Showing papers on "Serotonin published in 2011"

Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.

Abstract: The synthesis and structure−activity relationship of a novel series of compounds with combined effects on 5-HT3A and 5-HT1A receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT1A (Ki = 15 nM), 5-HT1B (Ki = 33 nM), 5-HT3A (Ki = 3.7 nM), 5-HT7 (Ki = 19 nM), and noradrenergic β1 (Ki = 46 nM) receptors, and SERT (Ki = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT3A and 5-HT7 receptors, partial agonist properties at 5-HT1B receptors, agonistic properties at 5-HT1A receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive d...

Tryptophan metabolism, from nutrition to potential therapeutic applications

Abstract: Tryptophan is an indispensable amino acid that should to be supplied by dietary protein. Apart from its incorporation into body proteins, tryptophan is the precursor for serotonin, an important neuromediator, and for kynurenine, an intermediary metabolite of a complex metabolic pathway ending with niacin, CO2, and kynurenic and xanthurenic acids. Tryptophan metabolism within different tissues is associated with numerous physiological functions. The liver regulates tryptophan homeostasis through degrading tryptophan in excess. Tryptophan degradation into kynurenine by immune cells plays a crucial role in the regulation of immune response during infections, inflammations and pregnancy. Serotonin is synthesized from tryptophan in the gut and also in the brain, where tryptophan availability is known to influence the sensitivity to mood disorders. In the present review, we discuss the major functions of tryptophan and its role in the regulation of growth, mood, behavior and immune responses with regard to the low availability of this amino acid and the competition between tissues and metabolic pathways for tryptophan utilization.

Essential Roles of Enteric Neuronal Serotonin in Gastrointestinal Motility and the Development/Survival of Enteric Dopaminergic Neurons

Abstract: The gut contains a large 5-HT pool in enterochromaffin (EC) cells and a smaller 5-HT pool in the enteric nervous system (ENS). During development, enteric neurons are generated asynchronously. We tested hypotheses that serotonergic neurons, which arise early, affect development/survival of later-born dopaminergic, GABAergic, nitrergic, and calcitonin gene-related peptide-expressing neurons and are essential for gastrointestinal motility. 5-HT biosynthesis depends on tryptophan hydroxylase 1 (TPH1) in EC cells and on TPH2 in neurons; therefore, mice lacking TPH1 and/or TPH2 distinguish EC-derived from neuronal 5-HT. Deletion of TPH2, but not TPH1, decreased myenteric neuronal density and proportions of dopaminergic and GABAergic neurons but did not affect the extrinsic sympathetic innervation of the gut; intestinal transit slowed in mice lacking TPH2 mice, but gastric emptying accelerated. Isolated enteric crest-derived cells (ENCDCs) expressed the serotonin reuptake transporter (SERT) and 15 subtypes of 5-HT receptor. Addition of 5-HT to cultures of isolated ENCDCs promoted total and dopaminergic neuronal development. Rings of SERT-immunoreactive terminal axons surrounded myenteric dopaminergic neurons and SERT knock-out increased intestinal levels of dopamine metabolites, implying that enteric dopaminergic neurons receive a serotonergic innervation. Observations suggest that constitutive gastrointestinal motility depends more on neuronal than EC cell serotonin; moreover, serotonergic neurons promote development/survival of some classes of late-born enteric neurons, including dopaminergic neurons, which appear to innervate and activate in the adult ENS.

Serotonin and prefrontal cortex function: neurons, networks, and circuits.

Abstract: Higher-order executive tasks such as learning, working memory, and behavioral flexibility depend on the prefrontal cortex (PFC), the brain region most elaborated in primates. The prominent innervation by serotonin neurons and the dense expression of serotonergic receptors in the PFC suggest that serotonin is a major modulator of its function. The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations (brain waves). Serotonergic signaling is altered in many psychiatric disorders such as schizophrenia and depression, where parallel changes in receptor expression and brain waves have been observed. Furthermore, many psychiatric drug treatments target serotonergic receptors in the PFC. Thus, understanding the role of serotonergic neurotransmission in PFC function is of major clinical importance. Here, we review recent findings concerning the powerful influences of serotonin on single neurons, neural networks, and cortical circuits in the PFC of the rat, where the effects of serotonin have been most thoroughly studied.

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Abstract: Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.

The monoamine neurotransmitter disorders: an expanding range of neurological syndromes

Abstract: The monoamine neurotransmitter disorders consist of a rapidly expanding heterogeneous group of neurological syndromes characterised by primary and secondary defects in the biosynthesis degradation, or transport of dopamine, norepinephrine, epinephrine, and serotonin. Disease onset can occur any time from infancy onwards. Clinical presentation depends on the pattern and severity of neurotransmitter abnormalities, and is predominated by neurological features (encephalopathy, epilepsy, and pyramidal and extrapyramidal motor disorders) that are primarily attributed to deficiency of cerebral dopamine, serotonin, or both. Many neurotransmitter disorders mimic the phenotype of other neurological disorders (eg, cerebral palsy, hypoxic ischaemic encephalopathy, paroxysmal disorders, inherited metabolic diseases, and genetic dystonic or parkinsonian syndromes) and are, therefore, frequently misdiagnosed. Early clinical suspicion and appropriate investigations, including analysis of neurotransmitters in CSF, are essential for accurate clinical diagnosis. Treatment strategies focus on the correction of monoamine deficiency by replacement of monoamine precursors, the use of monoamine analogues, inhibition of monoamine degradation, and addition of enzyme cofactors to promote monoamine production.

Serotonin receptors - from molecular biology to clinical applications.

Abstract: Serotonin (5-hydroxytryptamine) is an ubiquitary monoamine acting as one of the neurotransmitters at synapses of nerve cells. Serotonin acts through several receptor types and subtypes. The profusion of 5-HT receptors should eventually allow a better understanding of the different and complex processes in which serotonin is involved. Its role is expected in the etiology of several diseases, including depression, schizophrenia, anxiety and panic disorders, migraine, hypertension, pulmonary hypertension, eating disorders, vomiting and irritable bowel syndromes. In the past 20 years, seven distinct families of 5-HT receptors have been identified and various subpopulations have been described for several of them. Increasing number of 5-HT receptors has made it difficult to unravel the role of 5-HT receptor subpopulations due to the lack of suitable selective agents. The present review describes the different populations and nomenclature of recently discovered 5-HT receptors and their pharmacological relevance.

The role of serotonin receptor subtypes in treating depression: a review of animal studies.

Abstract: Rationale Serotonin reuptake inhibitors (SSRIs) are effective in treating depression. Given the existence of different families and subtypes of 5-HT receptors, multiple 5-HT receptors may be involved in the antidepressant-like behavioral effects of SSRIs.

Activation of Dorsal Raphe Serotonin Neurons Underlies Waiting for Delayed Rewards

Abstract: The serotonergic system plays a key role in the control of impulsive behaviors. Forebrain serotonin depletion leads to premature actions and steepens discounting of delayed rewards. However, there has been no direct evidence for serotonin neuron activity in relation to actions for delayed rewards. Here we show that serotonin neurons increase their tonic firing while rats wait for food and water rewards and conditioned reinforcement tones. The rate of tonic firing during the delay period was significantly higher for rewards than for tones, for which rats could not wait as long. When the delay was extended, tonic firing persisted until reward or tone delivery. When rats gave up waiting because of extended delay or reward omission, serotonin neuron firing dropped preceding the exit from reward sites. Serotonin neurons did not show significant response when an expected reward was omitted, which was predicted by the theory that serotonin signals negative reward prediction errors. These results suggest that increased serotonin neuron firing facilitates a rat's waiting behavior in prospect of forthcoming rewards and that higher serotonin activation enables longer waiting.

Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes

Abstract: Rationale The pharmacological actions of most antidepressants are ascribed to the modulation of serotonergic and/or noradrenergic transmission in the brain. During therapeutic treatment for major depression, fluoxetine, one of the most commonly prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, accumulates in the brain, suggesting that fluoxetine may interact with additional targets. In this context, there is increasing evidence that astrocytes are involved in the pathophysiology of major depression.

Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting

Abstract: Rotavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca2+ concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP3), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT3 receptor antagonists.

Convergence of the Insulin and Serotonin Programs in the Pancreatic β-Cell

Abstract: OBJECTIVE Despite their origins in different germ layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain. Therefore, we tested whether these developmental parallels have functional consequences. RESEARCH DESIGN AND METHODS We used transcriptional profiling, immunohistochemistry, DNA-binding analyses, and mouse genetic models to assess the expression and function of key serotonergic genes in the pancreas. RESULTS We found that islet cells expressed the genes encoding all of the products necessary for synthesizing, packaging, and secreting serotonin, including both isoforms of the serotonin synthetic enzyme tryptophan hydroxylase and the archetypal serotonergic transcription factor Pet1. As in serotonergic neurons, Pet1 expression in islets required homeodomain transcription factor Nkx2.2 but not Nkx6.1. In β-cells, Pet1 bound to the serotonergic genes but also to a conserved insulin gene regulatory element. Mice lacking Pet1 displayed reduced insulin production and secretion and impaired glucose tolerance. CONCLUSIONS These studies demonstrate that a common transcriptional cascade drives the differentiation of β-cells and serotonergic neurons and imparts the shared ability to produce serotonin. The interrelated biology of these two cell types has important implications for the pathology and treatment of diabetes.

Serotonin: From Cell Biology to Pharmacology and Therapeutics

Abstract: Serotonin research: historical overview.- Molecular Mechanisms in Serotonin Mediated Response.- Molecular biology of the serotonin receptor family.- Molecular structure of the central 5-HT1A receptor.- Biochemical characterization of the cloned human 5-HT1A receptor expressed in mammalian cells.- Amplifying effects of 5-hydroxytryptamine on human platelets and signal transduction.- Role of phosphoinositide hydrolysis and protein kinase C activation in 5HT2 receptor function in smooth muscle.- Adenylate cyclase-linked 5-hydroxytryptamine receptors in the brain.- Characterization and purification of the neuronal 5-HT transporter.- Structure and functional expression of cloned human liver MAO A and B.- Physiology of Serotonergic System: - Vascular System.- Amplifying effect of serotonin in the control of vascular tone.- Amplification mechanisms in platelet activation.- The role of the endothelium in the cardiovascular response to serotonin.- Endothelium-dependent relaxations to serotonin: signal transduction and effects of diets.- 5-Hydroxytryptamine in cerebrovascular sympathetic nerves and its effect on brain vessels.- The 5-HT system of blood platelets: physiological variations and pathophysiology in essential hypertension.- Serotonergic regulation of renin and vasopressin secretion.- 5HT, platelets and experimental atherosclerosis.- Responses to serotonin in atherosclerotic and hypertensive blood vessels.- Does the serotonin antagonist ketanserin have vascular protective effects?.- Central Nervous System.- Serotonin and coexisting peptides in cat and lamprey spinal cord.- Is there an endogenous modulation of serotonin uptake?.- Serotonin receptors regulating transmitter release.- Galanin/5-HT receptor interactions. A new integrative mechanism in the control of 5-HT neurotransmission in the central nervous system.- Changing views on the role of serotonergic mechanisms in the control of the sleep-wakefulness cycle.- Serotonin transmission and food intake.- Serotonin in medial hypotholamic nuclei controls circadian patterns of macronutrient intake.- Serotonin receptor sub-types and the organisation of feeding behaviour: experimental models.- Tryptophan availability and serotonin synthesis.- Gastrointestinal System.- Effects of serotonin on gastric secretion in vivo.- Serotonin in intestinal function.- Messenger function of Serotonin in the enteric nervous system.- 5-Hydroxytryptamine and cholinergic function in the gastrointestinal tract.- Serotonergic Receptors: Biochemistry, Physiology and Pharmacology.- Functional/clinical significance of 5-hydroxytryptamine binding sites.- Selective agonists and antagonists at 5-hydroxytryptamine receptor subtypes.- Electrophysiology of brain serotonin receptors: subtype specificity for effector mechanisms.- 5-Hydroxytryptamine (5-HT) receptor subtypes in invertebrates.- 5-Hydroxytryptamine1A receptors: pharmacological and functional characterization.- Modulation of serotonin release in the central nervous system via presynaptic 5-HT autoreceptors.- Receptor binding correlates of functional terminal 5-HT autoreceptors.- Pharmacology, function and adaptive regulation of 5HT-1c receptors.- Classification of serotonergic receptors: an example of a novel 5-HT11 like binding site in the rabbit caudate nucleus.- Central and peripheral 5-HT2 receptors: role in physiological versus pathological conditions.- 5-HT3 receptors.- Brain 5-HT3 receptors.- Heart 5-HT receptors. A novel 5-HT receptor in human atrium.- Characterization of the contractile 5HT receptor in the rat stomach fundus.- Peripheral neural 5-HT receptors: subtypes in the enteric nervous system.- Antagonistic modulation of A K+ channel activity by serotonin and the peptide FMRFamide in aplysia sensory neurons: molecular aspects and functional implications.- Visualization of serotonin receptor binding and their messenger RNA's in the mammalian brain: an update.- Pharmacology of Serotonergic System.- Upregulation of pain transmission from deficient serotonergic analgesia in migraine.- Selective 5-hydroxytryptaminel-like receptor agonists and migraine.- Recent insights into the antihypertensive mechanism of action of ketanserin.- Ketanserin interactions with nifedipine and captopril: two italian cross over trials.- International study of ketanserin in Raynaud's phenomenon.- Serotonin and portal hypertension.- Effects of serotonin and ketanserin on the functional morphology of skin: organotypical cultures of adult human skin and embryonic chick skin as experimental models.- Use of antagonists to 5-HT2 receptors of serotonin by topical application in healing skin ulcers.- Ketanserin in wound healing and fibrosis: investigations into its mechanism of action.- Central Nervous System.- Serotonin uptake inhibitors.- Serotonergic re-uptake inhibition and depression: the effects of fluvoxamine on sleep in depressed patients.- Chronobiological studies of serotonin uptake complex: relevance to antidepressant action.- Lack of serotonergic influence on desipramine induced ss-adrenergic receptor down-regulation.- Serotonin in depression and anxiety.- Investigations of 5-HT neuroendocrine function in depression.- Electrophysiological investigation of the effects of antidepressant treatments on serotonin receptors.- Role of 5HT2 receptors in anxiety and depression.- Effectiveness of ritanserin on pain and depression in chronic headache disorders.- 5-HT1A receptor partial agonists as anxiolytics.- 5HT2 receptor antagonism and slow wave sleep in man.- Serotonin involvement in the action of antipsychotic drugs.- Serotonin control of anxiety.- Neuroendocrine System.- Endocrine changes and 5-hydroxytryptamine receptor subtypes.- Neuroendocrine effects of serotonin agonists in rhesus monkeys, healthy humans and patients with depression or anxiety disorders: effects of antidepressant treatment.- Hormonal responses to serotonergic drugs as a means to evaluate brain serotonergic function in humans.- Role of serotonin in the control of prolactin secretion: effect of antiserotoninergic drugs in normal subjects and in hyperprolactinaemic states.- Serotonin agonist induced corticosterone and prolactin secretion: role of 5-HT2 and 5-HT1A receptors.- Role of serotonin in regulation of the pituitary- adrenocortical axis in rats.- Short and Long Term Effects of Substituted Amphetamines.- Toxicity of amphetamine-related drugs and resulting behavioral changes.- Effect of chronic D-fenfluramine administration on rat brain serotonin levels and release.- Behavioral effects of 5, 7-DHT and MDMA treatment in rats.- Immunohistochemical and autoradiographic investigations of high-dose fenfluramine treatment on monoamine neurons in rat brain.- Long term actions of dexfenfluramine on food intake, body weight and brain serotonin in rodents.- Significance of fenfluramine neurotoxicity: a kinetic approach.- Effect of D-fenfluramine on appetite in lean and obese human subjects and on changes associated with PMS (pre-menstrual syndrome).- Criteria for assessing drug-induced biochemical alterations and degeneration of serotonergic neurons.

CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity.

Abstract: Methylene blue has only recently been noted to cause severe central nervous system toxicity. Methylene blue is used for various conditions, including, intravenously, in methemoglobinemia, vasoplegia and as an aid to parathyroidectomy (at doses of 1-7.5 mg kg(-1)). This review of the current evidence concludes that 13 of 14 of the reported cases of CNS toxicity were serotonin toxicity that met the Hunter Serotonin Toxicity Criteria. That has important preventative and treatment implications. Serotonin toxicity is precipitated by the monoamine oxidase inhibitor (MAOI) property of methylene blue interacting with serotonin reuptake inhibitors. Serotonin toxicity is reviewed, using the lessons inherent in the methylene blue story and experience, to illustrate how the mechanisms and potency of serotonergic drugs interact to determine severity. Recent human data showed that an intravenous dose of only 0.75 mg kg(-1) of methylene blue produced a peak plasma concentration of 500 ng ml(-1) (1.6 µM), indicating that the concentration in the central nervous system reaches a level that inhibits monoamine oxidase A. That is consonant with the actual occurrence of severe serotonin toxicity in humans at the dose of only 1 mg kg(-1). It seems that all proposed uses of methylene blue entail levels that block monoamine oxidase, so cessation of serotonin reuptake inhibitors should be very carefully considered before using methylene blue.

Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

Abstract: The serotonin-1A (5-HT1A) receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A) using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019)G (rs6295) polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice

Abstract: Although the question of to whom a male directs his mating attempts(1,2) is a critical one in social interactions, little is known about the molecular and cellular mechanisms controlling mammalian sexual preference. Here we report that the neurotransmitter 5-hydroxytryptamine (5-HT) is required for male sexual preference. Wild-type male mice preferred females over males, but males lacking central serotonergic neurons lost sexual preference although they were not generally defective in olfaction or in pheromone sensing. A role for 5-HT was demonstrated by the phenotype of mice lacking tryptophan hydroxylase 2 (Tph2), which is required for the first step of 5-HT synthesis in the brain. Thirty-five minutes after the injection of the intermediate 5-hydroxytryptophan (5-HTP), which circumvented Tph2 to restore 5-HT to the wildtype level, adult Tph2 knockout mice also preferred females over males. These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference.

Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice

Abstract: Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT1A, 5-HT2A, and 5-HT2C receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that i...

Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression

Abstract: Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression. We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides. New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT1A, 5-HT1B and 5-HT2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences. Feedback to autoreceptors of the 5-HT1 family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT2 family expression may cause escalated aggression, whereas the phasic increase of 5-HT2 receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment.

Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy.

Abstract: Spinal cord stimulation (SCS) is extensively employed in the management of neuropathic pain, but the underlying mechanisms are only partially understood. Recently, we demonstrated that the pain-relieving effect of SCS appears to involve the spinal serotonin system, and the present study aimed at identifying the types of the spinal serotonin receptors involved. Experiments were performed on rats with neuropathy produced by partial ligation of the sciatic nerve. Tactile sensitivity was assessed using von Frey filaments, and cold and heat sensitivity with cold spray and radiant heat, respectively. Selective 5-HT receptor antagonists, methiothepin (5-HT1,6,7), ketanserin tartrate (5-HT2A), TICM (5-HT3), SDZ-205,557 (5-HT4), as well as receptor agonists, α-m-5-HT (5-HT2), m-CPBG (5-HT3) in per se ineffective doses, or vehicle, were administrated intrathecally 5 minutes prior to the application of SCS. Ketanserin and SDZ-205,557 significantly attenuated the suppressive effect of SCS on tactile hypersensitivity, while methiothepin and TICM were ineffective. The suppressive effect on cold hypersensitivity of SCS was counteracted by ketanserin only. None of the 5-HT receptor antagonists attenuated the suppressive effect on heat hyperalgesia of SCS. Subeffective doses of α-m-5-HT and m-CPBG enhanced the suppressive effect of SCS on tactile hypersensitivity. The enhancing effect of m-CPBG was abolished by a γ-aminobutyric acid (GABA)A or GABAB antagonist intrathecally. These results suggest that the activation of 5-HT2A, 5-HT3, and 5-HT4 receptors plays an important role in SCS-induced relief of neuropathic pain. The activation of 5-HT3 receptors appears to operate via spinal GABAergic interneurons.

Depression in women: windows of vulnerability and new insights into the link between estrogen and serotonin.

Abstract: Objective The purpose of this commentary is to provide an update on the research in both preclinical and clinical models regarding the cross-talk between estrogen and various serotonin molecular markers and the possible implications this may have on female-related mood disorders. Conclusions Animal and human studies provide strong and consistent evidence suggesting that estrogen is able to regulate the serotonin pathway at various levels. The general trend that emerges is that estrogen administration increases serotonin availability by altering mRNA and protein levels of various serotonin markers and by decreasing serotonin breakdown. These effects may have direct implications on female mood disorders such as premenstrual disorders and depression during pregnancy, postpartum, and during the menopausal transition.

The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment.

Abstract: Objective To review the evidence that agents which preferentially affect serotonin (5-HT) attenuate the ability of N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (NMDA-RA), e.g., phencyclidine (PCP), dizocilpine (MK-801), and ketamine, to stimulate locomotor activity (LA), and to impair novel object recognition (NOR).

Serotonin, a tryptophan-derived signal conserved in plants and animals, regulates root system architecture probably acting as a natural auxin inhibitor in Arabidopsis thaliana

Abstract: Serotonin (5-hydroxytryptamine) is a well-known neurotransmitter in mammals and is widely distributed in plants. This compound is synthesized from tryptophan and shares structural similarity with IAA. To date, little is known about the morphological, physiological and molecular responses of plants to serotonin. In this study, we characterized the effects of serotonin on growth and development in Arabidopsis thaliana seedlings. Gas chromatography-mass spectrometry (GC-MS) analysis showed that plants are able to take up serotonin from the growth medium, which coincided with greatly stimulated lateral root development at concentrations from 10 to 160 μM. In contrast, higher doses of serotonin repressed lateral root growth, primary root growth and root hair development, but stimulated adventitious root formation. To investigate the role of serotonin in modulating auxin responses, we performed experiments using transgenic Arabidopsis lines expressing the auxin-responsive marker constructs DR5:uidA, BA3:uidA and HS::AXR3NT-GUS, as well as a variety of Arabidopsis mutants defective at the AUX1, AXR1, AXR2 and AXR4 auxin-related loci. We found that serotonin strongly inhibited both DR5:uidA and BA3:uidA gene expression in primary and adventitious roots and in lateral root primordia. This compound also abolished the effects of IAA or naphthaleneacetic acid on auxin-regulated developmental and genetic responses, indicating an anti-auxin activity in the plant. Mutant analysis further showed that lateral root induction elicited by serotonin was independent of the AUX1 and AXR4 loci but required AXR1 and AXR2. Our results show that serotonin regulates root development probably by acting as a natural auxin inhibitor.

The serotonin transporter, gender, and 17β oestradiol in the development of pulmonary arterial hypertension

Abstract: Aims Idiopathic and familial forms of pulmonary arterial hypertension (PAH) predominantly affect females through an unknown mechanism. Activity of the serotonin transporter (SERT) may modulate the development of PAH, and mice overexpressing SERT (SERT+ mice) develop PAH and severe hypoxia-induced PAH. In the central nervous system, oestrogens influence activity of the serotonin system. Therefore, we examined the influence of gender on the development of PAH in SERT+ mice and how this is modulated by female hormones. Methods and results PAH was assessed via measurement of right ventricular systolic pressure (RVSP), pulmonary vascular remodelling (PVR), and right ventricular hypertrophy. Male SERT+ mice did not develop PAH. Female SERT+ mice demonstrated increased RVSP and PVR and this was abolished by ovariectomy. Following exposure to hypoxia, SERT+ mice exhibited severe PAH and this was also attenuated by ovariectomy. Chronic administration of 17β oestradiol re-established the PAH phenotype in ovariectomized, normoxic, and hypoxic SERT+ mice. 17β oestradiol also up-regulated tryptophan hydroxylase-1 (TPH1), 5-hydroytryptamine1B (5-HT1B) receptor, and SERT expression in human pulmonary arterial smooth muscle cells (hPASMCs). 17β oestradiol stimulated hPASMC proliferation and this was inhibited by both the TPH inhibitor para-chlorophenylalanine and the 5-HT1B receptor antagonist SB224289. Conclusion 17β oestradiol is critical to the development of PAH and severe hypoxia-induced PAH in female SERT+ mice. In hPASMCs, 17β oestradiol-induced proliferation is dependant on de novo serotonin synthesis and stimulation of the 5-HT1B receptor. These interactions between the serotonin system and 17β oestradiol may contribute to the increased risk of PAH associated with female gender.