5-HIAA Levels Research Articles

SLC6A4 polymorphisms modulate the efficacy of a tryptophan-enriched diet on age-related depression and social cognition

Background & aims In a placebo controlled study we sought to determine if a four-weeks tryptophan-enriched diet is able to improve age-related depression or social cognitive impairment, depending on polymorphisms located in the promoter region of Solute Carrier Family 6 Member 4 (SLC6A4), also known as serotonin transporter (SERT1) gene. Methods 91 young volunteers (age: 21 ± 2 yrs) and 127 above 50 years old (58 ± 6 yrs) healthy volunteers completed the study. Participants from the placebo and tryptophan group followed the same protocol. Before starting the study blood samples, to measure serotonin-transporter-linked polymorphic region (5-HTTLPR) and rs25531 polymorphisms, were collected. In addition, before and after completing the study urine samples (to measure 5-hydroxyindolacetic acid (5-HIAA) were taken, while psychological questionnaires (to assess depression and social cognition levels), and a one week dietary record (to calculate the tryptophan (TRP) intake) were assessed. Results The triallelic approach of SLC6A4 showed that in S'S´ subjects there was a positive correlation between TRP intake and 5-HIAA levels. Age of participants, SLC6A4 genotype, and experimental condition were important factors contributing to the outcome of depression and social cognition. Conclusions 5-HTTLPR and rs25531 polymorphisms play a key role in the response to the TRP- based nutritional intervention, improving only age-related depressive symptoms and empathy in S'S´ subjects who have a higher risk to show signs of depression during their lifetime. In a placebo controlled study we sought to determine if a four-weeks tryptophan-enriched diet is able to improve age-related depression or social cognitive impairment, depending on polymorphisms located in the promoter region of Solute Carrier Family 6 Member 4 (SLC6A4), also known as serotonin transporter (SERT1) gene. 91 young volunteers (age: 21 ± 2 yrs) and 127 above 50 years old (58 ± 6 yrs) healthy volunteers completed the study. Participants from the placebo and tryptophan group followed the same protocol. Before starting the study blood samples, to measure serotonin-transporter-linked polymorphic region (5-HTTLPR) and rs25531 polymorphisms, were collected. In addition, before and after completing the study urine samples (to measure 5-hydroxyindolacetic acid (5-HIAA) were taken, while psychological questionnaires (to assess depression and social cognition levels), and a one week dietary record (to calculate the tryptophan (TRP) intake) were assessed. The triallelic approach of SLC6A4 showed that in S'S´ subjects there was a positive correlation between TRP intake and 5-HIAA levels. Age of participants, SLC6A4 genotype, and experimental condition were important factors contributing to the outcome of depression and social cognition. 5-HTTLPR and rs25531 polymorphisms play a key role in the response to the TRP- based nutritional intervention, improving only age-related depressive symptoms and empathy in S'S´ subjects who have a higher risk to show signs of depression during their lifetime.

Androgenic activation, impairment of the monoaminergic system and altered behavior in zebrafish larvae exposed to environmental concentrations of fenitrothion

Fenitrothion is an organophosphorus insecticide usually found in aquatic ecosystems at concentrations in the range of low ng/L. In this manuscript we show that 24 h exposure to environmental concentrations of fenitrothion, from ng/L to low μg/L, altered basal locomotor activity, visual-motor response and acoustic/vibrational escape response of zebrafish larvae. Furthermore, fenitrothion and expression of gap43a, gfap, atp2b1a, and mbp exhibited a significant non-monotonic concentration-response relationship. Once determined that environmental concentrations of fenitrothion were neurotoxic for zebrafish larvae, a computational analysis identified potential protein targets of this compound. Some of the predictions, including interactions with acetylcholinesterase, monoamine-oxidases and androgen receptor (AR), were experimentally validated. Binding to AR was the most suitable candidate for molecular initiating event, as indicated by both the up-regulation of cyp19a1b and sult2st3 and the non-monotonic relationship found between fenitrothion and the observed responses. Finally, when the integrity of the monoaminergic system was evaluated, altered levels of L-DOPA, DOPAC, HVA and 5-HIAA were found, as well as a significant up-regulation of slc18a2 expression at the lowest concentrations of fenitrothion. These data strongly suggest that concentrations of fenitrothion commonly found in aquatic ecosystems present a significant environmental risk for fish communities.

Alpha-pyrrolidinopentiophenone and mephedrone self-administration produce differential neurochemical changes following short- or long-access conditions in rats

Stimulant-induced neurochemical changes may occur at different times for different brain regions or neurotransmitter systems. This study sought to examine the behavioral and neurochemical effects of extended access to α-pyrrolidinopentiophenone (α-PVP) and 4-methylmethcathinone (4MMC). Male and female Sprague-Dawley rats were trained to self-administer α-PVP (0.1 mg/kg/infusion) or 4MMC (0.5 mg/kg/infusion) through autoshaping, and then self-administered for 21 days during 1 h (short access; ShA) or 6 h (long access; LgA) sessions. Separate rats were assigned to a naïve control group. Amygdala, hippocampus, hypothalamus, prefrontal cortex (PFC), striatum, and thalamus were extracted, and tissue was analyzed with electrochemical detection and liquid chromatography mass spectrometry. Rats acquired self-administration of α-PVP and 4MMC, and LgA rats showed more escalation of self-administration than ShA rats. Synthetic cathinone administration produced several effects on neurotransmitters. LgA self-administration of α-PVP increased 5-HIAA levels in all brain regions, compared to control. In contrast, both LgA and ShA 4MMC self-administration decreased 5-HT and 5-HIAA levels in most brain regions. LgA exposure to both synthetic cathinones increased DOPAC levels in hypothalamus and striatum, and increased HVA levels in striatum compared to control. LgA self-administration of either synthetic cathinone produced region-specific increases in NE levels, whereas ShA self-administration lowered NE levels in select locations compared to control. These alterations in neurotransmitter levels indicate that synthetic cathinone use may produce differential neurochemical changes during the transition from use to abuse, and that 21 days of self-administration only models the beginning stages of dysregulated drug intake.

Cerebrospinal fluid monoamine levels in central disorders of hypersomnolence.

Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin (ORX) neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH), is currently unknown. Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non orexin-deficient (NT2 and IH), and 24 patients without objective sleepiness. Three trace amines were undetectable in the sample: tryptamine, octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels tended to increase in NT1 compared to other patients after adjustment. Most of the biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g. 3-methoxy-4-hydroxyphenylglycol and norepinephrine) correlated with daytime sleepiness and high rapid eye movement (REM) sleep propensity. We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1, NT2/IH, and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration.

The Role of Serum 5-HIAA as a Predictor of Progression and an Alternative to 24-h Urine 5-HIAA in Well-Differentiated Neuroendocrine Neoplasms.

Simple Summary5-hydroxyinoloacetic acid (5HIAA) is the breakdown product of serotonin and it is traditionally measured in 24-h urinary samples in patients with neuroendocrine neoplasms (NENs). 5HIAA measurement in patient serum has recently become available and has started replacing the traditional method in many centers, as it is more convenient and often preferred by patients. In this prospective, single center study, we aimed to investigate the clinical utility of serum 5HIAA for diagnostic purposes and disease surveillance in a cohort of patients with well-differentiated NENs. Our analysis confirmed an association between serum 5HIAA and the presence of liver metastases, as well as the extent of liver tumor involvement, demonstrating that the biomarker becomes positive in advanced disease stages. However, there was no evident association between a change in serum 5HIAA and change in disease status. Additionally, with respect to diagnostic purposes as compared to urinary 5HIAA testing, there was a substantial agreement between the two methods. In conclusion, serum 5HIAA performs well compared to urinary testing for diagnostic purposes but does not seem adequate as a solo biomarker of disease progression.Our aim was to investigate the clinical utility of serum 5HIAA for disease surveillance and diagnostic purposes in a cohort of patients with well-differentiated neuroendocrine neoplasms (WD-NENs). Forty-eight patients with WD-NENs and concurrent serum and urinary 5HIAA testing, as well as CT/MRI imaging, were included. Analysis of matching-pairs did not reveal any association between RECIST 1.1 responses and changes in serum 5HIAA levels (p = 0.673). In addition, no correlation was evident between RECIST 1.1 responses and >10%, >25% or >50% changes in serum 5HIAA levels (Fisher’s exact test p = 0.380, p > 0.999, and p > 0.999, respectively). The presence of liver metastases and extensive liver tumor involvement were associated with higher serum 5HIAA levels (p = 0.045 and p = 0.041, respectively). We also confirmed a strong linear correlation between the measurements of serum and urine 5HIAA (n = 24, r = 0.791, p < 0.0001). The concordance rate of serum and urinary 5HIAA positivity at standardized laboratory cut-offs was 75%. In patients with normal renal function tests, the concordance between the two methods was as high as 89%, and a sensitivity and specificity of 80% and 88.9%, respectively, was evident (Cohen’s kappa coefficient = 0.685). In conclusion, serum 5HIAA performs well compared to urinary testing for diagnostic purposes, mainly in advanced disease stages, and corresponds well to liver tumor burden. However, it is not adequate to predict tumor progression.

Tumor burden in serotonin secreting pancreatic neuroendocrine tumors after initiating telotristat ethyl.

367 Background: Pancreatic neuroendocrine tumors (pNETs) characterized by high serotonin levels and carcinoid syndrome (CS) are rare. We evaluated tumor burden in a subgroup of patients with pNETS from the real-world TELEACE study before and after initiating telotristat ethyl (TE) in US clinical practice. Methods: Detailed methods of the TELEACE study have been reported previously. This was a retrospective, single arm, pre-post physician panel-based chart review of patients who received TE for at least 6 months. Descriptive statistics analyzed demographic, clinical, laboratory and radiological data extracted from medical charts of TELEACE patients with pNETS. Results: Fifty-two patients with pNETS initiating TE were eligible for this analysis. The average age at the time of TE initiation was 60+10.4 years; 64% were males. The majority of patients had well-differentiated (60%) tumors and low-grade (54%) tumor status. Patients received TE for an average of 11.5+7.84 months, and 21% were still receiving TE at the time of data extraction. Diarrhea and flushing were the most common CS symptoms recorded at the time of TE initiation. Urinary 5-HIAA levels were reported for 9 patients before and for 2 patients after TE initiation. Mean (median) 5-HIAA levels before and after TE initiation were 693 (211) and 22 (22) µmol/24h, respectively. Significant mean reduction in tumor size of 0.67 cm after TE initiation (P = 0.017) was observed. Conclusions: This subgroup analysis of the TELEACE study population showed that the addition of TE to somatostatin analog treatment may positively impact tumor burden for patients with functional pNETs.

Ampullary neuroendocrine tumors: A window into a rare tumor using a national database.

373 Background: Ampullary neuroendocrine tumors (NET) make up &lt; 1% of all gastrointestinal NETs. Information about their behavior and prognosis is reliant on small case series. This study set out to describe the population of patients who are diagnosed with ampullary NETs and compare them to patients with duodenal and pancreatic head NETs. Methods: The National Cancer Database (2004 – 2016) was queried for patients with ampullary, duodenal, and pancreatic head NETs. Clinicopathologic and treatment characteristics were compared. Subset analysis was performed on patients who underwent surgery. Kaplan Meier (KM) analysis and Cox regression were used to analyze the survival of patients with ampullary NETs. Results: Overall, 872 patients were identified with ampullary NET, 9692 with duodenal NET, and 6562 with pancreatic head NET. Patients with ampullary NET had an average age of 60.9 +/- 14.5 years, were evenly split among men and women (N = 437, 50.1% vs N = 435, 49.9%, respectively), and primarily Caucasian (N = 663, 76.0%). 72.1% underwent local tumor destruction or surgery (N = 629). Most did not receive radiation (N = 832, 95.4%), chemotherapy (N = 627, 71.9%), or hormone therapy (N = 788, 90.4%). Patients with ampullary NETs had more poorly differentiated tumors (N = 119, 13.6%) than patients with duodenal (N = 159, 1.6%) or pancreatic head (N = 602, 9.2%) NETs. Patients with ampullary NETs had more positive lymph nodes (N = 288, 33%) than patients with duodenal (N = 915, 9.4%) or pancreatic head (N = 1381, 21%) NETs. At five years, the overall survival for patients with ampullary, duodenal, and pancreatic head NETs was 57%, 68%, and 46%, respectively. Within the surgical population, five-year survival for patients with ampullary (N = 367), duodenal (N = 991), and pancreatic head (N = 1961) NETs was 60%, 74%, and 72%, respectively. When compared, there was a statistically significant difference between the mean overall survival of patients with ampullary (98 +/- 4.7 months), duodenal (112 +/- 2.5 months), and pancreatic head (108 +/- 1.7 months) NETs (p &lt; 0.001). In the cox regression analysis, sex, Charlson-Deyo score, lymph node positivity, lymph-vascular invasion, mitotic rate, chromogranin A level, 5-HIAA level, and tumor size did not correlate with survival. Increasing age (HR 1.04, CI 1.01 – 1.07, p = 0.008) and worse tumor differentiation (poorly differentiated HR 3.33, CI 1.38 – 8.04, p = 0.008 and undifferentiated HR 8.31, CI 2.77 – 24.92, p &lt; 0.001 compared to well differentiated) were associated with increased mortality. Conclusions: This study sheds light on a rare tumor histology. When compared to patients who underwent surgical resection for duodenal or pancreatic head NETs, patients with ampullary NETs had a significantly worse prognosis. Identifying prognostic factors allows us to create more concrete treatment recommendations and provide patients with improved prognostic information.

Serotonin in the Pathogenesis of Lymphocytic Colitis.

Lymphocytic colitis (LC) is a chronic inflammatory disease associated with watery diarrhea, abdominal pain, and colonic intraepithelial lymphocytosis. Serotonin (5-hydroxytryptamine, 5-HT) is reported to increase in certain colon diseases; however, little is known regarding its metabolism in LC. In the present work, the level of 5-HT in serum and the number of enteroendocrine cells (EECs) as well as the expression of the 5-HT rate-limiting enzyme tryptophan hydroxylase 1 (TPH1) in colonic biopsies and urine 5-hydroxyindoeoacetic acid (5-HIAA) were determined in 36 LC patients that were treated with budesonide and 32 healthy controls. The 5-HT serum and 5-HIAA urine levels were measured using ELISA, the EEC number was determined immunohistochemically, and the colonic TPH1 mRNA expression was determined using RT-PCR. The levels of 5-HT and 5-HIAA and the number of EECs were higher in LC patients than in the controls, and positive correlations were observed between the 5-HT and 5-HIAA levels, 5-HT and EEC number, TPH1 mRNA and EEC number, as well as the severity of disease symptoms and 5-HIAA. Budesonide decreased the levels of 5-HT, 5-HIAA, and TPH1 expression and the number of EECs to values that did not differ from those for controls. In conclusion, the serotonin metabolism may be important for LC pathogenesis, and the urinary level of 5-HIAA may be considered as a non-invasive marker of this disease activity.

Dysfunction of the Monoaminergic Brain System in BALB/c Mice Progeny after Sodium Valproate Administration to Pregnant Females: Neurochemical Study

Abstract—We studied the dopamine-, serotonin-, and norepinephrinergic systems in various brain structures of BALB/c male mice on days 15, 42, and 64 of postnatal development (PND) in the model of autism spectrum disorder induced by sodium valproate administration (400 mg/kg, s/c) to pregnant females. It was found that the level of both catechol- and indolamines in the brain structures of control 15-day-old mice is considerably lower than in 64-day-old adult animals. Prenatal administration of sodium valproate (SV) caused a decrease in all parameters of monoaminergic neurotransmission in the striatum of mouse offspring aged 15 days but did not lead to neurochemical changes in other studied brain structures. By PND 42, the general pattern of changes in neurotransmitter concentrations did not differ from the developmental dynamics of neurotransmitter system maturation in the control group. The level of DA kept increasing and by PND 64, did not differ from controls. The parameters of serotonergic system changed similarly, with the peak serotonin concentration by PND 42 and a significant decrease by PND 64, whereas the level of 5-HIAA in the striatum increased gradually with maximum differences observed by PND 64. Thus, the data obtained suggest that administration of SV to pregnant females affects the activity of the dopamine- and serotonergic brain systems in the progeny, inducing its decrease in the striatum by PND 15 followed by recovery to control level by PND 64.

Difference in the brain serotonin and its metabolite level and anxiety-like behavior between forced and voluntary exercise conditions in rats

Physical exercise is beneficial to both physical and mental health, though it is unclear whether voluntary and forced exercise have the same effects. We investigated the effects of chronic forced and voluntary wheel running on brain levels of serotonin (5-HT), its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and anxiety-like behavioral change in rats. Forty-eight rats were randomly assigned to standard cages (sedentary control: SC); voluntary exercise (free running on a wheel, V-EX); voluntary limited exercise (wheel available only 1 h per day, VL-EX); and forced exercise (running on a motorized wheel, F-EX). After 4 weeks, rats either underwent the open field test (OFT) or their 5-HT and 5-HIAA levels were measured in the major serotonergic neural cell bodies and projection areas. 5-HT and 5-HIAA levels in the dorsal and median raphe nuclei were increased in the V-EX, but not in the VL-EX and F-EX groups, compared with the SC group. In the paraventricular hypothalamic nucleus and caudate putamen, only 5-HT levels were increased in the V-EX group. Interestingly, in the amygdala, only 5-HIAA levels were significantly increased in the V-EX group. Conversely, we found that F-EX rats showed no significant 5-HT changes and increased anxiety-like behavior. VL-EX did not have significant beneficial effects on any of the experimental parameters. These data suggest that only unlimited voluntary exercise stimulates the serotonergic system and suppresses anxiety-like behavior.

Biomarker of urinary 5-HIAA as a valuable predictor of acute appendicitis

BackgroundSerotonin-containing cells are abundantly found in the appendix. Studies have shown that acute appendicitis is likely to be characterized by altered urinary 5-hydroxyindole acetic acid (5-HIAA), an active serotonin metabolite. The aim of this study is to investigate the diagnostic potential of 5-HIAA as a biomarker for acute appendicitis. MethodThis cross-sectional study enrolled patients referred at the Madani Hospital, with right iliac fossa pain, suspected to having the acute appendicitis. Before the initiation of the basic treatment and surgery, urine samples were obtained from the patients. Enzyme-linked immunosorbent assay (ELISA) was used for the analysis of 5-HIAA urinary levels. The obtained data were statistically analyzed using SPSS v18. ResultsOf 129 patients included in the study with the mean age of 29 years, 62 (48.1%) were men and 67 (51.9%) were women. Appendectomy was performed in 96 patients, where 81 cases were that of acute appendicitis. The mean levels of 5-HIAA in acute appendicitis group and in the negative appendectomy group was not statistically significant. The sensitivity of the test was 54.3% based on 7.4 ​μmol/L as cut-off %-HIAA value. ConclusionOur study reports that 5-HIAA urine concentration is not a reliable diagnostic marker for the diagnosis of acute appendicitis.

Genetic Background Underlying 5-HT1A Receptor Functioning Affects the Response to Fluoxetine.

The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73–110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT1A receptors to chronic 8-OH-DPAT administration and higher 5-HT1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.

S2806 A Case of Ileocecal and Distal Sigmoid Carcinoid Tumor With Liver Metastasis

INTRODUCTION: Carcinoid tumors are rare, slow-growing neuroendocrine tumors (NET), often asymptomatic and may not become apparent until there is evidence of metastatic disease or carcinoid syndrome. Digestive involvement is most common in the appendix, mesentery and the ileum. We present a case of carcinoid tumor in the ileocecal valve and distal sigmoid colon, complicated by liver metastasis. CASE DESCRIPTION/METHODS: A 55 year-old African-American with no significant past medical history, presents for eight months of progressive weight loss, subjective fever, chronic watery diarrhea and episodes of flushing. Physical exam was significant for thin habitus. Laboratory tests revealed macrocytic anemia and progressive increase in transaminases (ALT 224 U/L, AST 217 U/L). Right upper quadrant US was showed scattered small indeterminate liver lesions of 1.5 cm. CT abdomen/pelvis revealed a 2.3 × 2.1 cm focal mass and thickening of the terminal ileum and a 2.1 cm mass in the distal sigmoid colon, in addition to multiple liver lesions. Percutaneous liver biopsy consistent with two minute clusters of NET cells at 0.15 mm and 0.10 mm showed positive immunohistochemistry (IHC) positive for synaptophysin an chromogranin. Further laboratory investigation included elevated urine 5-HIAA (60 mg/24 h) and elevated levels of serum chromogranin (167 ng/mL). Colonoscopy with terminal ileum intubation showed a 7 mm pedunculated broad based polyp in the sigmoid colon and a protruding polypoid irregular ileocecal valve. Histopathology from colonic mucosa showed non-specific chronic inflammation and immunoreactivity for CD45, which supports the diagnosis of NET. The patient was treated with Sandostatin injections monthly with significant clinical improvement, and is followed by Oncology and Gastroenterology services. DISCUSSION: Carcinoid tumors although rare, can be found throughout the gastrointestinal tract, generally in the appendix or ileum. Our patient presented with clinical and immunohistochemical characteristics consistent with carcinoid tumor, and apparent unusual localization in the ileocecal valve and distal sigmoid colon. Associated liver metastasis was evident. Recent literature reports that the overall incidence of carcinoid tumors has been steadily increasing likely due to advances in testing, however most cases are being detected after wide-spread disease.CONCLUSION. Further description of the biological and histopathological characteristics of carcinoid tumors is needed for implementation of early detection techniques.

Features of the involvement of the dopamine and serotonin brain systems in positive and negative emotional states in rats

The aim was to study the effect of rewarding and aversive stimulation of lateral hypothalamus on the turnover of monoamines in the terminal structures of the mesocorticolimbic and nigrostriatal systems: the nucleus accumbens (NAc) and striatum (St). The Wistar male rats were implanted electrodes in the lateral hypothalamus and further trained in self-stimulation test. Animals were also selected on aversive emotional reactions were observed after pressing the pedal for self-stimulation. Subsequently, forced stimulation was performed for 5 minutes and the animals were decapitated. The content of norepinephrine, dopamine (DA) and its metabolites 3,4-dioxiphenylacetic acid (DOPАС) and homovanilinic acid, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens and striatum were determined by high performance liquid chromatography with electrochemical detection. Positive and aversive stimulation of lateral hypothalamus decreased the level of DA in the NAc, however, only stimulation of the positive emotiogenic zone increased the DA and 5-HT turnover in the NAc, as evidenced by an increase in the DOPАС/DA and 5-HIAA/SER ratios, respectively. Rewarding and aversive stimulation decreased the level of 5-HT in St, however, only rewarding stimulation decreased the St level of 5-HIAA compared to control and animals with aversive stimulation. Rewarding stimulation increased the turnover of serotonin in St, as evidenced by the increase of 5-HIAA/5-HT ratios. The activity of the noradrenergic system did not change after rewarding and aversive stimulation. Thus, both rewarding and aversive electrical stimulation increases the turnover of DA and 5-HT in NAc and St. However, these changes are more significant after rewarding stimulation. DA turnover increases more in NAc, and 5-HT turnover in St. The data obtained indicate the specificity of the dopaminergic and serotonergic involvement for the formation of a modality of emotional reactions. Data may provide guidance for developing treatment strategies for neuropsychiatric diseases related to the malfunction of the reward system.

Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients

Introduction6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPSd) is a rare autosomal recessive disorder of synthesis of biogenic amines, which is characterized by variable neurological impairment and hyperphenylalaninemia. We aimed to assess the long-term clinical outcome of this disorder and the factors affecting it. MethodsAt total of 28 PTPSd patients (aged 19.9 ± 10.9 years) underwent clinical (neurological and psychiatric) and neuropsychological assessment (BRIEF, VABS-II, and IQ). Based on CSF homovanillic (HVA) and 5-hydroxyindolacetic acid (5-HIAA) and pterin concentrations at diagnosis, patients were classified as having either a severe [SF; low level of CSF, HVA, and 5-HIAA with altered neopterin/biopterin (Neo/Bio)] or mild form (MF; normal HVA and 5-HIAA with altered Neo/Bio) of PTPSd. ResultsApproximately 36% of patients had MF PTPSd. At the last examination, 43% of patients had movement disorders (2 MF, 10 SF), 43% of patients had variable degrees of intellectual disability (SF only), 39% met the criteria for a psychiatric disorder (3 MF, 9 SF). Applying a linear regression model, we found that HVA and phenylalanine levels at birth had a significant influence on IQ, BRIEF, and VABS-II variability. Lastly, 5-HIAA further contributed to VABS-II variability. The disease showed a self-limiting clinical course and its treatment, although delayed, is effective in improving the neurological status. ConclusionsNeurodevelopmental impairment due to PTPSd shows a self-limiting course. A continuous improvement in the neurological condition has been observed in patients receiving treatment, even when delayed. The severity of brain biogenic amine depletion at diagnosis predicts neurological and psychiatric outcomes.

Serotonin-Secreting Neuroendocrine Tumours of the Pancreas.

Background: Serotonin-secreting pancreatic neuroendocrine tumours (5-HT-secreting pNETs) are very rare, and characterised by high urinary 5-hydroxyindole-acetic acid (5-HIAA) levels (or high serum 5-HT levels). Methods: Patients with 5-HT-secreting pancreatic neoplasms observed in our unit (1986–2015) were included. Diagnosis was based on urinary 5-HIAA or serum 5-HT levels. Results: Seven patients were enrolled (4 M/3 F), with a median age of 64 (range 38–69) years. Two patients had a carcinoid syndrome. Serum 5-HT was elevated in four patients. Urinary 5-HIAA levels were positive in six patients. The median tumour size was 4.0 (range 2.5–10) cm. All patients showed liver metastases at diagnosis. None underwent resective surgery; lymph node/liver biopsies were taken. Six lesions were well-differentiated tumours and one a poorly differentiated carcinoma (Ki67 range 3.4–70%). All but one patient received chemotherapy. Four patients received somatostatin analogues; three patients underwent ablation of liver metastases. One patient is alive with disease 117 months after observation. All the others died from disease progression after a follow-up within 158 months. Conclusions: Primary 5-HT-secreting pNETs are mostly metastatic to the liver; patients are not amenable to resective surgery. Despite high 5-HIAA urinary levels, few patients present with carcinoid syndrome. A five-year survival rate of 42.9% may be achieved with multimodal treatment.

On the interaction between BDNF and serotonin systems: The effects of long-term ethanol consumption in mice.

We investigated the effect of chronic (6 weeks) consumption of 10% alcohol on the principal elements of BDNF (BDNF, proBDNF, p75, and TrkB receptors) and 5-HT (5-HT, 5-HIAA, tryptophan hydroxylase-2 [Tph-2], 5-HT transporter [5-HTT], 5-HT1A, 5-HT2A, and 5-HT7 receptors) systems in the brain of C57Bl/6 mice. BDNF mRNA level in the raphe nuclei area and BDNF protein level in the hippocampus were lowered in ethanol-treated mice. The increase in proBDNF protein level in the raphe nuclei area, cortex, and amygdala and the increase of p75 receptor protein levels in the raphe nuclei area were revealed after ethanol exposure. Alcohol intake reduced the protein level and increased the activity of Tph-2, the key enzyme for serotonin biosynthesis in the brain, and increased the main 5-HT metabolite 5-HIAA level and 5-HIAA/5-НТ ratio as well as the 5-HT7 receptor mRNA level in the raphe nuclei area. In the cortex, 5-HT2A receptor protein level was reduced, and 5-HIAA/5-HT ratio was increased. These data showed considerable impact of alcoholization on the BDNF system, resulting in proBDNF and p75 receptor expression enhancement. Alcohol-induced changes in BDNF and 5-HT systems were revealed in the raphe nuclei area where the majority of the cell bodies of the 5-HT neurons are localized, as well as in the cortex, hippocampus, and amygdala. Our data suggest that the BDNF/5-HT interaction contributes to the mechanism underlying chronic alcohol-induced neurodegenerative disorders.

Supplemental taurine during adolescence and early adulthood has sex-specific effects on cognition, behavior and neurotransmitter levels in C57BL/6J mice dependent on exposure window

The mammalian brain goes through final maturation during late adolescence and early adulthood with sex differences in timing. The key cellular processes, including changes in neurotransmitter receptor density and synaptic pruning, make this age uniquely vulnerable to neurotoxic insults. Teenagers and young adults are the major consumers of energy drinks, which contain high levels of taurine and caffeine. Taurine is one of the most abundant amino acids in the central nervous system, but the effects of supplemental taurine consumption during adolescence has not been well studied. We conducted an initial short-term exposure study with 0.12% taurine in drinking water and a long-term exposure dose-response study using 0.06 and 0.12% taurine in male and female C57BL/6J mice. We examined a broad range of cognitive functions and behaviors and measured neurotransmitter levels. We found no significant differences in anxiety, open field locomotor activity, or sensorimotor gating. However, we found impairments in novel object recognition and sex differences in Morris water maze. When taurine treatment stopped before behavioral experiments began, male mice had significant impairments in spatial learning and memory. In the dose-response study when taurine treatment continued throughout behavioral experiments, females had significant impairments. We also found sex differences in neurotransmitter levels with females having higher levels of glutamate, DOPAC and 5-HIAA. We conclude that both females and males are at risk from excess taurine consumption during final brain maturation.

P55 Carcinoid syndrome on etanercept and subsequent treatment with secukinumab in a patient with psoriatic arthritis

Abstract Background Psoriatic arthritis requires early recognition and treatment for prevention of disease progression. Conventional disease modifying drugs are first-line agents followed by biologic DMARDs for patients with active disease. TNF-alpha blockers are first line biologic agents in the UK. Th17 inhibitors are used since the elucidation of Th17 pathway. Safety and efficacy profiles of biologic agents inhibiting the Th17 pathway, including secukinumab (IL-17A) and ustekinumab (IL-12/23p40) have been studied. Methods We report a case of carcinoid syndrome in a lady on etanercept for psoriatic arthritis, carcinoid as a potential TNF alpha side effect. We also report safety of Th17 (secukinumab) inhibitors in the patient to date (&amp;gt;1 year). Results A female with a history of acne rosacea, was diagnosed with psoriatic arthritis in 2000 age 32. Initial sulphasalazine failed, then received methotrexate until 2011, when her arthritis flared. She was commenced on etanercept which proved effective. After 4 years of etanercept and methotrexate, her liver profile became deranged. Investigations off treatment included ultrasound abdomen demonstrating a liver mass, which resembled focal nodular hyperplasia on magnetic resonance imaging. Further screening revealed high urinary 5HIAA (527 umol/24h) and raised chromogranin A &amp; B levels (1574 pmol/L and 373 pmol/L respectively). She had no symptoms suggestive of carcinoid, although facial flushing could have been camouflaged by her rosacea. Octreotide scan was positive, CT enterogram showed a distal ileal neuroendocrine tumour with adjacent lymphadenopathy. She underwent right hemihepatectomy and hemicolectomy. Her liver profile deteriorated again on methotrexate, leflunomide was ineffective. In November 2017 she was started on ustekinumab, which was ineffective and was withdrawn after 8 months. There was no alteration in carcinoid blood markers and no CT changes. In July 2018, she was commenced on secukinumab, which has allowed reduction in steroids. The patient is aware of lack of safety data in her circumstances. Regular surveillance has shown no recurrence of carcinoid with serial negative 5HIAA and chromogranin levels. There are no progressive CT changes at 1 year. Conclusion This is a case of carcinoid tumour occurring on TNF-alpha blockers and may represent a rare complication. Screening biomarkers including 5HIAA and chromogranin levels can be useful if disease is suspected. We could not find other similar case reports to guide further management. Within time limited data available - ustekinumab had no effect on the carcinoid. Th17 inhibitors can be safe options for treating psoriatic arthritis and psoriasis with highly sustained efficacy and favourable safety profile seen in large clinical trials. In this case, after &amp;gt; one year of secukinumab treatment - there is no adverse effect on carcinoid syndrome. Disclosures A.S.F. Sheikh None. S.G. Srivastva None. F. Wood None.

Blast‐induced Traumatic Brain Injury Elicits Sociability Deficits and Aggressive Behaviors Coinciding with Transient Variations in CNS 5‐HT Levels and 5‐HT2A Hypersensitivity

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity. In the United States alone, TBI accounts for 2.8 million emergency department visits and an economic cost of nearly $80 billion annually. The lack of any FDA‐approved therapies for treatment of acute or chronic symptoms of TBI necessitates the identification and characterization of novel drug targets. TBI often results in the generation of neuropsychiatric disorders including major depressive disorder (MDD), anxiety, aggression, and social withdrawal within the first 12 months following injury, disorders linked to altered serotonin (5‐HT) signaling. Currently, the effects of TBI on physiologic function of the 5‐HT signaling system within the CNS are poorly understood. We hypothesize that TBI drives the formation of aberrant behavioral states linked to neuropsychiatric disorders through alterations of normal, physiologic 5‐HT signaling. To test this hypothesis, adult, wild type C57Bl/6J mice were subjected to a single, blast‐induced TBI or sham treatment, followed by behavioral and/or molecular analyses 0–30 days post‐injury (dpi). High performance liquid chromatography (HPLC) revealed a time‐dependent increase and subsequent decrease in total 5‐HT and 5HIAA levels within the dorsal raphe nucleus (DRN) 10 and 30 dpi, respectively. No effect of TBI on 5‐HT levels was found in prefrontal cortex (PFC) or somatosensory cortex (SSC), areas of high 5‐HT innervation. Using the tube test for social dominance, time‐dependent alterations in DRN 5‐HT levels were found to correlate with altered social dominance behavior. TBI resulted in decreased social dominance/aversion 10 dpi, but an increase in dominance behavior 30 dpi. Using the Crawley Three Chamber Sociability Assay, TBI‐induced decreases in sociability were observed 10 dpi, an effect not present at 30 dpi. To investigate alterations in 5‐HT receptor pharmacology associated with TBI, 5‐HT2A receptor sensitivity was determined using DOI‐induced head twitch response (HTR) assays. TBI rapidly increased 5‐HT2A receptor sensitivity, effects persisting for 10 dpi. TBI‐elicited increases in DOI‐induced HTR were attenuated by administration of the 5‐HT2A antagonist M100907, indicating a dependence on intact 5‐HT2A receptor signaling. [3H]Ketanserin receptor binding studies revealed an increase in cortical 5‐HT2A receptor binding at 3 and 10 dpi. Collectively, these data provide evidence that TBI elicits time‐dependent alterations in the 5‐HT architecture of the CNS, effects that coincide with altered social function. A more thorough understanding of specifically how neurotrauma alters 5‐HT signaling will allow for the informed clinical utilization of available 5‐HT‐oriented pharmacotherapies and may provide drug discovery targets for TBI‐elicited neuropsychiatric sequelae.Support or Funding InformationStudies were supported by the Brain &amp; Behavior Research Foundation, PhRMA Foundation, and the University of Cincinnati