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Since the 1950s, considerable circumstantial evidence had been presented that endogenous 5‐HT (serotonin) synthesized from within the wall of the gastrointestinal (GI) tract played an important role in GI motility and transit. However, identifying the precise functional role of gut‐derived 5‐HT has been difficult to ascertain, for a number of reasons. Over the past decade, as recording techniques have advanced significantly and access to new genetically modified animals improved, there have been major new insights and major changes in our understanding of the functional role of endogenous 5‐HT in the GI tract. Data from many different laboratories have shown that major patterns of GI motility and transit still occur with minor or no, change when all endogenous 5‐HT is pharmacologically or genetically ablated from the gut. Furthermore, antagonists of 5‐HT3 receptors are equally, or more potent at inhibiting GI motility in segments of intestine that are completely depleted of endogenous 5‐HT. Here, the most recent findings are discussed with regard to the functional role of endogenous 5‐HT in enterochromaffin cells and enteric neurons in gut motility and more broadly in some major homeostatic pathways. [ABSTRACT FROM AUTHOR]

Objective: This study aims to explore the therapeutic mechanism of Massa Medicata Fermentata (MMF) with different formulations on spleen deficiency constipation in mice by analyzing gastrointestinal hormones, D-xylose, intestinal microbiota, and intestinal enzyme activities. Methods: A spleen deficiency constipation model was established using an oral administration of Sennae Folium decoction combined with controlled diet and water intake. After successful model establishment, the mice with spleen deficiency constipation were treated with MMF S1, S2, S3. Following the intervention, serum samples from each group of mice were collected to measure VIP, 5-HT, and D-xylose. Additionally, small intestine contents were analyzed for intestinal enzyme activity and subjected to 16S rRNA high-throughput sequencing. Results: Mice with spleen deficiency constipation showed significant decreases in body weight and fecal water content. In contrast, the body weight of the CS2 and CS3 groups returned to normal levels, and fecal water content in the CS2 and CS3 groups also returned to normal. The MMF S2 and S3 significantly increased protease and sucrase enzymes levels compared with CM group. Serum D-xylose levels were significantly reduced in the CM and CS2 group. VIP levels increased significantly in the CM group but decreased in the CS2 and CS3 groups. Additionally, 5-HT levels in the CM and CS1 groups decreased significantly, with the CS2 group returning to normal and the CS3 group showing significant increases. 16S rRNA sequencing analysis revealed that all three MMF formulations effectively restored the intestinal microbiota composition in mice. LEfSe analysis identified characteristic microbiota linked to different intervention groups. The CS3 group significantly upregulated the chloroalkane and chloroalkene degradation and vibrio cholerae pathogenic cycle pathways compared to the CM group. Candidatus_Arthromitus in the CS3 group and Psychrobacter in the CS2 group were positive and negative correlations with 5-HT and VIP, respectively. Conclusion: The three formulations of MMF significantly alleviated spleen deficiency constipation symptoms by modulating intestinal enzyme activities, D-xylose, VIP, and 5-HT levels, and restoring intestinal microbiota balance. Psychrobacter and Candidatus_Arthromitus were identified as potential biomarkers for the treatment of spleen deficiency constipation. Different formulations of MMF have different mechanisms of regulating constipation through intestinal microbiota. [ABSTRACT FROM AUTHOR]

Background/Objectives: Serotonin and the serotonin transporter (SERT) may have a multifaceted, but not fully understood, role in obstructive sleep apnea (OSA) and its impact on mental health in this group of patients. This study aimed to investigate changes in serotonin and the serotonin transporter (SERT) and their association with depressive and insomnia symptoms. Methods: This study included 76 participants (OSA group: n = 36, control group (CG): n = 40) who underwent polysomnography, while venous blood samples (evening and morning) were analyzed for serotonin and the SERT using ELISA. SERT mRNA expression in peripheral leukocytes was measured via quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Participants were evaluated for depression, insomnia, and quality of life (QoL). Results: This study found no significant differences in SERT mRNA or serotonin between the OSA group and CG. In the CG, individuals without mood disorders had higher baseline SERT levels and evening/morning SERT ratios than those with depression. Among the OSA participants, those with good QoL had elevated serotonin levels in the evening (p = 0.028) and morning (p = 0.043) compared to those with poor QoL. Baseline SERT protein levels were higher in the CG than in the OSA group for insomnia, while SERT mRNA expression was higher in the OSA group. Linear regression models showed 13.3% and 13.1% for non-rapid eye movement sleep (NREM) apnea/hypopnea index (AHI) and AHI variability, respectively, which was accounted for by the morning SERT level, while 30.8% of the arousal index variability was explained by the morning serotonin level. Conclusions: Serotonergic signaling may influence quality of life, depression, and insomnia in OSA, as well as the severity of the disease itself. Stratifying patients by clinical and laboratory phenotypes could enable more personalized treatment. [ABSTRACT FROM AUTHOR]

There is increasing interest in the potential therapeutic role of 5-HT (serotonin) in the treatment of neurodegenerative diseases, which are characterized by the progressive degeneration and death of nerve cells. 5-HT is a vital neurotransmitter that plays a central role in regulating mood, cognition, and various physiological processes in the body. Disruptions in the 5-HT system have been linked to several neurological and psychiatric disorders, making it an attractive target for therapeutic intervention. Although the exact causes of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are not fully understood, researchers believe that regulating the 5-HT system could help alleviate symptoms and potentially slow the progression of these diseases. Here, we delve into the potential of harnessing 5-HT as a therapeutic target for the treatment of neurodegenerative diseases. It is important to note that the current clinical drugs targeting 5-HT are still limited in the treatment of these complex diseases. Therefore, further research and clinical trials are needed to evaluate the feasibility and effectiveness of its clinical application. [ABSTRACT FROM AUTHOR]

Time perception is a fundamental cognitive function essential for adaptive behavior and shared across species. The neural mechanisms underlying time perception, particularly its neuromodulation, remain debated. In this review, we examined the role of the serotonergic system in time perception (at the scale of seconds and minutes), building a translational bridge between human and non-human animal studies. The literature search was conducted according to the PRISMA statement in PubMed, APA PsycINFO, and APA PsycARTICLES. Sixty papers were selected for full-text review, encompassing both human (n = 10) and animal studies (n = 50). Summarizing the reviewed literature, we revealed consistent evidence for the role of serotonin in timing behavior, highlighting its complex involvement across retrospective, immediate, and prospective timing paradigms. Increased serotonergic activation appears to accelerate internal time speed, which we interpret through the dual klepsydra model as accelerated discharge of the temporal accumulator. However, some findings challenge this framework. Additionally, we link impulsivity—associated with decreased serotonergic functioning in our review—to a slower internal time speed. Variability in prospective timing tasks underscores the need for further research into how serotonin modulates reward-based temporal decisions, using novel approaches to disentangle internal time speed, response inhibition, and other factors. [ABSTRACT FROM AUTHOR]

Cissus quadrangularis Linn. (C. quadrangularis, Vitaceae) is a plant reported to treat injured tendons, broken bones, asthma, stomach ache, scurvy, and digestive disorders. The present study evaluated the antihyperalgesic effects of ethanolic extract of C. quadrangularis Linn. Vincristine sulfate (100 μg/kg, i.p.) was administered in rats for 10 days with 2 days break to induce painful peripheral neuropathy. Mechanical hyperalgesia and allodynia tests were performed to assess the threshold of painful neuropathy. Calcium levels in the sciatic nerve, oxidant stress markers, and levels of GABA and 5‐HT were also determined in the brain and spinal cord after 15 days. Ethanolic extract of C. quadrangularis (180 and 360 mg/kg) and pregabalin (50 mg/kg) were administered for 15 consecutive days. The results revealed that the extract significantly (p < 0.001) inhibited hyperalgesia and allodynia in animals after vincristine administration. The extract decreased total calcium levels in the sciatic nerve, MDA levels while increasing GSH activity, 5‐HT level, as well as GABA levels in the brain and spinal cord. The results of this study suggest that the ethanolic extract of C. quadrangularis uses antioxidant capacity, calcium inhibitory action, and neuromodulation of GABA and 5‐HT to prevent the development of painful neuropathy after vincristine administration. This demonstrates that C. quadrangularis is a promising molecule for the management of peripheral neuropathic pain induced by anticancer drugs. [ABSTRACT FROM AUTHOR]

AbstractConvenient multiday dosing of antiemetic regimens for the prevention of chemotherapy-induced nausea and vomiting (CINV) are needed in pediatric patients, who are more likely than adults to be treated with emetogenic chemotherapy over multiple consecutive days. Intravenous (IV) fosaprepitant is approved for the prevention of CINV in children aged 6 months and older. This open-label, single-arm study assessed the safety and tolerability of a 3-day fosaprepitant regimen (consecutive daily IV administration on days 1–3) plus a serotonin receptor antagonist with or without dexamethasone in pediatric patients (6 months to 17 years) receiving emetogenic chemotherapy. Study treatment was initiated at the start of a chemotherapy cycle (cycle 1); patients completing cycle 1 could participate in optional cycles 2 and 3. Primary endpoints included adverse events (AEs) and AE-related discontinuation during cycle 1.98/100. Patients completed cycle 1; 69 participated in optional cycles 2 and 3. The AE profile during cycle 1 was typical of cancer patients receiving emetogenic chemotherapy; 80/100 (80.0%) patients experienced ≥1 AE. AE rates were generally similar between patients aged 6 months to <2 years (11/15 patients [73.3%]), 2 to <6 years (22/30 [73.3%]), 6 to <12 years (24/25 [96.0%]), and 12–17 years (23/30 [76.7%]). Rates of drug-related AEs (4/100 [4.0%]) and AE-related discontinuations (2/100 [2.0%]) were low. Similar trends in safety outcomes were observed during cycles 2 and 3. No deaths were reported. The 3-day IV fosaprepitant regimen for the prevention of CINV was generally well tolerated in pediatric patients receiving emetogenic chemotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD) is commonly characterized by severe dopamine (DA) depletion within the substantia nigra (SN) leading to a myriad of motor and non-motor symptoms. One underappreciated and prevalent non-motor symptom, Parkinson's disease-associated psychosis (PDAP), significantly erodes patient and caregiver quality of life yet remains vastly understudied. While the gold standard pharmacotherapy for motor symptoms Levodopa (LD) is initially highly effective, it can lead to motor fluctuations like LD-induced dyskinesia (LID) and non-motor fluctuations such as intermittent PDAP. One source of these fluctuations could be the serotonergic raphe nuclei and their projections. Serotonin (5-HT) neurons possess the machinery necessary to convert and release DA from exogenous LD. In DA-depleted brain regions these 5-HT projections can act as surrogates to the DA system initially compensating but chronically leading to aberrant neuroplasticity which has been linked to LID and may also contribute to non-motor fluctuations. In support, recent work from our lab established a positive relationship between LID and PDAP in parkinsonian rats. Therefore, it was hypothesized that normalizing 5-HT forebrain input would reduce the co-expression of LID and PDAP. Methods: To do so, we expressed 5-HT projection specific inhibitory designer receptor exclusively activated by designer drugs (DREADDs) using Cre-dependent AAV9-hM4di in tryptophan hydroxylase 2 (TPH2)-Cre bilaterally 6-OHDA-lesioned rats. Thereafter we used the designer drug Compound 21 to selectively inhibit 5-HT raphe projections during LD treatment to modulate the expression of PDAP, assayed by prepulse inhibition (PPI) and LID, quantified by the abnormal involuntary movements (AIMs) test. Results: Our results suggest that chemogenetic inhibition of 5-HT raphe-projecting cells significantly reduces LID without affecting stepping ability or established sensorimotor gating deficits Discussion: Overall, this study provides further evidence for the complex influence of 5-HT raphe-projecting neurons on LD's neurobehavioral effects. [ABSTRACT FROM AUTHOR]

Background and Purpose: The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5‐HT in the antidepressant effects of ketamine remains unclear. Experimental approach: The chronic restraint stress procedure was performed to induce depression‐like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant‐like effects of ketamine. Tph2 knockout or depletion of 5‐HT by PCPA and 5,7‐DHT were used to manipulate the brain 5‐HT system. ELISA and fibre photometry recordings were used to measure extracellular 5‐HT levels in the brain. Key Results: 60 min after injection, ketamine (10 mg·kg−1, i.p.) produced rapid antidepressant‐like effects and increased brain 5‐HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5‐HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant‐like effects of ketamine were abrogated by PCPA and 5,7‐DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg−1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5‐HT levels and abolished the sustained antidepressant‐like effects of ketamine in naïve or CRS‐treated mice. Conclusion and Implications: This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant‐like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets. [ABSTRACT FROM AUTHOR]

Psoriasis exhibits a higher incidence of anxiety and depression. However, the diagnostic process heavily relies on subjective evaluation. Fatty acid‐binding protein 7 (FABP7) and serotonin (5‐HT) are considered as potential plasma biomarkers. We aimed to investigate the potentiality of plasma FABP7 and 5‐HT as biomarkers for predicting anxiety and depression in psoriasis. Data were analysed from 140 patients with psoriasis in the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH). Unsupervised clustering was employed to group patients based on their FABP7 and 5‐HT profiles. Subsequently, patients were categorised into Group 1 (lower FABP7 and higher 5‐HT) or Group 2. Multivariate logistic regression was employed to investigate the correlation between the FABP7‐5‐HT pattern and anxiety or depression in psoriasis patients. Patients with psoriasis have a higher incidence of anxiety or depression, as well as higher levels of FABP7 and lower levels of 5‐HT. After clustering patients using K‐means clustering, Group 2 showed a higher body mass index, a higher incidence of hypertension, more severe psoriasis, and more significant anxiety and depression compared to Group 1. Multivariate logistic regression shows that adjusting for covariates except PASI, duration of psoriasis, and psoriatic arthritis, Group 2 had a higher risk of anxiety and depression compared to Group 1. Further adjustment for covariates yielded similar results. Pattern of FABP7‐5‐HT that may indicate an association with psoriasis accompanied by anxiety or depression. [ABSTRACT FROM AUTHOR]

Ding Yang,1 Rulan Bai,1 Chengzhong Li,2 Yan Sun,2 Hongyu Jing,1 Zixu Wang,1 Yaoxing Chen,1 Yulan Dong1 1College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China; 2Department of Horticulture and Landscape Architecture, Jiangsu Agri-Animal Husbandry Vocational College, Taizhou, People’s Republic of ChinaCorrespondence: Yulan Dong, Email ylbcdong@cau.edu.cnBackground: The early childhood period is a critical development stage, and experiencing stress during this time may increase the risk of gastrointestinal disorders, including irritable bowel syndrome (IBS). Neonatal maternal separation (NMS) in rodent models has been shown to cause bowel dysfunctions similar to IBS, and 5-HT is considered to be a key regulator regulating intestinal function, but the precise underlying mechanisms remain unclear.Results: We established a maternal separation stress mouse model to simulate early-life stress, exploring the expression patterns of 5-HT under chronic stress and its mechanisms affecting gut function. We observed a significant increase in 5-HT expression due to NMS, leading to disruptions in intestinal structure and function. However, inhibiting 5-HT reversed these effects, suggesting its potential as a therapeutic target. Furthermore, our research revealed that excess 5-HT in mice with early life stress increased intestinal neural network density and promoted excitatory motor neuron expression. Mechanistically, 5-HT activated the Wnt signaling pathway through the 5-HT4 receptor, promoting neurogenesis within the intestinal nervous system.Conclusion: These findings shed light on the intricate changes induced by early life stress in the intestines, confirming the regulatory role of 5-HT in the enteric nervous system and providing potential insights for the development of novel therapies for gastrointestinal disorders.Keywords: 5-HT, IBS, early-life stress, neurogenesis

Substance use disorder (SUD) is a chronic condition, with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies. The signalling, expression profile, and neurological function of the serotonin 2C receptor (5‐HT2C receptor) make it a candidate of interest for the treatment of SUD. Recently, psychedelics, which broadly act at 5‐HT2 receptors, have indicated potential for the treatment of SUD, implicating the 5‐HT2C receptor. The modern psychedelic movement has rekindled interest in the 5‐HT2C receptor, resulting in many new studies, especially structural analyses. This review explores the structural, molecular and cellular mechanisms governing 5‐HT2C receptor function in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration. [ABSTRACT FROM AUTHOR]

The structures of glycans, specifically their terminal positions, play an important role as ligands for receptors in regulating the adhesion ability of platelets. Recent advances in our understanding of free/unbound serotonin (5-HT) in blood plasma at supraphysiological levels implicate it as one of the most profound influencers in remodeling the platelet's surface N-glycans. Proteomic analysis of the membrane vesicles identified enzymes, specifically glycosyltransferases, only on the surface of the platelets isolated from the supraphysiological level of 5-HT-containing blood plasma. However, these enzymes can only be effective on the cell surface under certain biological conditions, such as the level of their substrates, temperature, and pH of the environment. We hypothesize that exosomes released from various cells coordinate the required criteria for the enzymatic reaction on the platelet surface. The elevated plasma 5-HT level also accelerates the release of exosomes from various cells, as reported. This review summarizes the findings from a wide range of literature and proposes mechanisms to coordinate the exosomes and plasma 5-HT in remodeling the structures of N-glycans to make platelets more prone to aggregation. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho‐inhibition and sympatho‐excitation, mainly via 5‐HT1D/1A and 5‐HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5‐HT sympatho‐modulatory role in female rats, characterising the 5‐HT receptors involved.Female Wistar (14‐ to 16‐week‐old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1–5 Hz) or i.v. noradrenaline (0.01–0.5 μg·kg−1). 5‐HT‐related drug effects on adrenergic system were determined. Age‐matched male rats were used as control.Basal MBP in females was lower than in male rats, whereas electrical‐induced increases in MBP were similar. In females, 5‐HT exerted a dose‐dependent inhibition on the sympathetic‐evoked vasoconstrictions, that was reproduced by some agonists; 5‐CT (5‐HT1/5/7) and L‐694,247 (5‐HT1D), whereas the selective 5‐HT2A/2B/2C (α‐methyl‐5‐HT) and 5‐HT3 agonist (1‐PBG) increased the electrically‐produced vasopressor responses. None of the other drugs tested (targeting 5‐HT1A/1B/1F, 5‐HT2B/2C, 5‐HT4, 5‐HT5A or 5‐HT7) modified these vasoconstrictions. Only 1‐PBG (5‐HT3) modified the vasoconstrictions induced by exogenous noradrenaline.In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5‐HT1D receptor activation, whereas pre and/or postjunctional 5‐HT3 and prejunctional 5‐HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex‐differential therapeutic strategies for treating cardiovascular conditions. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the contributions of multiple transport mechanisms to the intestinal uptake of serotonin (5-HT) by employing a variety of in vitro experimental techniques, focusing on organic cation transporters expressed in the gastrointestinal (GI) tract, such as SERT, PMAT, THTR2, OCT3, and OCTN2. Analysis of the concentration dependence of 5-HT uptake by Caco-2 cells revealed multi-affinity kinetics with high-affinity and low-affinity components, suggesting that multiple transporters are involved in the intestinal 5-HT uptake. Comparative analysis of transporters using K m values obtained in Xenopus oocyte expression systems suggested that SERT is responsible for the high-affinity transport, while PMAT, THTR2, and OCT3 contribute to the low-affinity transport. Further analysis indicated that the relative contributions of SERT and PMAT to the intestinal 5-HT uptake (0.01 µM) are approximately 94.9% and 1.1%, respectively. Interestingly, at the concentration of 10 µM, the reported steady-state concentration of 5-HT in the human colon, the contributions of SERT, PMAT, THTR2, and OCT3 were estimated to be approximately 37.0%, 1.0%, 18.2%, and 20.5%, respectively. In conclusion, the present study indicated that the contributions of multiple transporters to 5-HT uptake in the GI tract are dependent upon the colon luminal concentration of 5-HT. [ABSTRACT FROM AUTHOR]

Background: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention. Objectives: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms. Results: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT2A, 5-HT2C, and 5-HT7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition. Conclusions: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression. [ABSTRACT FROM AUTHOR]

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Purpose: Our study aimed to explore the efficacy of Bifidobacterium breve 207-1 on specific neurotransmitters and hormones and the ability to regulate lifestyle behaviors in healthy adults. Methods: In total, 120 healthy adults with high mental stress, overweight, insomnia, and constipation were randomly assigned to receive low-dose B. breve 207-1 (LD, n = 40), high-dose B. breve 207-1 (HD, n = 40), or placebo (n = 40) for 28 days. Fecal and blood samples were collected and questionnaires were answered before and after the trial. Neurotransmitters and serum hormones were detected using enzyme-linked immunosorbent assay. The gut microbiota composition was assessed using 16 S rRNA sequencing. Short–chain fatty acids (SCFAs) concentrations were determined via gas chromatography–mass spectrometry (GC–MS). Results: The primary outcome of our study was changes in mental wellness, including neurotransmitters, the hypothalamic–pituitary–adrena (HPA) axis hormones, and the psychological scales. The results showed that γ-aminobutyric acid (GABA) increased significantly and the HPA axis hormones were suppressed overall in the probiotic groups while 5-hydroxytryptamine (5-HT) did not change significantly. However, there was no significant change in mood scale scores. The secondary outcome focused on the ability of 207-1 to regulate the body and lifestyle of healthy adults (e.g., sleep, diet, exercise, etc.). The PSQI scores in the probiotics groups significantly decreased, indicating improved sleep quality. Meanwhile, the probiotic groups had a slight increase in exercise consumption while dietary intake stabilized. By physical examination, the participants showed weight loss although no statistically significant difference was observed between the groups. Then, validated by gut microbiota, changes in the gut microbiota were observed under the effective intervention of 207-1 while short-chain fatty acids (SCFAs) increased in the LD group, particularly acetic and propionic acids. There was a slight decrease in alpha–diversity in the HD group. Conclusion: Bifidobacterium breve 207-1 entered the organism and affected neurotransmitter and the HPA axis hormone levels via the microbiome-gut-brain axis. Meanwhile, 207-1 supplementation improved daily lifestyle behaviors in healthy adults, which may in turn lead to changes in their bodies (e.g. weight and lipid metabolism). However, this study did not find significant mood-modulating efficacy. The mechanism of the overall study is unclear, but we hypothesize that SCFAs may be the key pathway, and more experiments are needed for validation in the future. Trial registration: This trial was retrospectively registered in the Chinese Clinical Trial Registry under the accession number ChiCTR2300069453 on March 16, 2023. [ABSTRACT FROM AUTHOR]

Background: The traditional herbal medicine Atractylodes macrocephala Koidz. (A. macrocephala) is commonly utilized for alleviating symptoms associated with spleen deficiency, abdominal distension, diarrhea, and constipation. These pharmacological effects are attributed to a variety of active constituents. However, the specific bioactive compounds responsible for promoting defecation and gastrointestinal transit in A. macrocephala remain unidentified. Methods: The primary polysaccharide characteristics of PAMK was elucidated by HPLC, FT‐IR, and HGPGC. Efficacy of PAMK (0.07, 0.14, and 0.28 mg/g) on mice was evaluated in a spleen deficiency constipation mouse model by analyzing stool parameters, constipation‐related physiological indexes, and SCFAs. The expression levels of 5‐HT3R, 5‐HT4R, and related receptor genes were examined by RT‐qPCR, and neurotransmitters were examined using ELISA. Finally, the diversity of gut microbiota was analyzed with 16S rDNA sequencing. Key Results: The results showed that PAMK significantly reduced the gastrointestinal transport time and increased the number of fecal pellets and fecal water content in spleen deficiency constipation model mice. PAMK kept the balance of 5‐HT, SCFAs, TPH‐1, SERT, CgA, and neurotransmitter levels (VIP, SP, MTL) in mice colon. In addition, PAMK could regulate the abundance of gut microbiota such as Alistopes, Bacteroides, and Odoribacter in spleen deficiency constipation model mice gut. Conclusions and Inferences: It can be concluded that PAMK effectively ameliorated the symptoms of spleen deficiency constipation in mice by modulating the expression of 5‐HT and its associated receptors. The underlying mechanism was elucidated, providing a solid theoretical foundation for the therapeutic application of A. macrocephala in treating spleen deficiency constipation and offering potential for developing novel approaches to address this condition. [ABSTRACT FROM AUTHOR]

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse effects of the CDNF injection on feed and water consumption or locomotor activity were observed for 3 days afterwards. Decreases in body weight and sleep duration were transient. CDNF-treated animals demonstrated improved performance on the operant learning task and a substantial decrease in anxiety and behavioral despair. CDNF in all the doses enhanced serotonin (5-HT) turnover in the murine frontal cortex, hippocampus, and midbrain. This alteration was accompanied by changes in the mRNA levels of the 5-HT1A and 5-HT7 receptors and in monoamine oxidase A mRNA and protein levels. We found that CDNF dramatically increased c-Fos mRNA levels in all investigated brain areas but elevated the phosphorylated-c-Fos level only in the midbrain. Similarly, enhanced CREB phosphorylation was found in the midbrain in experimental animals. Additionally, the upregulation of a spliced transcript of XBP1 (UPR regulator) was detected in the midbrain and frontal cortex. Thus, we can hypothesize that exogenous CDNF modulates the UPR pathway and overall neuronal activation and enhances 5-HT turnover, thereby affecting learning and emotion-related behavior. [ABSTRACT FROM AUTHOR]

Introduction: Major depressive disorder (MDD) is a common and disabling mental health condition; the currently available treatments for MDD are insufficient to meet clinical needs due to their limited efficacy and slow onset of action. Hypidone hydrochloride (YL-0919) is a sigma-1 receptor agonist and a novel fast-acting antidepressant that is currently under clinical development. Methods: To further understand the fast-acting antidepressant activity of YL-0919, this study focused on the role of 5-HTergic neurons in the dorsal raphe nucleus (DRN) in mice. Using fiber photometry to assess neural activity in vivo and two behavioral assays (tail suspension test and forced swimming test) to evaluate antidepressant-like activity. Results: It was found that 3 or 7 days of YL-0919 treatment significantly activated serotonin (5-HT) neurons in the DRN and had significant antidepressant-like effects on mouse behaviors. Chemogenetic inhibition of 5-HTergic neurons in the DRN significantly blocked the antidepressant-like effect of YL-0919. In addition, YL-0919 treatment significantly increased the 5-HT levels in the prefrontal cortex (PFC). These changes were drastically different from those of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, which suggested that the antidepressant-like effects of the two compounds were mechanistically different. Conclusion: Together, these results reveal a novel role of 5-HTergic neurons in the DRN in mediating the fast-acting antidepressant-like effects of YL-0919, revealing that these neurons are potential novel targets for the development of fast-acting antidepressants for the clinical management of MDD. [ABSTRACT FROM AUTHOR]

Zebrafish (Danio rerio) are unusual in having two paralogues of the serotonin re-uptake transporter (Sert), slc6a4a (serta) and slc6a4b (sertb), the transporter that serves in serotonin re-uptake from a synapse into the pre-synaptic cell or in serotonin uptake from the extracellular milieu into cells in the peripheral tissues. To address a knowledge gap concerning the specific roles of these paralogues, we used CRISPR/Cas9 technology to generate zebrafish knockout lines predicted to lack functional expression of Serta or Sertb. The consequences of loss-of-function of Serta or Sertb were assessed at the gene expression level, focusing on the serotonergic signalling pathway, and at the behaviour level, focusing on aggression. Whereas serta mRNA was expressed in all tissues examined, with high expression in the heart, gill and brain, only the brain displayed substantial sertb mRNA expression. In both serta−/− and sertb−/− fish, changes in transcript abundances of multiple components of the serotonin signalling pathway were detected, including proteins involved in serotonin synthesis (tph1a, tph1b, tph2, ddc), packaging (vmat2) and degradation (mao), and serotonin receptors (htr1aa, htr1ab). Using a mirror aggression test, serta−/− male but not female fish exhibited greater aggression than wildtype fish. However, both male and female sertb−/− fish displayed less aggression than their wildtype counterparts. These differences in behaviour between serta−/− and sertb−/− individuals hold promise for increasing our understanding of the neurophysiological basis of aggression in zebrafish. [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine (5-HT) plays a substantial role in mitigating depression and anxiety. However, the potential effects of 5-HT against posttraumatic stress disorder (PTSD) and its underlying mechanisms remain unclear. Elevated plus maze test evaluates anxiety-related behaviors, and the open field test is used to assess overall activity levels and anxiety. Inflammatory cytokine levels were determined using ELISA. The levels of 5-HT and dopamine were measured using HPLC. mRNA and protein levels were examined by PCR and Western blot, respectively. Rats exposed to single prolonged stress (SPS) exhibited typical PTSD-like phenotypes, with decreased levels of 5-HT in the hippocampus and significant reductions in its downstream targets, brain-derived neurotrophic factor (BDNF) and TrkB. In addition, it was discovered that the autophagy signaling pathway might be involved in regulating hippocampal BDNF in rats exposed to SPS. Subsequent treatment with an intracerebral injection of sh-SERT significantly inhibited anxiety and cognitive dysfunction in rats. Moreover, sh-SERT treatment was observed to substantially reverse the increase in autophagy signaling protein expression and consequently improve the expression of BDNF and TrkB proteins, which had been reduced. The current study demonstrates that sh-SERT exhibits significant anti-PTSD effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity. NEW & NOTEWORTHY: The study demonstrated that sh-SERT exhibits significant anti-posttraumatic stress disorder (PTSD) effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity. [ABSTRACT FROM AUTHOR]

Objectives: Acute and chronic orofacial pain are very common and remain a vexing health problem that has a negative effect on the quality of life. Serotonin (5‐HydroxyTryptamine, 5‐HT) is a kind of monoamine neurotransmitter that is involved in many physiological and pathological processes. However, its role in orofacial pain remains inconclusive. Therefore, this review aims to summarize the recent advances in understanding the effect exerted by 5‐HT on the modulation of orofacial pain. Subjects and Methods: An extensive search was conducted on PubMed and Web of Science for pertinent studies focusing on the effects of 5‐HT on the modulation of orofacial pain. Results: In this review, we concisely review how 5‐HT mediates orofacial pain, how 5‐HT is regulated and how we can translate these findings into clinical applications for the prevention and/or treatment of orofacial pain. Conclusions: 5‐HT plays a key role in the modulation of orofacial pain, implying that 5‐HT modulators may serve as effective treatment for orofacial pain. However, further research on the precise mechanisms underlying the modulation of orofacial pain is still warranted. [ABSTRACT FROM AUTHOR]

A dual-template molecularly imprinted electrochemical sensor was developed for the simultaneous detection of serotonin (5-HT) and glutamate (Glu). First, amino-functionalized reduced graphene oxide (NRGO) was used as the modification material of a GCE to increase its electrical conductivity and specific surface area, using Glu and 5-HT as dual-template molecules and o-phenylenediamine (OPD) with self-polymerization ability as functional monomers. Through self-assembly and electropolymerization, dual-template molecularly imprinted polymers were formed on the electrode. After removing the templates, the specific recognition binding sites were exposed. The amount of NRGO, polymerization parameters, and elution parameters were further optimized to construct a dual-template molecularly imprinted electrochemical sensor, which can specifically recognize double-target molecules Glu and 5-HT. The differential pulse voltammetry (DPV) technique was used to achieve simultaneous detection of Glu and 5-HT based on their distinct electrochemical activities under specific conditions. The sensor showed a good linear relationship for Glu and 5-HT in the range 1 ~ 100 μM, and the detection limits were 0.067 μM and 0.047 μM (S/N = 3), respectively. The sensor has good reproducibility, repeatability, and selectivity. It was successfully utilized to simultaneously detect Glu and 5-HT in mouse serum, offering a more dependable foundation for objectively diagnosing and early warning of depression. Additionally, the double signal sensing strategy also provides a new approach for the simultaneous detection of both electroactive and non-electroactive substances. [ABSTRACT FROM AUTHOR]

The roles of brain asymmetry in Drosophila are diverse, encompassing the regulation of behavior, the creation of memory, neurodevelopment, and evolution. A comprehensive examination of the Drosophila brain has the potential to enhance our understanding of the functional significance of brain asymmetry in cognitive and behavioral processes, as well as its role in evolutionary perspectives. This study explores the influence of brain asymmetry on interval timing behaviors in Drosophila, with a specific focus on the asymmetric body (AB) structure. Despite being bilaterally symmetric, the AB exhibits functional asymmetry and is located within the central complex of the fly brain. Interval timing behaviors, such as rival-induced prolonged mating duration: longer mating duration behavior (LMD) and sexual experience-mediated shorter mating duration behavior (SMD), are essential for Drosophila. We utilize genetic manipulations to selectively activate or inhibit AB neurons and evaluates their impact on LMD and SMD behaviors. The results indicate that specific populations of AB neurons play unique roles in orchestrating these interval timing behaviors. Notably, inhibiting GAL4R38D01-labeled AB neurons disrupts both LMD and SMD, while GAL4R42C09 neuron inhibition affects only LMD. Moreover, hyperexcitation of GAL4R72A10-labeled AB neurons perturbs SMD. Our study identifies NetrinB (NetB) and Abdominal-B (Abd-B) are important genes for AB neurons in LMD and highlights the role of 5-HT1B neurons in generating LMD through peptidergic Pigment-dispersing factor (PDF) signaling. In summary, this study underscores the importance of AB neuron asymmetry in mediating interval timing behaviors and provides insights into the underlying mechanisms of memory formation and function in Drosophila. [ABSTRACT FROM AUTHOR]

Bupropion (Bup), an antidepressant, is used to treat depression and aid in quitting smoking. We aim to investigate the influence of Bup on nicotine withdrawal (NW)-associated disturbances in serotonergic neurotransmission and behavior in mice. Adult albino mice were categorized into control and NW groups. Each group was further divided into saline and Bup-administered (n=6/group). NW groups received nicotine at a concentration of 3.08 mg (equivalent to 1 milligram of free base) in 100 ml of tap water for four weeks, while the control group received nicotine-free water. To induce nicotine withdrawal, the nicotine-containing water was substituted with tap water for 72 hours. Bup (20 mg/kg) and saline were administered (i.p.) three hours before the completion of the 72-hour withdrawal period to the test and control groups, respectively. NW signs were monitored in both groups. Bup-treated NW mice demonstrated a decline in corticosterone levels while concurrently exhibiting an increase in 5-HT synthesis with decreased 5-HT turnover compared to NW saline controls. A positive correlation between plasma corticosterone and 5-HT turnover was also found in Bup-administered NW mice. Taken together, Bup has potential therapeutic effects on nicotine withdrawal-associated somatic signs due to its ability to attenuate 5-HT turnover and plasma corticosterone in dependent mice. [ABSTRACT FROM AUTHOR]

Serotonin syndrome is a rare, life-threatening toxidrome caused by serotonergic agents. This syndrome classically presents with a combination of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. However, diagnosing the condition is difficult because of its variable symptoms at presentation. As a result, serotonin syndrome often is underreported, making it harder to understand, recognize, and treat. Patients with this condition may present to primary or urgent care or an ED, and may become acutely symptomatic during an inpatient admission. Clinicians must be able to identify at-risk patients and intervene to prevent potentially lethal complications. [ABSTRACT FROM AUTHOR]

ObjectiveThis study aims to explore the therapeutic mechanism of Massa Medicata Fermentata (MMF) with different formulations on spleen deficiency constipation in mice by analyzing gastrointestinal hormones, D-xylose, intestinal microbiota, and intestinal enzyme activities.MethodsA spleen deficiency constipation model was established using an oral administration of Sennae Folium decoction combined with controlled diet and water intake. After successful model establishment, the mice with spleen deficiency constipation were treated with MMF S1, S2, S3. Following the intervention, serum samples from each group of mice were collected to measure VIP, 5-HT, and D-xylose. Additionally, small intestine contents were analyzed for intestinal enzyme activity and subjected to 16S rRNA high-throughput sequencing.ResultsMice with spleen deficiency constipation showed significant decreases in body weight and fecal water content. In contrast, the body weight of the CS2 and CS3 groups returned to normal levels, and fecal water content in the CS2 and CS3 groups also returned to normal. The MMF S2 and S3 significantly increased protease and sucrase enzymes levels compared with CM group. Serum D-xylose levels were significantly reduced in the CM and CS2 group. VIP levels increased significantly in the CM group but decreased in the CS2 and CS3 groups. Additionally, 5-HT levels in the CM and CS1 groups decreased significantly, with the CS2 group returning to normal and the CS3 group showing significant increases. 16S rRNA sequencing analysis revealed that all three MMF formulations effectively restored the intestinal microbiota composition in mice. LEfSe analysis identified characteristic microbiota linked to different intervention groups. The CS3 group significantly upregulated the chloroalkane and chloroalkene degradation and vibrio cholerae pathogenic cycle pathways compared to the CM group. Candidatus_Arthromitus in the CS3 group and Psychrobacter in the CS2 group were positive and negative correlations with 5-HT and VIP, respectively.ConclusionThe three formulations of MMF significantly alleviated spleen deficiency constipation symptoms by modulating intestinal enzyme activities, D-xylose, VIP, and 5-HT levels, and restoring intestinal microbiota balance. Psychrobacter and Candidatus_Arthromitus were identified as potential biomarkers for the treatment of spleen deficiency constipation. Different formulations of MMF have different mechanisms of regulating constipation through intestinal microbiota.

The synthesized compound 1-(2-chlorophenyl) 6-7-dimethoxy-3-methyl-3,4-dihydroisoquinoline (DIQ) was investigated as a biological agent. Its potential to affect muscle contractility was predicted through in silico PASS analysis. Based on the in silico analysis, its capabilities were experimentally investigated. The study aimed to investigate the effects of DIQ on the ex vivo spontaneous contractile activity (CA) of smooth muscle (SM) tissue. DIQ was observed to reduce the strength of Ca2+-dependent contractions in SM preparations (SMP), possibly by increasing cytosolic Ca2+ levels through the activation of a voltage-gated L-type Ca2+ channel. DIQ potently affected calcium currents by modulating the function of muscarinic acetylcholine receptors (mAChRs) and 5-hydroxytryptamine (5-HT) receptors at a concentration of 50 μM. Immunohistochemical tests showed a 47% reduction in 5-HT2A and 5-HT2B receptor activity in SM cells and neurons in the myenteric plexus (MP), further confirming the effects of DIQ. Furthermore, a significant inhibition of neuronal activity was observed when the compound was co-administered with 5-HT to SM tissues. The conducted experiments confirm the ability of the isoquinoline analog to act as a physiologically active molecule to control muscle contractility and related physiological processes. [ABSTRACT FROM AUTHOR]

Introduction: Since the discovery of gonadotropin-inhibitory hormone (GnIH), it has been found to play a critical role in reproduction in vertebrates. Recently, a regulatory role of GnIH in appetite and energy metabolism has emerged, although its precise physiological mechanisms remain unknown. Methods: Thus, the present study evaluated the effects of a single or long-term intraperitoneal GnIH treatment on the food intake, weight, and glucolipid metabolism of chickens, as well as investigating the possible neuroendocrinology factors and mechanisms involved in GnIH-induced obesity and glucolipid metabolism disorder. Results: Our results show that the intraperitoneal administration of GnIH to chickens resulted in a marked body mass increase, hyperlipidemia, hyperglycemia, and glucose intolerance. Subsequently, the results of metabolomics studies and the pharmacological inhibition of the 5-HT2C receptor revealed that blocking the 5-HT2C receptor reinforced the effects of GnIH on food intake, body weight, and blood glucose and lipid levels, resulting in even worse cases of GnIH-induced hyperglycemia, hyperlipidemia, and hepatic lipid deposition. This suggests that, via the 5-HT2C receptor, peripheral 5-HT may act as a negative feedback regulator to interplay with GnIH and jointly control energy balance homeostasis in chickens. Discussion: Our present study provides evidence of cross-talk between GnIH and 5-HT in food intake and energy metabolism at the in vivo pharmacological level, and it proposes a molecular basis for these interactions, suggesting that functional interactions between GnIH and 5-HT may open new avenues for understanding the mechanism of the neuroendocrine network involved in appetite and energy metabolism, as well as providing a new therapeutic strategy to prevent obesity, diabetes, and metabolic disorders. [ABSTRACT FROM AUTHOR]

Background and Aims: Vitamin D deficiency impacts a significant proportion of the world's population, and this deficiency has been linked to various conditions characterized by imbalanced serotonin regulation. The objective of this systematic review and meta‐analysis was to evaluate the effect of vitamin D supplementation on serum serotonin levels. Methods: We conducted a comprehensive search of PubMed, Scopus, Cochrane Central for Randomized Clinical Trials, and Web of Science up to September 2022, without any language restrictions. The effect sizes were calculated using the standard mean difference (SMD) and 95% confidence interval (CI). Results: Six randomized clinical trials involving 356 participants were included in the analysis. Our findings indicated no significant changes in serotonin levels between the intervention and control groups (SMD: 0.24 ng/mL, 95% CI: −0.28, 0.75, p > 0.10). Subgroup analysis also did not reveal any significant changes in serotonin levels among children, participants with autism spectrum disorders, interventions lasting 10 weeks or longer, or those receiving vitamin D doses below 4000 IU/day. Conclusion: Although the results obtained in this systematic review are inconclusive, they support the need for further well‐designed randomized trials to assess the potential role of vitamin D supplementation in regulating serotonin levels and potentially ameliorating depression and related disorders. [ABSTRACT FROM AUTHOR]

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a lightresponsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationships between the serum 5-hydroxytryptamine (5-HT) and nerve growth factor (NGF) levels and recurrence after selective resection of the dorsal nerve of the penis in patients with primary premature ejaculation. Methods Totally 200 patients who underwent selective resection of the dorsal nerve of the penis were selected as the study subjects. Six months after surgery, they were divided into the recurrent group (n=23) and nonrecurrent group (n=177) based on whether the patients had recurrence or not. The clinical data, serum levels of 5-HT and NGF were compared between two groups. The correlations between 5-HT and NGF with the Chinese Index of Premature Ejaculation-5 questionnaire (CIPE-5), International Index of Erectile Function-5（IIEF-5) score, and ejaculation latency time (IELT) were analyzed. Factors affecting postoperative recurrence were analyzed, and we constructed a nomogram model to evaluate the consistency between the postoperative recurrence predicted by model containing serum indicators and the actual observation, and used the decision curve to evaluate the clinical benefit of the model. Results The serum 5- HT level, IELT, and CIPE-5 score in the recurrent group were lower than those in the non-recurrent group at 3 months after surgery, while the NGF level was higher than that in the non-recurrent group (all P<0. 05) . The serum 5-HT level was positively correlated with CIPE-5 score and IELT in patients with primary premature ejaculation before surgery, 1 months after surgery, and 3 months after surgery (all P<0. 05), but was not related to IIEF-5 score (P>0. 05) ； the serum NGF level was negatively correlated with CIPE-5 score and IELT (all P<0. 05), but was not related to IIEF-5 score (P>0. 05) .IELT, CIPE-5 score, serum 5-HT, and NGF levels at 3 months after surgery were independent influencing factors for postoperative recurrence in patients with primary premature ejaculation (all P<0. 05) . The consistency index of the nomogram model in predicting postoperative recurrence related factors in patients with primary premature ejaculation was 0. 775 (95% CI=0. 674-0. 802) . The decision curve showed that when the model containing serum indicators predicted postoperative recurrence in patients with primary premature ejaculation in the range of 0. 2-0. 85, it could provide additional clinical benefits. Conclusion The serum 5-HT level decreases and NGF level increases 3 months after selective resection of the dorsal penile nerve, which has certain reference value for predicting postoperative recurrence in patients with primary premature ejaculation [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) encompasses several debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation associated with altered serotonin (5-hydroxytryptamine or 5-HT) signaling. This altered 5-HT signaling is also found across various animal models of colitis. Of the 14 known receptor subtypes, 5-HT receptor type 7 (5-HT7) is one of the most recently discovered. We previously reported that blocking 5-HT signaling with either a selective 5-HT7 receptor antagonist (SB-269970) or genetic ablation alleviated intestinal inflammation in murine experimental models of colitis. Here, we developed novel antagonists, namely, MC-170073 and MC-230078, which target 5-HT7 receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by using dextran sulfate sodium (DSS) and the transfer of CD4+CD45RBhigh T cells to induce intestinal inflammation. Inhibition of 5-HT7 receptor signaling with the antagonists, MC-170073 and MC-230078, ameliorated intestinal inflammation in both acute and chronic colitis models, which was accompanied by lower histopathological damage and diminished levels of proinflammatory cytokines compared with vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT7 receptors by these selective antagonists ameliorates the severity of colitis across various experimental models and may, in the future, serve as a potential treatment option for patients with IBD. In addition, these findings support that 5-HT7 is a viable therapeutic target for IBD. NEW & NOTEWORTHY: This study demonstrates that the novel highly selective 5-HT7 receptor antagonists, MC-170073 and MC-230078, significantly alleviated the severity of colitis across models of experimental colitis. These findings suggest that inhibition of 5-HT7 receptor signaling by these new antagonists may serve as an alternative mode of treatment to diminish symptomology in those with inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effect of J147 on depression, anxiety, and gut malfunction triggered by stress in a mouse model exhibiting symptoms of irritable bowel syndrome (IBS). Methods: An IBS mouse model was established by chronic/acute combined stress and housed individually. The stressed mouse was exposed to 21 consecutive days of random chronic unpredictable stress and received 3 h of acute restraint stress on day 2. Forced swimming test (FST) and elevated plus-maze test were used to evaluate depressive and anxiety behaviour, respectively. The intestinal motility and visceral sensitivity of mouse were measured by abdominal withdrawal reflex test (AWR). Also, 8-OH-DPAT (a 5-HT1A receptor agonist) and NAN-190 hydrobromide (a 5-HT1A receptor antagonist) were used in combination with different doses of J147 (2 and 10 mg/kg) for three weeks and AWR test was done. Furthermore, IBS-related protein expression (PKA, pCREB, BDNF) in the hippocampus, colon and ileum was determined by western blotting. Results: After CACS induction, mice showed depression/anxiety-like behaviour along with intestinal allergy, and altered levels of 5-hydroxytryptamine (5-HT) in both the hippocampus and gut. Furthermore, J147 significantly alleviated depression, anxiety, intestinal motility disorders, and intestinal hypersensitivity. Additionally, it normalized abnormal levels of brain-gut 5-HT neurotransmitters observed in IBS mice. Pre-treatment with NAN-190 reversed the effect of J147, whereas the addition of 8-OH-DPAT, augmented the effect of low dose J147 (2 mg/kg) on behavioural abnormalities associated with CACS. Furthermore, J147 significantly increased expression levels of IBS-related proteins in the hippocampus, and decreased their levels in the ileum and colon. Conclusion: J147 inhibits IBS-like depression, anxiety, and visceral hypersensitivity by modulating the 5-HT1A-dependent PKA-CREB-BDNF signaling pathway. Thus, there is need for further studies on the development of J147 in the treatment of irritable bowel syndrome. [ABSTRACT FROM AUTHOR]