Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT4 activation in bovine lateral saphenous vein.

To better understand mechanisms of serotonin- (5-HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists. Vessels were pre-contracted with 1 × 10-4 M phenylephrine and exposed to increasing concentrations of 5-HT or 5-HT receptor agonists that were selective for 5-HT1B, 5-HT2B, 5-HT4, and 5-HT7. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction. At 1 × 10-7 M 5-HT, a relaxation was observed with an 88.7% decrease (p < 0.01) from the phenylephrine maximum. At 1 × 10-4 M 5-HT, a contraction was observed with a 165% increase (p < 0.01) from the phenylephrine maximum. Increasing concentrations of agonists selective for 5-HT2B, 5-HT4, or 5-HT7 resulted in a 27%, 92%, or 44% (p < 0.01) decrease from the phenylephrine maximum, respectively. Of these 5-HT receptor agonists, the selective 5-HT4 receptor agonist resulted in the greatest potency (-log EC50) value (6.30) compared with 5-HT2B and 5-HT7 receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5-HT4 in 5-HT-mediated vasorelaxation, blood vessels were exposed to either DMSO (solvent control) or a selective 5-HT4 antagonist (1 × 10-5 M) for 5-min prior to the phenylephrine pre-contraction and 5-HT additions. Antagonism of the 5-HT4 receptor attenuated the vasorelaxation caused by 5-HT. Approximately 94% of the vasorelaxation occurring in response to 5-HT could be accounted for through 5-HT4, providing strong evidence that 5-HT-mediated vasorelaxation occurs through 5-HT4 activation in bovine peripheral vasculature.

Key Enzymes of the Serotonergic System - Tryptophan Hydroxylase 2 and Monoamine Oxidase A - In the Brain of Rats Selectively Bred for a Reaction toward Humans: Effects of Benzopentathiepin TC-2153.

At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes - tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) - in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.

Early biomarkers in the presymptomatic phase of cognitive impairment: changes in the endocannabinoidome and serotonergic pathways in Alzheimer's-prone mice after mTBI.

BACKGROUND: Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer's disease (AD). METHODS: Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI. RESULTS: We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aß1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma. CONCLUSIONS: Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.

Carcinoid crisis: The challenge is still there.

Carcinoid crisis (CC) has classically been considered the extreme end of the spectrum of carcinoid syndrome (CS). However, this presumption and other aspects of CC remain poorly understood. Consequently, current clinical guidelines are based on a low quality of evidence. There is no standard definition of CC and its incidence is unknown. Patients with florid CS and elevated serotonin (or its derivatives) which develop CC have been reported during decades. Nevertheless, the hypothesis that CC is due to the sudden massive release of serotonin or other vasoactive substances is unproven. Many triggers of CC (surgery, anaesthesia, peptide receptor radionuclide therapy, tumour biopsy or liver-directed treatments) have been proposed. However, data from studies are heterogeneous and even contradictory. Finally, the role of octreotide in the prevention of CC has been questioned. Herein, we report a clinical case and perform a critical review of the evidence available today on this topic.

Involvement of serotonergic receptors in depressive processes and their modulation by ß-arrestins: A review.

Over time, several studies have been conducted to demonstrate the functions of the neurotransmitter 5-hydroxytryptamine (5-HT), better known as serotonin. This neurotransmitter is associated with the modulation of various social and physiological behaviors, and its dysregulation has consequences at the behavioral level, leading to various neurophysiological disorders. Disorders such as anxiety, depression, schizophrenia, epilepsy, sexual disorders, and eating disorders, have been closely linked to variations in 5-HT concentrations and modifications in brain structures, including the raphe nuclei (RN), prefrontal cortex, basal ganglia, hippocampus, and hypothalamus, among others. The involvement of ß-arrestin proteins has been implicated in the modulation of the serotonergic receptor response, as well as the activation of different signaling pathways related to the serotonergic system, this is particularly relevant in depressive disorders. This review will cover the implications of alterations in 5-HT receptor expression in depressive disorders in one hand and how ß-arrestin proteins modulate the response mediated by these receptors in the other hand.

Dorsal raphe nucleus-hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice.

BACKGROUND: Depressive symptoms often occur in patients with Alzheimer's disease (AD) and exacerbate the pathogenesis of AD. However, the neural circuit mechanisms underlying the AD-associated depression remain unclear. The serotonergic system plays crucial roles in both AD and depression. METHODS: We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches, chemogenetic manipulations, optogenetic manipulations, pharmacological methods, behavioral testing, and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model. RESULTS: We found that the activity of dorsal raphe nucleus serotonin neurons (DRN5-HT) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN5-HT-dCA1CaMKII) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN5-HT-dCA1CaMKII neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT1BR) and 4 (5-HT4R). Pharmacological activation of 5-HT1BR or 5-HT4R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN5-HT-dCA1CaMKII neural circuit to improve synaptic plasticity. CONCLUSIONS: These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.

Oxidative stress in relation to serotonin under general anaesthesia in dogs undergoing ovariectomy.

Abdominal surgery such as ovariectomy is a traumatic event that can cause oxidative stress. The aim of the present study was to evaluate the concentration of serotonin in relation to ovariectomy-induced oxidative stress in dogs undergoing general anesthesia. Thirty-two female dogs, under general anesthesia, received meloxicam before surgery (0.2 mgkg-1 SC) and after surgery (0.1 mgkg-1 OS every 24 h). The physiological, hematological, and biochemical parameters: glycemia, aspartate transaminase (AST), alanine aminotransferase (ALT), total protein, albumin and BUN were evaluated. Oxidative stress was determined by malondialdehyde (MDA) assay, catalase (CAT), superoxide dismutase (SOD), myeloperoxidase (MPO) and butyrylcholinesterase (BuChe) at baseline, 36 and 48 h after the last administration of meloxicam. Serotonin (5-HT) concentration was also evaluated at baseline, 36 and 48 h after the last administration of meloxicam. Responses to surgical stimulus were evaluated. Physiological and hematological parameters they fell within the normal ranges for anesthetized dogs. Glycemia increased, albumin levels decreased after surgery. No rescue analgesia was required. MDA and 5-HT concentrations significantly increased from the baseline at 36 and 48 h after surgery (p < .001). 5-HT levels could be used as an indicator for oxidative stress induced by surgery and it might be employed for objectively quantifying the well-being of the surgical patient.

Serotonin Influences Insulin Secretion in Rat Insulinoma INS-1E Cells.

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine that plays a critical role in insulin secretion, energy metabolism, and mitochondrial biogenesis. However, the action of serotonin in insulin production and secretion by pancreatic ß cells has not yet been elucidated. Here, we investigated how exogenous nanomolar serotonin concentrations regulate insulin synthesis and secretion in rat insulinoma INS-1E cells. Nanomolar serotonin concentrations (10 and 50 nM) significantly increased insulin protein expression above the constant levels in untreated control cells and decreased insulin protein levels in the media. The reductions in insulin protein levels in the media may be associated with ubiquitin-mediated protein degradation. The levels of membrane vesicle trafficking-related proteins including Rab5, Rab3A, syntaxin6, clathrin, and EEA1 proteins were significantly decreased by serotonin treatment compared to the untreated control cells, whereas the expressions of Rab27A, GOPC, and p-caveolin-1 proteins were significantly reduced by serotonin treatment. In this condition, serotonin receptors, Gαq-coupled 5-HT2b receptor (Htr2b), and ligand-gated ion channel receptor Htr3a were significantly decreased by serotonin treatment. To confirm the serotonylation of Rab3A and Rab27A during insulin secretion, we investigated the protein levels of Rab3A and Rab27A, in which transglutaminase 2 (TGase2) serotonylated Rab3A but not Rab27A. The increases in ERK phosphorylation levels were consistent with increases in the expression of p-Akt. Also, the expression level of the Bcl-2 protein was significantly increased by 50 and 100 nM serotonin treatment compared to the untreated control cells, whereas the levels of Cu/Zn-SOD and Mn-SOD proteins decreased. These results indicate that nanomolar serotonin treatment regulates the insulin protein level but decreases this level in media through membrane vesicle trafficking-related proteins (Rab5, Rab3A, syntaxin6, clathrin, and EEA1), the Akt/ERK pathway, and Htr2b/Htr3a in INS-1E cells.

Correlation between Neurotransmitters (Dopamine, Epinephrine, Norepinephrine, Serotonin), Prognostic Nutritional Index, Glasgow Prognostic Score, Systemic Inflammatory Response Markers, and TNM Staging in a Cohort of Colorectal Neuroendocrine Tumor Patients.

Neuroendocrine tumors are uncommon in the gastrointestinal system but can develop in the majority of the body's epithelial organs. Our goal was to examine the presence and clinical application of serum dopamine (DA), serotonin (ST), norepinephrine (NE), and epinephrine (EPI), in addition to determining the significance of the Prognostic Nutritional Index (PNI), Glasgow Prognostic Score (GPS), and systemic inflammatory response (SIR) markers as a prognostic factor for patients with colorectal neuroendocrine tumors (CR-NETs), in various tumor-node-metastasis (TNM) stages. We also wanted to identify the possible connection between them. This study included 25 consecutive patients who were diagnosed with CR-NETs and a control group consisting of 60 patients with newly diagnosed colorectal cancer (CRC). We used the Enzyme-Linked Immunosorbent Assay (ELISA) technique. This study revealed that CR-NET patients showed significantly higher serum levels of DA compared to CRC patients. We showed that serum DA was present in the early stages of CR-NETs, with increasing levels as we advanced through the TNM stages. Moreover, we found a close relationship between the levels of DA and the inflammation and nutritional status of the CR-NET patients in this study. CR-NET patients from the PNI < 47.00 subgroup had a higher level of DA than those from the PNI ≥ 47.00 subgroup. Pearson's correlation analysis revealed correlations between DA, PNI, and the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR). Both hematological indices were negatively correlated with albumin (ALB). Our investigation's findings relating to the PNI, GPS, SIR, and DA indicate that these tools can be markers of nutritional and systemic inflammatory status, are simple to use, and are repeatable. Further research on this topic could provide valuable insights into which biomarkers to incorporate into clinical practice for the management of CR-NET patients.

Potential Differences in Psychedelic Actions Based on Biological Sex.

The resurgence of interest in psychedelics as treatments for psychiatric disorders necessitates a better understanding of potential sex differences in response to these substances. Sex as a biological variable (SABV) has been historically neglected in medical research, posing limits to our understanding of treatment efficacy. Human studies have provided insights into the efficacy of psychedelics across various diagnoses and aspects of cognition, yet sex-specific effects remain unclear, making it difficult to draw strong conclusions about sex-dependent differences in response to psychedelic treatments. Compounding this further, animal studies used to understand biological mechanisms of psychedelics predominantly use one sex and present mixed neurobiological and behavioral outcomes. Studies that do include both sexes often do not investigate sex differences further, which may hinder the translation of findings to the clinic. In reviewing sex differences in responses to psychedelics, we will highlight the direct interaction between estrogen (the most extensively studied steroid hormone) and the serotonin system (central to the mechanism of action of psychedelics), and the potential that estrogen-serotonin interactions may influence the efficacy of psychedelics in female participants. Estrogen influences serotonin neurotransmission by affecting its synthesis and release, as well as modulating the sensitivity and responsiveness of serotonin receptor subtypes in the brain. This could potentially influence the efficacy of psychedelics in females by modifying their therapeutic efficacy across menstrual cycles and developmental stages. Investigating this interaction in the context of psychedelic research could aid in the advancement of therapeutic outcomes, especially for conditions with sex-specific prevalence.

A probiotic NVP1704 alleviates stress-induced sleeplessness/depression-like symptoms in mice by upregulating serotonergic and GABAergic systems and downregulating NF-κB activation.

Sleeplessness (insomnia) is a potential symptom of depression. A probiotic NVP1704 alleviates depression-like behavior and neuroinflammation in mice. Therefore, to understand whether NVP1704 could be effective against sleeplessness in vivo, we exposed immobilization stress (IS) in mice, then orally administered NVP1704 for 5 days, and assayed depression/anxiety-like behavior in the open field, elevated plus maze, and tail suspension tests, sleeping latency time, and sleep duration, euthanized then by exposure to CO2, and analyzed their related biomarkers. Oral administration of NVP1704 decreased IS-induced depression/anxiety-like behavior and sleeping latency time and increased IS-suppressed sleeping duration. NVP1704 increased IS-suppressed expression of γ-aminobutyric acid (GABA), GABAA receptor α1 (GABAARα1) and α2 subunits (GABAARα2), serotonin, 5-HT receptors (5-HT1AR and 5-HT1BR), and melatonin receptors (MT1R and MT2R) in the prefrontal cortex and thalamus. NVP1704 also increased the IS-suppressed GABAARα1-positive cell population in the prefrontal cortex and decreased IS-induced corticosterone, TNF-α, and IL-6 expression and the NF-κB+Iba1+ cell population in the brain and myeloperoxidase, TNF-α, and IL-6 expression and the NF-κB+CD11c+ cell population in the colon. Based on these findings, NVP1704 may alleviate depression/anxiety/sleeplessness-like behaviors through the upregulation of serotonergic and GABAergic systems and downregulation of NF-κB activation.

Dorsal raphe nucleus to basolateral amygdala 5-HTergic neural circuit modulates restoration of consciousness during sevoflurane anesthesia.

The advent of general anesthesia (GA) has significant implications for clinical practice. However, the exact mechanisms underlying GA-induced transitions in consciousness remain elusive. Given some similarities between GA and sleep, the sleep-arousal neural nuclei and circuits involved in sleep-arousal, including the 5-HTergic system, could be implicated in GA. Herein, we utilized pharmacology, optogenetics, chemogenetics, fiber photometry, and retrograde tracing to demonstrate that both endogenous and exogenous activation of the 5-HTergic neural circuit between the dorsal raphe nucleus (DR) and basolateral amygdala (BLA) promotes arousal and facilitates recovery of consciousness from sevoflurane anesthesia. Notably, the 5-HT1A receptor within this pathway holds a pivotal role. Our findings will be conducive to substantially expanding our comprehension of the neural circuit mechanisms underlying sevoflurane anesthesia and provide a potential target for modulating consciousness, ultimately leading to a reduction in anesthetic dose requirements and side effects.

The blood serum metabolome profile after different phases of a 4-km cycling time trial: Secondary analysis of a randomized controlled trial.

It has been assumed that exercise intensity variation throughout a cycling time trial (TT) occurs in alignment of various metabolic changes to prevent premature task failure. However, this assumption is based on target metabolite responses, which limits our understanding of the complex interconnection of metabolic responses during exercise. The current study characterized the metabolomic profile, an untargeted metabolic analysis, after specific phases of a cycling 4-km TT. Eleven male cyclists performed three separated TTs in a crossover counterbalanced design, which were interrupted at the end of the fast-start (FS, 600 ± 205 m), even-pace (EP, 3600 ± 190 m), or end-spurt (ES, 4000 m) phases. Blood samples were taken before any exercise and 5 min after exercise cessation, and the metabolomic profile characterization was performed using Nuclear Magnetic Resonance metabolomics. Power output (PO) was also continually recorded. There were higher PO values during the FS and ES compared to the EP (all p < 0.05), which were accompanied by distinct metabolomic profiles. FS showed high metabolite expression in TCA cycle and its related pathways (e.g., glutamate, citric acid, and valine metabolism); whereas, the EP elicited changes associated with antioxidant effects and oxygen delivery adjustment. Finally, ES was related to pathways involved in NAD turnover and serotonin metabolism. These findings suggest that the specific phases of a cycling TT are accompanied by distinct metabolomic profiles, providing novel insights regarding the relevance of specific metabolic pathways on the process of exercise intensity regulation.

Relationships between Serotonin Transporter Availability and the Global Efficiency of the Executive Control Brain Network.

The diverse effects of serotonin on cognition may emerge from the modulation of large-scale brain networks that support distinct cognitive processes. Yet, the specific effect of serotoninergic modulation on the properties of these networks remains elusive. Here, we used a simultaneous PET-fMRI scanner combined with graph theory analyses to investigate the modulation of network properties by the Serotonin Transporter (SERT) availability measured in the dorsal raphe nucleus (DRN). We defined global efficiency as the average mean of efficiencies over all pairs of distinct nodes of specific brain networks, and determined whether SERT levels correlated with the global efficiency of each network. SERT availability in the DRN correlated negatively with the global efficiency of the executive control brain network, which is engaged in cognitive control and directed attention. No relationship was observed between SERT availability and the global efficiency of the default mode or the salience brain networks. These findings indicate a specific role of serotoninergic modulation in the executive control brain network via a change in its global efficiency.

Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans.

Declined memory is a hallmark of Alzheimer's disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HT2CR signaling regulates memory, which may inform the use of 5-HT2CR agonists in the treatment of dementia.

Accelerated Electron Ionization-Induced Changes in the Myenteric Plexus of the Rat Stomach.

The influence of accelerated electrons on neuronal structures is scarcely explored compared to gamma and X-rays. This study aims to investigate the effects of accelerated electron radiation on some pivotal neurotransmitter circuits (cholinergic and serotonergic) of rats' myenteric plexus. Male Wistar rats were irradiated with an electron beam (9 MeV, 5 Gy) generated by a multimodality linear accelerator. The contractile activity of isolated smooth muscle samples from the gastric corpus was measured. Furthermore, an electrical stimulation (200 µs, 20 Hz, 50 s, 60 V) was performed on the samples and an assessment of the cholinergic and serotonergic circuits was made. Five days after irradiation, the recorded mechanical responses were biphasic-contraction/relaxation in controls and contraction/contraction in irradiated samples. The nature of the contractile phase of control samples was cholinergic with serotonin involvement. The relaxation phase involved ACh-induced nitric oxide release from gastric neurons. There was a significant increase in serotonergic involvement during the first and second contractile phases of the irradiated samples, along with a diminished role of acetylcholine in the first phase. This study demonstrates an increased involvement of serotonergic neurotransmitter circuits in the gastric myenteric plexus caused by radiation with accelerated electrons.

Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities.

BACKGROUND: Serotonin (5-hydroxytryptamine) is a multifunctional bioamine serving as a neurotransmitter, peripheral hormone and mitogen in the vertebrate system. It has pleiotropic activities in central nervous system and gastrointestinal function via an orchestrated action of serotonergic elements, particularly serotonin receptor-mediated signalling cascades. The mitogenic properties of serotonin have garnered recognition for years and have been exploited for repurposing serotonergic-targeted drugs in cancer therapy. However, emerging conflicting findings necessitate a more comprehensive elucidation of serotonin's role in cancer pathogenesis. MAIN BODY AND CONCLUSION: Here, we provide an overview of the biosynthesis, metabolism and action modes of serotonin. We summarise our current knowledge regarding the effects of the peripheral serotonergic system on tumourigenesis, with a specific emphasis on its immunomodulatory activities in human cancers. We also discuss the dual roles of serotonin in tumour pathogenesis and elucidate the potential of serotonergic drugs, some of which display favourable safety profiles and impressive efficacy in clinical trials, as a promising avenue in cancer treatment. KEY POINTS: Primary synthesis and metabolic routes of peripheral 5-hydroxytryptamine in the gastrointestinal tract. Advanced research has established a strong association between the serotonergic components and carcinogenic mechanisms. The interplay between serotonergic signalling and the immune system within the tumour microenvironment orchestrates antitumour immune responses. Serotonergic-targeted drugs offer valuable clinical options for cancer therapy.

Effect of Dietary L-Theanine on Protein Expression in the Hippocampus of Senescence-Accelerated Mice (SAMP8).

L-Theanine is contained in green tea at 1-3% per dry matter as an amino acid with an umami taste, and the antidepressant effect and protective effect against stress-induced brain atrophy in mice, as well as the related mechanism have been reported. However, effects of theanine on the hippocampus from the proteome analysis and the action mechanism have not been examined. In this study, we mainly investigated the possibility of theanine's cognitive impairment-preventing function and the action mechanism by proteomics in the hippocampus of SAMP8 administered with theanine. In addition to improvement in the aging score with theanine administration, in proteomics, significant suppressions in the expressions of synapsin 2, α-synuclein, ß-synuclein, and protein tau were observed by theanine administration, and the expression of CAM kinase II beta and alpha exhibited a significant increase and increasing tendency with theanine administration, respectively. The expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein tended to increase by theanine administration. On the other hand, serotonin/tryptophan, GABA/glutamic acid and glutamine/glutamic acid ratios in the hippocampus showed an increasing tendency, a significant increase, and an increasing tendency with theanine administration, respectively. These results suggested that theanine might have been involved in the improvement of neurodegeneration or cognitive impairment by suppressing the productions of synapsin, synuclein and protein tau which are considered to be produced along with aging and oxidation, and by enhancing the production of serotonin by increasing the expression of CAM kinase II, and further by affecting the metabolism of glutamate.

Individual differences in the boldness of female zebrafish are associated with alterations in serotonin function.

One of the most prevalent axes of behavioral variation in both humans and animals is risk taking, where individuals that are more willing to take risk are characterized as bold while those that are more reserved are regarded as shy. Brain monoamines (i.e. serotonin, dopamine and noradrenaline) have been found to play a role in a variety of behaviors related to risk taking. Using zebrafish, we investigated whether there was a relationship between monoamine function and boldness behavior during exploration of a novel tank. We found a correlation between serotonin metabolism (5-HIAA:5-HT ratio) and boldness during the initial exposure to the tank in female animals. The DOPAC:DA ratio correlated with boldness behavior on the third day in male fish. There was no relationship between boldness and noradrenaline. To probe differences in serotonergic function in bold and shy fish, we administered a selective serotonin reuptake inhibitor, escitalopram, and assessed exploratory behavior. We found that escitalopram had opposing effects on thigmotaxis in bold and shy female animals: the drug caused bold fish to spend more time near the center of the tank and shy fish spent more time near the periphery. Taken together, our findings indicate that variation in serotonergic function has sex-specific contributions to individual differences in risk-taking behavior.

Impact of Serotonin Deficiency on Circadian Dopaminergic Rhythms.

Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain-including those involving serotonin and dopamine-exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.