Showing papers on "Serotonin published in 2008"
TL;DR: It is shown that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex that may be involved in the altered cortical processes of schizophrenia.
Abstract: The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.
757 citations
TL;DR: It is shown here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum, and decreasing serotonin blood levels normalizes bone formation and bone mass in L rp5-deficient mice.
751 citations
TL;DR: Evidence for an even greater degree of operational diversity is supported by the existence of a great number of splice and editing variants for several 5-HT receptors, their possible modulation by accessory proteins and chaperones, as well as their potential to form homo or heteromers both at the GPCR and at the ligand-gated channel level.
683 citations
TL;DR: Brain-derived neurotrophic factor promotes the survival and differentiation of 5-HT neurons and administration of antidepressant selective serotonin reuptake inhibitors (SSRIs) enhances BDNF gene expression.
676 citations
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TL;DR: The physiology of serotonin and its involvement in the pathophysiologic mechanisms of various conditions, including the Serotonin Syndrome, are reviewed.
Abstract: 5-Hydroxytryptamine, or serotonin, is a biogenic amine most noted for its role as a neurotransmitter. Manipulation of serotonin in animal models was used as a tool for studying its role in humans. Through such research serotonin has been shown to modulate gastrointestinal motility, peripheral vascular tone, cerebral vascular tone, and platelet function and has been implicated in the pathophysiology of mood disorders, emesis, migraine, irritable bowel syndrome (IBS), and pulmonary and systemic hypertension. The knowledge gained is being directly applied back to animals in research on drugs that manipulate the serotonergic system in dogs and cats. Increasing use and availability of drugs that manipulate the serotonergic system has created a circumstance through which a novel toxicity was discovered in both humans and animals. Serotonin Syndrome describes the clinical picture seen in humans and animals with serotonin toxicity. This paper provides a review the physiology of serotonin and its involvement in the pathophysiologic mechanisms of various conditions, including the Serotonin Syndrome.
341 citations
TL;DR: B/cJ mice show a robust response to chronic SSRI treatment in the FST, which is not mediated by an increase in new neurons in the hippocampus, and does not require the 5-HT1A receptor, suggesting that SSRIs can produce antidepressant-like effects via distinct mechanisms in different mouse strains.
305 citations
TL;DR: The data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-DesalkylquetiAPine through NET inhibition and partial 5-HT1A agonism.
297 citations
TL;DR: It was observed that the selective loss of DA neurons achieved by the intra-ventral tegmental area (VTA) injection of 6-OHDA increased the firing activity of a subset of locus coeruleus (LC) NE neurons, demonstrating a net inhibitory role of the NE input on VTA DA neurons.
Abstract: Anatomical studies have established the existence of reciprocal relationships between the main population of monoamine, serotonin (5-HT), norepinephrine (NE) and dopamine (DA) neurons in the brain. The present study was thus conducted to examine the firing activity of 5-HT and NE neurons in DA-depleted rats, as well as the firing activity of DA neurons in 5-HT- or NE-depleted rats. The selective lesion of DA neurons elicited by 6-hydroxydopamine (6-OHDA) decreased the spontaneous firing activity of dorsal raphe (DR) nucleus 5-HT neurons by 60%, thus revealing the excitatory effect of the DA input on these 5-HT neurons. In contrast, the selective lesion of 5-HT neurons produced by 5,7-dihydroxytryptamine (5,7-DHT) enhanced by 36% the firing activity of VTA DA neurons, thereby indicating an inhibitory effect of the 5-HT input on these DA neurons. With regard to the reciprocal interaction between DA and NE neurons, it was observed that the selective loss of DA neurons achieved by the intra-ventral tegmental area (VTA) injection of 6-OHDA increased the firing activity of a subset of locus coeruleus (LC) NE neurons by 47%. The selective loss of NE neurons in response to the intra-LC injection of 6-OHDA enhanced the firing activity of VTA DA neurons by 70%, demonstrating a net inhibitory role of the NE input on VTA DA neurons. These findings have important consequences for antidepressant treatments aimed at enhancing simultaneously 5-HT, NE and DA transmission. Indeed, based on the understanding of such interactions, it may be possible to develop strategies to improve the effectiveness of antidepressant drugs by preventing counter-productive negative feedback actions.
262 citations
TL;DR: Evidence that compounds acting on serotonin receptors can have positive effects on learning and memory is reviewed, raising the possibility that such compounds could be developed as adjunct therapeutics with existing treatments to improvelearning and memory deficits, which are core symptoms of Alzheimer's disease, schizophrenia and depression.
250 citations
TL;DR: An update is provided on how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala in mice and inbred mouse strains.
245 citations
TL;DR: The behavioral effects observed in the TPH2 KO and DKO mice strongly confirm the role of 5-HT and its synthetic enzymes in the etiology and treatment of affective disorders.
Abstract: The neurotransmitter serotonin (5-HT) plays an important role in both the peripheral and central nervous systems. The biosynthesis of serotonin is regulated by two rate-limiting enzymes, tryptophan hydroxylase-1 and -2 (TPH1 and TPH2). We used a gene-targeting approach to generate mice with selective and complete elimination of the two known TPH isoforms. This resulted in dramatically reduced central 5-HT levels in Tph2 knockout (TPH2KO) and Tph1/Tph2 double knockout (DKO) mice; and substantially reduced peripheral 5-HT levels in DKO, but not TPH2KO mice. Therefore, differential expression of the two isoforms of TPH was reflected in corresponding depletion of 5-HT content in the brain and periphery. Surprisingly, despite the prominent and evolutionarily ancient role that 5-HT plays in both vertebrate and invertebrate physiology, none of these mutations resulted in an overt phenotype. TPH2KO and DKO mice were viable and normal in appearance. Behavioral alterations in assays with predictive validity for antidepressants were among the very few phenotypes uncovered. These behavioral changes were subtle in the TPH2KO mice; they were enhanced in the DKO mice. Herein, we confirm findings from prior descriptions of TPH1 knockout mice and present the first reported phenotypic evaluations of Tph2 and Tph1/Tph2 knockout mice. The behavioral effects observed in the TPH2 KO and DKO mice strongly confirm the role of 5-HT and its synthetic enzymes in the etiology and treatment of affective disorders.
TL;DR: This study confirms, with a larger sample size and higher resolution PET scanning, the earlier report that elevated DArel is a primary defect in TS and suggests a condition of increased phasic DArel modulated by low 5-HT in concomitant OCD.
TL;DR: Regulation of serotonin transporter density by season is a previously undescribed physiologic mechanism that has the potential to explain seasonal changes in normal and pathologic behaviors.
Abstract: Context It is a common experience in temperate zones that individuals feel happier and more energetic on bright and sunny days and many experience a decline in mood and energy during the dark winter season. Brain serotonin is involved in the regulation of physiologic functions, such as mating, feeding, energy balance, and sleep. Although these behaviors and serotonin-related conditions show a clear seasonal pattern in humans, the molecular background of seasonal changes in serotonin function is entirely unknown. The serotonin transporter is a key element in regulating intensity and spread of the serotonin signal. Objectives To detect seasonal variations in serotonin transporter binding in the living human brain and to detect correlations between serotonin transporter binding and duration of daily sunshine. Design Regional serotonin transporter binding potential values, an index of serotonin transporter density, were assessed from December 1, 1999, to December 9, 2003, in a consecutive sample of healthy volunteers. Binding potential values were related to meteorologic data. Setting Tertiary care psychiatric hospital. Participants Volunteer sample of 88 drug-naive healthy individuals. Intervention Carbon 11–labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile positron emission tomography. Main Outcome Measure Regional serotonin transporter binding potential values. Results Serotonin transporter binding potential values were significantly higher in all investigated brain regions in individuals investigated in the fall and winter compared with those investigated in the spring and summer ( P = .01 to .001). Moreover, binding potential values showed negative correlations with average duration of daily sunshine in all brain regions (ρ = −0.21 to −0.39; P = .05 to Conclusions Serotonin transporter binding potential values vary throughout the year with the seasons. Since higher serotonin transporter density is associated with lower synaptic serotonin levels, regulation of serotonin transporter density by season is a previously undescribed physiologic mechanism that has the potential to explain seasonal changes in normal and pathologic behaviors.
TL;DR: Serotonin accumulation was preceded by a transient increase in the tryptamine content and by marked activation of Trp decarboxylase, indicating that enhanced Trp production is linked to the formation of serotonin from Trp via tryptamines.
Abstract: The upregulation of the tryptophan (Trp) pathway in rice leaves infected by Bipolaris oryzae was indicated by: (i) enhanced enzyme activity of anthranilate synthase (AS), which regulates metabolic flux in the Trp pathway; (ii) elevated levels of the AS (OASA2, OASB1, and OASB2) transcripts; and (iii) increases in the contents of anthranilate, indole, and Trp. The measurement of the contents of Trp-derived metabolites by high-performance liquid chromatography coupled with tandem mass spectrometry revealed that serotonin and its hydroxycinnamic acid amides were accumulated in infected leaves. Serotonin accumulation was preceded by a transient increase in the tryptamine content and by marked activation of Trp decarboxylase, indicating that enhanced Trp production is linked to the formation of serotonin from Trp via tryptamine. Feeding of radiolabeled serotonin to inoculated leaves demonstrated that serotonin is incorporated into the cell walls of lesion tissue. The leaves of a propagating-type lesion mimic mutant (sl, Sekiguchi lesion) lacked both serotonin production and deposition of unextractable brown material at the infection sites, and showed increased susceptibility to B. oryzae infection. Treating the mutant with serotonin restored deposition of brown material at the lesion site. In addition, the serotonin treatment suppressed the growth of fungal hyphae in the leaf tissues of the sl mutant. These findings indicated that the activation of the Trp pathway is involved in the establishment of effective physical defenses by producing serotonin in rice leaves.
TL;DR: This 2008 M. Rapport Memorial Serotonin Review focuses on some of the most recent discoveries involving serotonin that are based on genetic methodologies, and provides in-depth examples of gene-based discoveries that have clarified serotonin's many important homeostatic functions in humans, non-human primates, mice and other species.
TL;DR: Serotonin is widely distributed throughout the gut within both the enteric nerves and enterochromaffin (EC) cells, and Irritable bowel syndrome (IBS) developing after gastrointestinal infection and IBS with diarrhoea is associated with excess 5-HT.
TL;DR: Compared to men, women had significantly higher 5-HT(1A) receptor and lower5-HTT binding potentials in a wide array of cortical and subcortical brain regions, which may help in understanding sex differences in drug treatment responses to drugs affecting the serotonin system.
TL;DR: The changes in TRP metabolism by proinflammatory cytokines under stress is reviewed, which is assumed to be a risk factor for major depression, and the relationship between physiological risk factors for major depressions and pro inflammatory cytokines is reviewed.
Abstract: Alteration of tryptophan (TRP) metabolism elicited by proinflammatory cytokines has gained attention as a new concept to explain the etiological and pathophysiological mechanisms of major depression. The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is the main TRP metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. Proinflammatory cytokines induce IDO under stress, promote the KYN pathway, deprive the 5-HT pathway of TRP, and reduce 5-HT synthesis. The resultant decrease in 5-HT production may relate to the monoamine hypothesis of major depression. Furthermore, metabolites of the KYN pathway have neurotoxic/neuroprotective activities; 3-hydroxykynurenine and quinolinic acid are neurotoxic, whereas kynurenic acid is neuroprotective. The hippocampal atrophy that appears in chronic depression may be associated with imbalances in neurotoxic/neuroprotective activities. Because proinflammatory cytokines also activate the hypothalamo-pituitary-adrenal (HPA) a...
TL;DR: In summary, neurotransmitters activate vital T-cell functions in a direct, potent and specific manner, and may serve for communicating between the brain and the immune system to elicit an effective and orchestrated immune function, and for new therapeutic avenues, to improve T- cell eradication of cancer and infectious organisms.
Journal Article•
TL;DR: In this article, 5-methyltetrahydrobiopterin (BH4) was used as a substitute for 5-MTHF to improve depressive symptoms.
Abstract: Depression is common - one-fourth of the U.S. population will have a depressive episode sometime in life. Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response.
TL;DR: Acetaminophen‐induced analgesia could involve the following sequence: (1) FAAH‐dependent metabolism of acetaminophen into AM404; (2) indirect involvement of CB1 receptors by this metabolite; (3) endocannabinoid‐dependent reinforcement of the serotonergic bulbospinal pathways, and (4) involvement of spinal pain‐suppressing Serotonergic receptors.
Abstract: Acetaminophen is the most used analgesic/antipyretic drug. Its unclear mechanism of action could rely on cyclooxygenase inhibition, NO synthesis blockade or reinforcement of the serotonergic system. Here we show that in thermal, mechanical and chemical pain tests, AM-251, a specific CB(1) receptor antagonist, abolished the analgesic action of acetaminophen, which was also lost in CB(1) receptor knockout mice. Moreover, acetaminophen was shown unable to bind to CB(1) receptors demonstrating an indirect involvement of these receptors in the analgesic effect of this compound. Accordingly with these results, we also demonstrated that the inhibition of FAAH, an enzyme involved in the cerebral metabolism of acetaminophen into AM404, known to reinforce the activity of the endocannabinoid system, suppressed the antinociceptive effect of acetaminophen. In addition, similarly to the interaction of acetaminophen with bulbospinal serotonergic pathways and spinal serotonin receptors, we observed that the antinociceptive activity of ACEA, a CB(1) receptor agonist, was inhibited by lesion of bulbospinal serotonergic pathways and antagonists of spinal 5-HT receptors. We therefore propose that acetaminophen-induced analgesia could involve the following sequence: (1) FAAH-dependent metabolism of acetaminophen into AM404; (2) indirect involvement of CB(1) receptors by this metabolite; (3) endocannabinoid-dependent reinforcement of the serotonergic bulbospinal pathways, and (4) involvement of spinal pain-suppressing serotonergic receptors.
TL;DR: This study suggests that the 5-HT2AR–β-arrestin interaction may be particularly important in receptor function in response to endogenous serotonin levels, which could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.
Abstract: Visual and auditory hallucinations accompany certain neuropsychiatric disorders, such as schizophrenia, and they also can be induced by the use or abuse of certain drugs. The heptahelical serotonin 2A receptors (5-HT2ARs) are molecular targets for drug-induced hallucinations. However, the cellular mechanisms by which the 5-HT2AR mediates these effects are not well understood. Drugs acting at the 5-HT2AR can trigger diverse signaling pathways that may be directed by the chemical properties of the drug. β-arrestins are intracellular proteins that bind to heptahelical receptors and represent a point where such divergences in ligand-directed functional signaling could occur. Here we compare the endogenous agonist, serotonin, to a synthetic 5-HT2AR hallucinogenic agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), in mice lacking β-arrestin-2, as well as in cells lacking β-arrestins. In mice, we find that serotonin induces a head twitch response by a β-arrestin-2-dependent mechanism. However, DOI invokes the behavior independent of β-arrestin-2. The two structurally distinct agonists elicit different signal transduction and trafficking patterns upon activation of 5-HT2AR, which hinge on the presence of β-arrestins. Our study suggests that the 5-HT2AR–β-arrestin interaction may be particularly important in receptor function in response to endogenous serotonin levels, which could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.
TL;DR: The co-existence of serotonergic and dopaminergic dysfunction in the same homogeneous group of drug-naive OCD patients provides in vivo evidence for the complex molecular mechanisms of OCD, and represents the basis for further studies on the effect of therapeutic agents with specific modulatory effects on these neurotransmission systems.
TL;DR: In this article, the effect of the 5-HTT genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover is investigated, which suggests that high brain serotonin may be a biological substrate of major depressive disorder.
Abstract: Context The biological basis for the development of major depressive disorder (MDD) remains incompletely understood. Objective To quantify brain serotonin (5-hydroxytryptamine [5-HT]) turnover in patients with MDD. Design Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated. Setting Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. Participants Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria for MDD and in 40 healthy volunteers. Interventions Treatment for patients consisted of SSRI administration for approximately 12 weeks. Main Outcome Measures Brain serotonin turnover before and after SSRI therapy. Results Brain serotonin turnover was significantly elevated in unmedicated patients with MDD compared with healthy subjects (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 [4.3] vs 1.6 [2.4] nmol/L, respectively; P = .003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 [4.7] vs 2.7 [2.9] nmol/L, respectively; P = .04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 [4.0] nmol/L prior to treatment vs 2.0 [3.3] nmol/L following therapy; P = .008). Conclusions Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD.
TL;DR: All 5-hydroxytryptamine (5-HT; serotonin) receptors, except the 5-HT6 type, have been shown to be involved in cardiovascular regulation, and the physiological role of these receptors in the central regulation of the sympathetic nervous system is unclear.
TL;DR: Female mice treated neonatally with a highly selective serotonin reuptake inhibitor, escitalopram, exhibited signs of depression in the form of sleep anomalies, anhedonia, increased helplessness reversed by chronic antidepressant treatment, enhanced response to acute stress, and increased serotoninergic autoinhibitory feedback.
Abstract: Dysfunction of the serotonin system is implicated in sleep and emotional disorders. To test whether these impairments could arise during development, we studied the impact of early-life, transient versus genetic, permanent alterations of serotonin reuptake on sleep-wakefulness patterns, depression-related behavior, and associated physiological features. Here, we show that female mice treated neonatally with a highly selective serotonin reuptake inhibitor, escitalopram, exhibited signs of depression in the form of sleep anomalies, anhedonia, increased helplessness reversed by chronic antidepressant treatment, enhanced response to acute stress, and increased serotoninergic autoinhibitory feedback. This syndrome was not reproduced by treatment in naive adults but resembled the phenotype of mutant mice lacking the serotonin transporter, except that these exhibited decreased serotonin autoreceptor sensitivity and additional anxiety-like behavior. Thus, alteration of serotonin reuptake during development, whether induced by external or genetic factors, causes a depressive syndrome lasting into adulthood. Such early-life impairments might predispose individuals to sleep and/or mood disorders.
TL;DR: The preliminary results indicate that in Tph2 knockout mice raphe neurons are completely devoid of 5-HT, whereas no obvious alteration in morphology and fiber distribution are observed, and suggest that TPH2-synthesized 5- HT is not required for serotonergic neuron formation.
Abstract: The relative contribution of the two tryptophan hydroxylase (TPH) isoforms, TPH1 and TPH2, to brain serotonergic system function is controversial. To investigate the respective role of TPH2 in neuron serotonin (5-HT) synthesis and the role of 5-HT in brain development, mice with a targeted disruption of Tph2 were generated. The preliminary results indicate that in Tph2 knockout mice raphe neurons are completely devoid of 5-HT, whereas no obvious alteration in morphology and fiber distribution are observed. The findings confirm the exclusive specificity of Tph2 in brain 5-HT synthesis and suggest that Tph2-synthesized 5-HT is not required for serotonergic neuron formation.
TL;DR: Preliminary results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner.
Abstract: Background: Women are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI. Methodology/Principal Findings: In order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetineexposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring. Conclusions: These results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner.
TL;DR: The present review focuses on what is known of basic serotonin physiology in the human body and describes serotonin biochemistry and metabolism and summarize the results of studies that have contributed significantly to the understanding of serotonin physiology.
Abstract: The present review focuses on what is known of basic serotonin physiology in the human body. Here, we describe serotonin biochemistry and metabolism and summarize the results of studies that have contributed significantly to our understanding of serotonin physiology. We report the well-established role of serotonin in cardiovascular, gastrointestinal, and circulatory physiology. Emphasis is placed on the role of serotonin in peripheral physiological systems rather than in the central nervous system. A brief overview is provided on the emerging role of serotonin in novel areas such as bone pathways and glucose uptake. We also report a select few animal studies and animal models that have provided worthwhile contributions to the understanding of serotonin in human physiology. In addition, we summarize the results of large-scale genetic studies on serotonin and serotonin transporter genes, performed in relation to behavioral and mood disorders.
TL;DR: Less autoreceptor binding in the DRN of depressed suicides may represent a homeostatic response to less serotonin release, increasing serotonin neuron firing, and more autoradiograms in rostral DRN might contribute to deficient serotonin release in ventromedial prefrontal cortex by lower neuronal firing.