenuated the acquisition of morphine reward probably through an increase in CSF serotonin, while could not maintain the extinguished CPP and had no effect on the reinstatement. Therefore, Raha syrup as a useful adjunctive therapeutic strategy may exert a protective effect against opiate-related rewards, while it may be ineffective to prevention of motivation or drug-seeking reinstatement (relapse).

Raha syrup attenuates the morphine withdrawal-induced locomotor sensitisation by increasing the cerebrospinal fluid serotonin in rats receiving the opium tincture maintenance treatment

Morphine withdrawal increases locomotor sensitisation, relapse and impair regulation of serotonin system. We evaluated the effectiveness of Raha syrup on the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitisation in morphine-withdrawn rats receiving the opium tincture (OT). Morphine withdrawal rats gavaged daily with OT and Raha syrup (for 30 days) and then challenged with morphine and evaluated for locomotor activity and CSF serotonin levels before morphine challenge and 2 weeks after cessation of treatment. Raha syrup attenuated locomotor activity, increased the CSF serotonin after morphine challenge, and continued 2 weeks after cessation of treatment in rats receiving OT. Whereas, rats receiving OT alone after morphine challenge exhibited a relative decrease in locomotor activity, without changing CSF serotonin. Raha syrup attenuated locomotor sensitisation in morphine-withdrawn rats receiving OT probably by increasing serotonin. Therefore, administration of Raha syrup along with OT may benefit to treatment relapse in addicts receiving OT maintenance treatment.

Time of day does not impact spinal serotonin levels in humans.

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 67.7nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 75.8nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p =.762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

Cerebrospinal Fluid Serotonin level as Biomarker for Neurotoxicity after 3,4-Methylenedioxymethamphetamine (MDMA)

A persistent 3,4-Methylenedioxymethamphetamine (MDMA) exposure may disrupt the human body serotonergic system which subsequently leads to physical and psychiatric chaos. Serotonin, a well-known monoamine neurotransmitter which is the main target of MDMA can be found in cerebrospinal (CSF) fluid. Its variation reflects the severity of neuronal damage caused by MDMA exposure. Hence, this article aimed to review the potential of serotonin as biomarker for neuronal damage posed by MDMA. Articles from main databases including PubMed, Scopus and Web of Science were analysed and its information about serotonin variation in cerebrospinal fluid in response to MDMA exposure were extracted. MDMA is affine to serotonergic system, and can represents as a change in the level of serotonin in the CSF. It provides critical information about underlying mechanisms of neuronal damage from neurotoxicity, neurodegenerative process, excitotoxicity and hallucination due to MDMA exposure. Since serotonin variation in the CSF reflects the severity of neuronal damages, serotonin is potentially be used as an early indicator to assess neural injury caused by MDMA that plays an important role in intervention purpose. Serotonin variation in the CSF reflects the severity of neuronal damages. Its variation in CSF can be used as a biomarker for assessing neuronal damage following MDMA exposure.

Identification of cerebrospinal fluid and serum metabolomic biomarkers in first episode psychosis patients

Psychotic disorders are currently diagnosed by examining the patient’s mental state and medical history. Identifying reliable diagnostic, monitoring, predictive, or prognostic biomarkers would be useful in clinical settings and help to understand the pathophysiology of schizophrenia. Here, we performed an untargeted metabolomics analysis using ultra-high pressure liquid chromatography coupled with time-of-flight mass spectroscopy on cerebrospinal fluid (CSF) and serum samples of 25 patients at their first-episode psychosis (FEP) manifestation (baseline) and after 18 months (follow-up). CSF and serum samples of 21 healthy control (HC) subjects were also analyzed. By comparing FEP and HC groups at baseline, we found eight CSF and 32 serum psychosis-associated metabolites with non-redundant identifications. Most remarkable was the finding of increased CSF serotonin (5-HT) levels. Most metabolites identified at baseline did not differ between groups at 18-month follow-up with significant improvement of positive symptoms and cognitive functions. Comparing FEP patients at baseline and 18-month follow-up, we identified 20 CSF metabolites and 90 serum metabolites that changed at follow-up. We further utilized Ingenuity Pathway Analysis (IPA) and identified candidate signaling pathways involved in psychosis pathogenesis and progression. In an extended cohort, we validated that CSF 5-HT levels were higher in FEP patients than in HC at baseline by reversed-phase high-pressure liquid chromatography. To conclude, these findings provide insights into the pathophysiology of psychosis and identify potential psychosis-associated biomarkers.

The behavioral neuroendocrinology of dopamine systems in differently reared juvenile male rhesus monkeys (Macaca mulatta)

Dopamine (DA) is a critical neuromodulator of behavior. With propensities for addiction, hyper-activity, cognitive impairment, aggression, and social subordinance, monkeys enduring early maternal deprivation evoke human disorders involving dopaminergic dysfunction. To examine whether DA system alterations shape the behavioral correlates of adverse rearing, male monkeys (Macaca mulatta) were either mother-reared (MR: N = 6), or separated from their mothers at birth and nursery-reared (NR: N = 6). Behavior was assessed during 20-minute observations of subjects interacting with same- or differently-reared peers. Cerebrospinal fluid (CSF) biogenic amines, and serum testosterone (T), cortisol (CORT), and prolactin (PRL) were collected before and after pharmacologic challenge with saline or the DA receptor-2 (DRD2) antagonist Raclopride (RAC). Neuropeptide correlations observed in MR were non-existent in NR monkeys. Compared to MR, NR showed reduced DA tone; higher basal serum T; and lower CSF serotonin (5-HT). RAC increased PRL, T and CORT, but the magnitude of responses varied as a function of rearing. Levels of PRL significantly increased following RAC in MR, but not NR. Elevations in T following RAC were only significant among MR. Contrastingly, the net change (RAC CORT – saline CORT) in CORT was greater in NR than MR. Finally, observations conducted during the juvenile phase in a novel play-arena revealed more aggressive, self-injurious, and repetitive behaviors, which negatively correlated with indexes of dopaminergic tone in NR monkeys. In conclusion, early maternal deprivation alters brain DA systems, and thus may be associated with characteristic cognitive, social, and addiction outcomes.

Fibroblast growth factor 21 associating with serotonin and dopamine in the cerebrospinal fluid predicts impulsivity in healthy subjects

BackgroundImpulsivity is more commonly reported in subjects with mental disorders compared to healthy subjects, suggesting a potential application of impulsivity in predicting impulsivity-related mental disorders. However, no biomarker of impulsivity available so far. This study explored the association between cerebrospinal fluid (CSF) fibroblast growth factor 21 (FGF21), a key hormonal mediator of the stress response, and impulsivity in healthy subjects.MethodsA total of 126 healthy persons subjected to surgery of anterior cruciate ligament were recruited in the present study. The impulsiveness of the subjects was evaluated by the Chinese version of the Barratt Impulsiveness Scale (BIS)-11 before surgery. CSF and blood samples of the subjects were collected before spinal anesthesia for surgery. The levels of FGF21, serotonin and dopamine in CSF and the level of FGF21 in blood of the subjects were measured by ELISA using commercial kits.ResultsNegative correlations were found between BIS-11 total score and either FGF21, serotonin or dopamine in CSF. However, BIS-11 total score was not correlated with FGF21 in blood. In addition, FGF21 was positively correlated with serotonin and dopamine in CSF, respectively. Multivariable linear regression models indicated that the decrease of FGF21 level associating with the decrease of serotonin and dopamine level in CSF contributed to the higher impulsivity. Furthermore, receiver operating characteristic curve (ROC) analysis indicated an important role of CSF FGF21 predicting high impulsivity.ConclusionsFGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions. The decrease of CSF FGF21 is related to higher impulsivity, and indicate that CSF FGF21 may predict impulsivity in healthy subjects.

Estrogen and serotonin enhance stress-induced visceral hypersensitivity in female rats by up-regulating brain-derived neurotrophic factor in spinal cord.

We previously reported that female offspring of dams subjected to chronic prenatal stress (CPS) develop enhanced visceral hypersensitivity (VHS) following exposure to chronic stress in adult life that is mediated by up-regulation of spinal cord BDNF. The aims of this study were to examine the roles of estrogen receptor alpha (ERα) and an increase in spinal serotonin signaling in promoting this enhanced VHS in female rats and up-regulation of spinal cord BDNF transcription. Pregnant dams were exposed to chronic stress from E11 until delivery. At 8weeks, a chronic adult stress (CAS) protocol was applied for nine days. Ovariectomy before CAS or treatment with letrozole before and during CAS significantly prevented the development of enhanced VHS in female CPS+CAS rats. Intrathecal application of ERα siRNA significantly reduced VHS, decreased lumbar-sacral spinal cord expression of both ERα and BDNF, and reversed pro-transcriptional epigenetic modifications at BDNF promoter lX. Cerebrospinal fluid serotonin levels and 5HT3A receptor expression in the LS spinal cord were both significantly increased in female CPS+CAS rats. During CAS, intrathecal infusion of alosetron significantly decreased VHS, reduced BDNF and ERα expression in the LS spinal cord, and attenuated RNA pol II and ERα binding to the BNDF core promoter IX. Serotonin-mediated activation of 5HT3A receptors in the spinal cord drives the development of enhanced female-specific VHS in our two hit CPS+CAS through up-regulation of spinal cord ERα.

Saffron (Crocus sativus L.) stigma reduces symptoms of morphine-induced dependence and spontaneous withdrawal in rats

ABSTRACT Background: Chronic morphine induces physical and psychological dependence signs. Saffron (Crocus sativus L.) stigma has been shown to have anxiolytic, antidepressant, and antinociceptive properties and to alleviate naloxone-precipitated withdrawal signs. Objectives: Therefore, this study was designed to examine the effects of saffron aqueous extract on the severity of physical-psychological dependence, voluntary morphine consumption, and the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitization in morphine-dependent rats and in rats undergoing morphine withdrawal. Materials: Adult male rats were treated with morphine (10 mg/kg, sc twice daily) for 10 days. Rats received saffron extract (60 mg/kg, ip) daily, during the induction of morphine dependence and/or withdrawal. Then, rats were tested for spontaneous withdrawal signs, anxiety using the elevated plus-maze, depression using sucrose preference test, and voluntary morphine consumption using a two-bottle choice paradigm, and then challenged with morphine (1 mg/kg, ip) to evaluate of locomotor sensitization and CSF serotonin levels. Results: The results showed saffron extract during induction of morphine dependence decreased the severity of withdrawal signs (P = .05), while it had no effect on anxiety and depression-like behaviors. Saffron extract during morphine withdrawal exhibited an increase in the percentage (or ratio) of open/total arm entries (P = .017), higher levels of sucrose preference (P = .0001), a lower morphine preference ratio (P = .02) and also, a decrease in locomotor activity (P = .004) and an increase in the CSF serotonin levels (P = .041) in rats challenged to morphine. Conclusions: Saffron extract may exert a protective effect against morphine-induced behavioral sensitization in rats, probably through increasing serotonin levels.

0048 CEREBRAL SEROTONIN EXPRESSION PREDICTS DAYTIME SLEEP AND SLEEP DEVELOPMENT IN INFANT RHESUS MONKEYS

Cerebral serotonin expression and sleep share a complex and as yet unclear association in early development. Though serotonin is linked with sleep-wake patterns in early childhood, whether this association emerges during infancy remains to be discovered. We hypothesized that the developing serotonergic system will be associated with the development of sleep-wake patterns. We investigated the associations between cerebral serotonin expression and sleep development during the first month of life in 152 nursery-reared infant rhesus macaques (Macaca mulatta). Cerebral serotonin expression was determined using cerebrospinal fluid serotonin metabolite 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations, relative to weight, sampled at 2 and 4 weeks post-birth. Sleep-wake states were rated by trained observers every two hours from 0800-2000 hours. Sleep-wake states were scored as awake=1, drowsy=2, or asleep=3. For analyses, daytime sleep-wake states were averaged across the 7 days prior to each CSF sampling. Paired-samples t-test, Wilcoxon signed ranks test, and Spearman’s ρ were utilized to explore associations between time points, averages, and change scores (week 4 minus week 2) for both CSF 5-HIAA and sleep-wake states. Daytime sleep (t(239)=17.27, p<.001) and CSF 5-HIAA (Z = -9.9, p<.001) decreased significantly from week 2 to week 4. Higher CSF 5-HIAA was associated with more daytime sleep during the first month of development (ρ=.25, p=.003). Lower week 2 CSF 5-HIAA predicted greater reductions in sleep from week 2-week 4 (ρ=.16, p=.05). Greater reductions in CSF 5-HIAA from week 2 to week 4 predicted lower sleep at week 4 (ρ=-.18, p =.03). These important findings are among the first to demonstrate that, from birth, daytime sleep-wake patterns are predicted by cerebral serotonin expression. Considering the link between serotonin, sleep, and mood disorders later in life, these results have exciting implications for improving sleep with serotonin interventions. This research was supported by the Laboratory of Comparative Ethology at the National Institute of Child Health & Human Development, National Institute of Health.

Noradrenaline, Serotonin, GABA, and Glycine in Cerebrospinal Fluid during Labor Pain: A Cross-Sectional Prospective Study.

Background and Aims The inhibitory pathways that play a role in spinal modulation include local interneurons and descending control. Clinical data regarding the role of these pathways in acute pain is lacking. Accordingly, the aim of this study was to evaluate cerebrospinal fluid (CSF) levels of noradrenaline, serotonin, gamma-aminobutyric acid (GABA), and glycine in parturients with labor pain compared to those without labor pain. Methods One hundred term uncomplicated pregnant women receiving spinal anesthesia for cesarean section were enrolled in this prospective cross-sectional study. CSF noradrenaline, serotonin, GABA, and glycine levels were analyzed by enzyme-linked immunosorbent assay. Labor pain score was assessed by numerical rating scale. Results Median CSF serotonin concentration in parturients with labor pain was significantly lower than in those without pain (p < 0.001). Median CSF glycine level in the labor pain group was significantly higher than in the control group (p < 0.001). There were no significant differences in median CSF level of noradrenaline or GABA between parturients with and without labor pain. Subsequent analysis showed labor pain scores to be negatively correlated with CSF serotonin (r = −0.217, p = 0.04) but positively correlated with CSF glycine (r = 0.415, p < 0.001). Conclusion CSF serotonin and glycine were significantly correlated with labor pain scores. These findings suggest that the serotonergic and glycinergic systems may play a role in spinal modulation of visceral pain.

Potential use of cerebrospinal fluid serotonin level as a marker of neuronal injury after exposure to 3, 4-Methylenedioxymethamphetamine

Potential use of cerebrospinal fluid serotonin level as a marker of neuronal injury after exposure to 3, 4-Methylenedioxymethamphetamine

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.

Evaluation of Postmortem Cerebrospinal Fluid S100B Protein and Serotonin Levels: Comparison of Suicidal Versus Nonsuicidal Deaths in Konya, Turkey

Although suicide is a preventable public health problem, objective assays for suicide risk are limited. In this study, it was aimed to determine levels of S100B protein and serotonin as a marker for risk of suicide. S100B protein and serotonin levels were investigated with ELISA method in the cerebrospinal fluid (CSF) in medicolegal autopsy cases, including those of suicide cases (n = 32) and nonsuicide cases (n = 56). The CSF S100B levels were higher (9.3 ± 2.9 ng/mL vs. 5.4 ± 2.0 ng/mL), and serotonin levels were lower (10.4 ± 4.9 ng/mL vs. 19.0 ± 5.7 ng/mL) in suicide group than nonsuicide group (p < 0.05). There was no correlation between S100B protein and serotonin levels with gender, age groups, postmortem interval, and cause of death. It is concluded that both S100B protein and serotonin in CSF may be useful for determination of suicide risk.

Descending nociceptive inhibition is modulated in a time-dependent manner in a double-hit model of chronic/tonic pain

Clinical evidences suggest that an imbalance between descending inhibition and facilitation drives the development of chronic pain. However, potential mechanisms promoting the establishment of a persistent pain state and the increased pain vulnerability remain unknown. This preclinical study was designed to evaluate temporal changes in descending pain modulation at specific experimental endpoints (12, 28, 90 and 168days) using a novel double-hit model of chronic/tonic pain (first hit: chronic constriction injury (CCI) model; second hit: tonic formalin pain in the contralateral hindpaw). Basal activity of bulbo-spinal monoaminergic systems was further assessed through liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) screening of cerebrospinal fluid (CSF). We found that CCI-operated rats exhibited a reduced nociceptive response profile, peaking on day 28, when subjected to tonic pain. This behavioral response was accompanied by a rapid increase in basal CSF serotonin and norepinephrine levels 12days after neuropathy, followed by a return to sham levels on day 28. These molecular and behavioral adaptive changes in descending pain inhibition seemed to slowly fade over time. We therefore suggest that chronic neuropathic pain produces a transient hyperactivation of bulbo-spinal monoaminergic drive when previously primed using a tonic pain paradigm (i.e., formalin test), translating into inhibition of subsequent nociceptive behaviors. Altogether, we propose that early hyperactivation of descending pain inhibitory mechanisms, and its potential ensuing exhaustion, could be part of the temporal neurophysiological chain of events favoring chronic neuropathic pain establishment.

The role of serotonin in impulsive aggression, suicide, and homicide in adolescents and adults: a literature review.

This is a literature review discussing previous studies on the associations between impulsive aggression and the serotonergic system in adults, adolescents, and children. The review demonstrates that there is a clear association between low cerebrospinal fluid serotonin and impulsive aggression. However, studies on neurotransmitter receptor profiles, functional imaging, genetics, and epigenetics reviewed in this article suggest a more complicated picture that includes consideration of gene vs. environment in the evaluation of risk. Serotonin supplementation studies suggest that selective serotonin reuptake inhibitors may reduce impulsive aggression in some adults but are less effective in adults with pathological aggression and also in children and adolescents. Child and adolescent studies are less conclusive, in part due to the heterogeneous physiologic and psychosocial changes occurring over the course of development. The author thus concludes that psychiatrists can reduce risk in these special patient populations by creating safer environments in the form of changes in policy and increased support services.

CSF miR-16 is decreased in major depression patients and its neutralization in rats induces depression-like behaviors via a serotonin transmitter system

BackgroundAnimal and cell line studies demonstrated that miR-16 may be associated with major depressive disorder (MDD) via regulation of the expression of serotonin transporter (SERT) gene. However, human studies about miR-16 of patients with MDD are still lacking. The aim of this study was to investigate the possible involvement of miR-16 in the mechanism of MDD in humans. MethodsThirty-six drug-free patients with MDD and 30 healthy controls aged between 18 and 45 years old were recruited. 24-item Hamilton depression scale test was performed for each subject. MiR-16 in cerebrospinal fluid (CSF) and blood, as well as serotonin in CSF were assayed by the qRT-PCR or ELISA method. To confirm the role of CSF miR-16 in MDD, animal study about intracerebroventricular injection of anti-miR-16 was also performed. Depression-like behaviors, CSF miR-16 and serotonin, blood miR-16, and raphe SERT protein of rats were also tested. ResultsCSF miR-16 in MDD patients was significantly lower than that in controls. It was negatively correlated with Hamilton scores and positively associated with CSF serotonin. However, blood miR-16 was not significantly different between two groups and it was not statistically correlated with CSF miR-16. In animal study, anti-miR-16-treated rats were evaluated to exhibit depression-like behaviors, extremely lower CSF miR-16, significantly higher CSF serotonin, and obviously higher raphe SERT protein than control rats. LimitationWe did not detect SERT protein in human brain due to the impossibility of sample collection. ConclusionOur study suggested that CSF miR-16 participated in the physiopathology of MDD via the modulation of serotonin transmitter system in brain.

Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene

BackgroundPatients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF).MethodsWe sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis.ResultsThe known heterozygous p.Gly56Ala mutation in the SLC6A4 gene was equally found in the ASD and control populations. Using a genetic candidate gene approach, we identified, in 8 patients of a cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous non-synonymous mutations within the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients, c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G (p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed that these PMAT mutations were not de novo but inherited mutations. Upon analyzing over 15,000 normal control chromosomes, only SLC29A4 c.86A > G was found in 23 alleles (0.14%), while neither c.412G > A (<0.007%) nor c.978 T > G (<0.007%) were observed in all chromosomes analyzed, emphasizing the rareness of the three alterations. Expression of mutations PMAT-p.Ala138Thr and p.Asp326Glu in cellulae revealed significant reduced transport uptake activity towards a variety of substrates including serotonin, dopamine, and 1-methyl-4-phenylpyridinium (MPP+), while mutation p.Asp29Gly had reduced transport activity only towards MPP+. At least two ASD subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with altered serotonin transport activity had, besides low 5HIAA in CSF, elevated serotonin levels in blood and platelets. Moreover, whole exome sequencing revealed additional alterations in these two ASD patients in mainly serotonin-homeostasis genes compared to their non-affected family members.ConclusionsOur findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD.

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.

Effect of traumatic imagery on cerebrospinal fluid dopamine and serotonin metabolites in posttraumatic stress disorder

Dopaminergic mechanisms may be involved in the pathophysiology of posttraumatic stress disorder (PTSD), although the evidence for this is limited; serotonergic mechanisms are implicated largely by virtue of the modest efficacy of serotonergic drugs in the treatment of the disorder. Basal cerebrospinal fluid (CSF) dopamine and serotonin metabolite concentrations are normal in PTSD patients. However, in the present experiment, we postulated that perturbations in CSF dopamine and serotonin metabolites could be induced by acute psychological stress. Ten volunteers with war-related chronic PTSD underwent 6-h continuous lumbar CSF withdrawal on two occasions per patient (6–9 weeks apart), using a randomized, within subject-controlled, crossover design. During one session a 1-h video with trauma-related footage (traumatic video) was shown and in the other session subjects viewed a 1-h neutral video. We quantified the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF at 10-min intervals, before, during, and after video provocation. Blood pressure, heart rate, and subjective anxiety and mood were monitored. Significant drop in mood and increases in anxiety and blood pressure occurred during the traumatic relative to the neutral movie. CSF HVA concentrations diminished significantly after the traumatic video (p < 0.05), in comparison with the neutral, while 5-HIAA tended to diminish (p < 0.10). We conclude that an acute decline in CNS HVA concentrations is associated with laboratory-induced symptoms in chronic PTSD patients. While further research is required to determine if the stress-induced dopaminergic changes are normative or pathological, the present data suggest that increasing dopaminergic neurotransmission be explored as a potential therapy, or adjunctive therapy, for PTSD.