Elevated Serotonin Research Articles

Serotonin 1A receptors and sexual behavior in female rats: A review

This review focuses on the role of serotonin and especially 5-HT1A receptors in female rat sexual behavior. In addition, the differences and/or similarities with male rats are discussed. Overall, in both males and females 5-HT1A receptors do not appear to be involved in sexual behavior under normal circumstances, but become very important under conditions of elevated serotonin levels. 5-HT1A receptor agonists facilitate sexual behavior in male rats, but inhibit female sexual activity. At first sight, this seems quite conflicting, but could be due to our definitions of different elements of sexual behavior. Three different phases can be distinguished in rats' sexual cycle, the introductory (precopulatory), the copulatory and the executive (ejaculatory) phases. Different mechanisms and brain regions are involved in these phases. If the appropriate phases of males and females are properly compared, the role of 5-HT1A receptors in rats might be more similar than assumed thus far.

Chin tremors associated with paroxetine in a patient with pancreatic adenocarcinoma.

There have been many cases of medication-induced tremors. We report a patient who developed significant chin tremors after the administration of paroxetine.A 68-year-old Vietnamese female with a past medical history including GIST and pancreatic cancer status post Whipple procedure and six months of adjuvant chemotherapy with gemcitabine presented with symptoms of anxiety for which she was treated with paroxetine. Within 2 weeks she developed chin tremors which resolved after paroxetine was discontinued.To our knowledge, this is the first case report of a temporary chin tremor associated with paroxetine. The exact mechanism of this phenomenon is unclear. However, it has been suggested that movement disorders such as chin tremors may be related to elevated serotonin levels causing an inhibition of central dopamine.

Carcinoid syndrome caused by a serotonin-secreting pituitary tumour

Neuroendocrine tumours are most frequently located in the gastrointestinal organ system or in the lungs, but they may occasionally be found in other organs. We describe a 56-year-old woman suffering from a carcinoid syndrome caused by a large serotonin-secreting pituitary tumour. She had suffered for years from episodes of palpitations, dyspnoea and flushing. Cardiac disease had been suspected, which delayed the diagnosis, until blood tests revealed elevated serotonin and chromogranin A in plasma. The somatostatin receptor (SSR) scintigraphy showed a single-positive focus in the region of the pituitary gland and MRI showed a corresponding intra- and suprasellar heterogeneous mass. After pre-treatment with octreotide leading to symptomatic improvement, the patient underwent trans-cranial surgery with removal of the tumour. This led to a clinical improvement and to a normalisation of SSR scintigraphy, as well as serotonin and chromogranin A levels. To our knowledge, this is the first reported case of a serotonin-secreting tumour with a primary location in the pituitary.

Bronchial Carcinoid and Primary Hyperparathyroidism

Our patient, a 62-year-old female, presented for management of primary hyperparathyroidism. Subsequent to confirmatory lab testing, she underwent Tc-sestamibi imaging for localization of parathyroid adenoma. The imaging was suspicious for right inferior parathyroid adenoma and showed a posterior right lower lobe lung nodule (2.4 1.8 cm) (Figures 1 and 2). Biopsy of the right lung mass showed a lowgrade neuroendocrine tumor (carcinoid). An octreotide scan confirmed the presence of carcinoid in the right lower lobe. Biochemical work-up for carcinoid was unrevealing except for elevated serum serotonin levels at 394 ng/mL (normal range, 50 –220 ng/mL). Subsequent to resection of the lung mass and right inferior/left inferior and right superior parathyroid glands, her serum

Acute administration of 5-HT precursor 5-hydroxytryptophan upregulates constitutive isoform of neuronal nitric oxide synthase activity in the rat brain

The possibility that endogenous elevation of serotonin is influencing blood–/INS;brain barrier (BBB) permeability, neuronal nitric oxide synthase activity was examined in the brain and spinal cord of rats. Elevation of endogenous serotonin level was achieved by administration of its precursor, 5-hydroxytryptophan (150mg/kg, i.p.). The elevation of serotonin level in the brain and spinal cord was confirmed by immunohistochemical demonstration of 5-HT activity. Four hours/INS; after administration of 5-HTP, the animals exhibited hyperthermia and other behavioral symptoms.

Impact of Elevated Plasma Serotonin on Global Gene Expression of Murine Megakaryocytes

BackgroundSerotonin (5-HT) is a biogenic amine that also acts as a mitogen and a developmental signal early in rodent embryogenesis. Genetic and pharmacological disruption of 5-HT signaling causes various diseases and disorders via mediating central nervous system, cardiovascular system, and serious abnormalities on a growing embryo. Today, neither the effective modulators on 5-HT signaling pathways nor the genes affected by 5-HT signal are well known yet.Methodology/Principal FindingsIn an attempt to identify the genes altered by 5-HT signaling pathways, we analyzed the global gene expression via the Illumina array platform using the mouse WG-6 v2.0 Expression BeadChip containing 45,281 probe sets representing 30,854 genes in megakaryocytes isolated from mice infused with 5-HT or saline. We identified 723 differentially expressed genes of which 706 were induced and 17 were repressed by elevated plasma 5-HT.Conclusions/SignificanceHierarchical gene clustering analysis was utilized to represent relations between groups and clusters. Using gene ontology mining tools and canonical pathway analyses, we identified multiple biological pathways that are regulated by 5-HT: (i) cytoskeletal remodeling, (ii) G-protein signaling, (iii) vesicular transport, and (iv) apoptosis and survival. Our data encompass the first extensive genome-wide based profiling in the progenitors of platelets in response to 5-HT elevation in vivo.

Elevated serotonin and 5‐HIAA in the brainstem and lower serotonin turnover in the prefrontal cortex of suicides

Using high pressure liquid chromatography, we find more brainstem 5-HT and 5-HIAA in suicides compared with nonpsychiatric, sudden death controls throughout the rostrocaudal extent of the brainstem DRN and MRN. This suggests that 5-HT synthesis in suicides is greater within all DRN subnuclei and the MRN compared with controls.

Windows of vulnerability: Maternal separation, age, and fluoxetine on adolescent depressive-like behavior in rats

Early exposure to stressful life events plays a significant role in adolescent depression. Clinical studies have identified a number of factors that increase the risk of depression, including sex of the subject, duration of the stressor, and genetic polymorphisms that elevate serotonin levels. In this study we used the maternal separation (MS) model to investigate to what extent these factors interacted during development to manifest in depressive-like behavior in male and female rats. The triadic model of learned helplessness parses depressive-like behavior into aspects of controllable, uncontrollable, and motivational behaviors. This model was used to investigate how the timing of MS between the ages of postnatal day (P) 2–9 and P9–16 interacted with either simultaneous vehicle (saline; 1ml/kg; i.p.) or fluoxetine (10mg/kg) exposure, which was used to enhance serotonin levels; these experiments also compared the effect of a vehicle injection during these developmental periods to a no injection control. Vehicle injections alone increased helplessness in the controllable condition in male rats when injected between P9–16 only, and did not interact further with MS. MS at both ages decreased controllability in male adolescents; females demonstrated an increase in controllability after MS. Elevated serotonin at P2–9 increased escape latencies in male and female control and MS subjects. Fluoxetine exposure at P9–16 increased helplessness in controls. Fluoxetine decreased helplessness in MS males independent of age, but increases helplessness in MS females. This study highlights the importance of age of MS (MS between P2–9 increases helplessness in males more than females), the duration of the stressor (previous results show females are effected by longer MS [P2–20], but not shorter [this study]), and that elevated serotonin increases escape latencies to a greater extent in females.

NK1 receptor antagonism lowers occupancy requirement for antidepressant-like effects of SSRIs in the Gerbil forced swim test

The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.

Regulating Prefrontal Cortex Activation: An Emerging Role for the 5-HT2A Serotonin Receptor in the Modulation of Emotion-Based Actions?

The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions.

Elevated CSF serotonin and dopamine metabolite levels in overweight subjects

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

Elevated TNFR1 and Serotonin in Bone Metastasis Are Correlated with Poor Survival following Bone Metastasis Diagnosis for Both Carcinoma and Sarcoma Primary Tumors

There is an urgent need for therapies that will reduce the mortality of patients with bone metastasis. In this study, we profiled the protein signal pathway networks of the human bone metastasis microenvironment. The goal was to identify sets of interacting proteins that correlate with survival time following the first diagnosis of bone metastasis. Using Reverse Phase Protein Microarray technology, we measured the expression of 88 end points in the bone microenvironment of 159 bone metastasis tissue samples derived from patients with primary carcinomas and sarcomas. Metastases originating from different primary tumors showed similar levels of cell signaling across tissue types for the majority of proteins analyzed, suggesting that the bone microenvironment strongly influences the metastatic tumor signaling profiles. In a training set (72 samples), TNF receptor 1, alone (P = 0.0013) or combined with serotonin (P = 0.0004), TNFα (P = 0.0214), and RANK (P = 0.0226), was associated with poor survival, regardless of the primary tumor of origin. Results were confirmed by (i) analysis of an independent validation set (71 samples) and (ii) independent bioinformatic analysis using a support vector machine learning model. Spearman rho analysis revealed a highly significant number of interactions intersecting with ERα S118, serotonin, TNFα, RANKL, and matrix metalloproteinase in the bone metastasis signaling network, regardless of the primary tumor. The interaction network pattern was significantly different in the short versus long survivors. TNF receptor 1 and neuroendocrine-regulated protein signal pathways seem to play an important role in bone metastasis and may constitute a novel drug-targetable mechanism of seed-soil cross talk in bone metastasis.

Serotonin: is it a marker for the diagnosis of hepatocellular carcinoma in cirrhotic patients?

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer mortality among men worldwide. Serotonin is biogenic amine, ligand for family of 5-HT receptors reflect the diversity of serotonergic actions.Majority of serotonin in body 90% synthesised by enterochromaffin cells of the gastrointestinal tract and exported to various sites. Serotonin regulate blood flow and vascular tone at portal and sinusoidal levels, serotonin mitogen for hepatocytes and promotes liver regeneration. 5HT emerging as mediator of different pathological conditions (double edged sowrd). It contributes to liver fibrosis, mediates oxidative stress in nonalcoholic steatotic hepatitis and aggravates viral hepatitis, these conditions involved in tumorgenesis of hepatocellular carcinoma (HCC). Impaired metabolic function in liver cirrhosis and slow uptake and storage of serotonin by the platelets is sequelae of kinetic change of serotonin transport mechanisms or abnormal serotonin release from dense granules of activated platelets condition defined “platelet exhaustion”, contributes to elevated plasma serotonin which may facilitate tumor growth of primary liver hepatocellular carcinoma. Aim of this work: was to determine whether serotonin is a marker for the diagnosis of hepatocellular carcinoma in cirrhotic patients. Methods: patients were classified into 2 groups; 45 patients with cirrhosis only and 30 patients with cirrhosis and HCC. 10 healthy subjects was taken as controls. Patients underwent; full history taking,clinical examination,abdominal ultrasonography. Laboratory methods include SGOT, SGPT, GGT, bilirubin, alkaline phosphatase, total proteins, albumin, CBC, prothrombin, INR, APRI score, Child-Pugh score, MELD score, AFP and serum serotonin. Results: plasma serotonin was significantly higher in patients group with cirrhosis with a median level 119.4 ng/ml than in control group showed median value of 51.5 ng/ml p< 0.001.Also a significance difference between cirrhosis &HCC group with median value 478.35 ng/ml than control group and cirrhosis group p<0.001was found. Conclusion: Plasma serotonin level was significantly higher in patients with cirrhosis and HCC than in those with cirrhosis only and it was involved in tumorgenesis of hepatocellular carcinoma.

Involvement of serotonin mechanism in methamphetamine-induced chronic pulmonary toxicity in rats

The widest distribution and the highest uptake of methamphetamine (MA) in the human body occurred in the lungs, so that more and more attention should be paid to MA-induced pulmonary toxicity. MA induces the release of serotonin, which is an important mediator in pulmonary disease. The purpose of this study is to investigate the chronic response of the lung to MA and its potential mechanism in rats. Models of the chronic toxicity of MA were established with MA of 5mg/kg and 10mg/kg (intraperitoneally, twice per day) for 5weeks. It was found that the high dose of MA induced rat pulmonary toxicity: crowded lung parenchyma, thickened septum, reduced number of alveolar sacs, inflammatory cell infiltration, and pulmonary arteriolar remodeling. In addition, MA resulted in a significant increase in the lung serotonin concentration and the marked upregulation of tryptophan hydroxylase 1, vesicular monoamine transporter 2, serotonin transporter, and downregulation of monoamine oxidase-A. These findings suggest that MA induced chronic pulmonary toxicity, which is concerned with the elevated serotonin concentration in rat lungs by increased synthesis, reduced metabolism, augmented accumulation, and promoted release of serotonin.

Serotonin Hypothesis of Autism: Implications for Selective Serotonin Reuptake Inhibitor Use during Pregnancy

Serotonin, a neurotransmitter found throughout the brain and body, has long been of interest in autism. Repeated findings of elevated platelet serotonin levels in approximately one third of children with autism has led some to believe that dysfunctional serotonin signaling may be a causal mechanism for the disorder. Because serotonin is critical to fetal brain development, concerns have arisen regarding prenatal exposure to substances that manipulate serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs). This review examines evidence regarding the serotonin system and autism spectrum disorders (ASD), as well as what the literature has reported thus far on developmental effects of prenatal exposure to SSRIs. Possible mechanisms by which SSRIs could affect the fetus during pregnancy and clinical implications are also discussed. Though the majority of studies conducted in infants and children suggest prenatal exposure to SSRIs does not affect neurodevelopment, interpretation must be tempered given small sample sizes. The only published study that focused on prenatal SSRI exposure and ASD found an increased risk with exposure to SSRIs, especially during the first trimester. Obstacles that will be faced in future research are isolating medication effects from maternal depression and, given the infrequent occurrence of exposure and outcome, obtaining an adequate sample size. Whether serotonin is an etiologic factor in ASD, and what it points to as a marker for subgrouping, remains unclear. Understanding how the development of ASD might be affected by prenatal factors that influence serotonin levels, such as SSRIs, could identify modifiable targets for prevention.

Screening of the antidepressant-like effect of the traditional Chinese medicinal formula Si-Ni-San and their possible mechanism of action in mice

Background:The traditional Chinese medicine formula Si-Ni-San has well therapeutic applications in improvement of mental diseases including depression. However, the neuropharmacological and neuroendocrine mechanisms of the formula on antidepressant-like action have not been reported.Objective:Herein, we explored the antidepressant-like effect and its mechanism of Si-Ni-San.Materials and Methods:Acute effect of Si-Ni-San on the immobility time was assessed in the mouse forced swim test (FST) and tail suspension test (TST). Moreover, we investigated the neurochemical, neuroendocrine, and neurotrophin systems involved in the antidepressant-like effect of this formula.Results:Si-Ni-San significantly decreased the immobility time after acute treatment in the mouse TST (1300 mg/kg) but not in the FST compared with the control group. In addition, pretreatment of mice with PCPA or AMPT prevented the anti-immobility effect of Si-Ni-San (1300 mg/kg) in the TST. Moreover, acute Si-Ni-San (1300 mg/kg) decreased serum corticosterone levels, elevated serotonin (5-HT), norepinephrine (NE), and dopamine (DA) levels without affecting brain-derived neurotrophic factor (BDNF) levels in the whole brain exposed to TST.Conclusion:The acute antidepressant-like action of Si-Ni-San is mediated by the monoaminergic and neuroendocrine systems although underlying mechanism still remains to be further elucidated, and this formula should be further investigated as an alternative therapeutic approach for the treatment of depression.

RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis.

Current antidepressants, which inhibit the serotonin transporter (SERT), display limited efficacy and slow onset of action. Here, we show that partial reduction of SERT expression by small interference RNA (SERT-siRNA) decreased immobility in the tail suspension test, displaying an antidepressant potential. Moreover, short-term SERT-siRNA treatment modified mouse brain variables considered to be key markers of antidepressant action: reduced expression and function of 5-HT1A-autoreceptors, elevated extracellular serotonin in forebrain and increased neurogenesis and expression of plasticity-related genes (BDNF, VEGF, Arc) in hippocampus. Remarkably, these effects occurred much earlier and were of greater magnitude than those evoked by long-term fluoxetine treatment. These findings highlight the critical role of SERT in serotonergic function and show that the reduction of SERT expression regulates serotonergic neurotransmission more potently than pharmacological blockade of SERT. The use of siRNA-targeting genes in serotonin neurons (SERT, 5-HT1A-autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants.

Early infant exposure to excess multivitamin: a risk factor for autism?

Autism, a neurodevelopmental disorder that affects boys more than girls, is often associated with altered levels of monoamines (serotonin and catecholamines), especially elevated serotonin levels. The monoamines act as both neurotransmitters and signaling molecules in the gastrointestinal and immune systems. The evidence related to monoamine metabolism may be summarized as follows: (i) monoamine neurotransmitters are enzymatically degraded/inactivated by three mechanisms: oxidative deamination, methylation, and sulfation. The latter two are limited by the supply of methyl groups and sulfate, respectively. (ii) A decrease in methylation- and sulfation-mediated monoamine inactivation can be compensated by an increase in the oxidative deamination catalyzed by monoamine oxidase, an X-linked enzyme exhibiting higher activity in females than in males. (iii) Vitamins can, on one hand, facilitate the synthesis of monoamine neurotransmitters and, on the other hand, inhibit their inactivation by competing for methylation and sulfation. Therefore, we postulate that excess multivitamin feeding in early infancy, which has become very popular over the past few decades, may be a potential risk factor for disturbed monoamine metabolism. In this paper, we will focus on the relationship between excess multivitamin exposure and the inactivation/degradation of monoamine neurotransmitters and its possible role in the development of autism.

Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder

SummaryChromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,XY*O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,XY*O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,XY*O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a ‘foraging’ task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or ‘ability to wait’, it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,XY*O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,XY*O model.

Neuroendocrine tumor presenting as metastatic carcinoid and later as insulinoma: a rare metamorphosis

We describe a very rare case of a neuroendocrine tumor, which initially presented as metastatic carcinoid with lesions in the liver and bones. Diagnosis was made by an elevated blood serotonin level and 24 hour urine 5HIAA. Liver biopsy confirmed the presence of a well differentiated neuroendocrine tumor (NET) staining positive for Chromogranin and negative for insulin. Two years after the initial diagnosis, the patient started to experience neuroglycopenic symptoms. Insulin and C-peptide levels were markedly elevated along with severe and recurrent hypoglycemic episodes. Due to extremely high insulin secretion from a large tumor burden, the patient’s clinical condition rapidly deteriorated in spite of maximal medical treatment. Shortly after the diagnosis of metastatic Insulinoma with unknown primary was made, the patient developed multiple organ system failure which limited invasive diagnostic techniques for localization. It appears that this patient’s neuroendocrine tumor had undergone a partial or complete change in its humoral function from a carcinoid or indolent neuroendcorine tumor to an Insulinoma or that the tumor started to co-secrete insulin along with serotonin. Less likely, he may have developed a separate tumor in the pancreas which was unable to be visualized by conventional imaging. Excess secretion of both Serotonin and Insulin from a single tumor is extremely rare and very few cases have been reported in the literature where a gastroenteopancreatic NET was found to secrete both insulin and serotonin.