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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]

Background: Diabetic neuropathic pain is a known complication of diabetes mellitus (DM) and results from the complex interaction of various factors affecting the nervous system. Yokuansan (YKS) is a versatile traditional Japanese herbal medicine with a wide range of applications, especially in pain management and neurological manifestations. YKS has analgesic properties for nerve damage and is a potential treatment for DM-induced neuropathic pain, especially in patients with diabetic neuropathy. Thus, we examined the anti-allodynic effect of YKS on DM-induced neuropathic pain. Methods: All experiments were performed on 6-week-old male Sprague–Dawley rats. DM and diabetic neuropathy were induced in rats with streptozotocin. Mechanical allodynia was assessed using dynamic plantar esthesiometry. Additionally, we conducted an immunological assessment of microglia cell changes in the spinal cord and an experiment to clarify the involvement of serotonin. Results: Diabetes significantly reduced withdrawal thresholds in rats during the initial two weeks of the experiment, which stabilized thereafter. However, this effect was not investigated in the control group. We assessed, using the dynamic plantar test, the anti-allodynic effects of orally administered YKS (1 g/kg). Daily YKS administration significantly increased the withdrawal threshold in DM animals. Additionally, oral YKS reduced the expression of Ibal-1-positive microglia. To elucidate the mechanism of action of YKS, we explored the involvement of serotonin (5-hydroxytryptamine [5-HT]) receptors in mediating its effects. Intrathecal administration of 5-HT receptor antagonists (WAY-100635, ketanserin, and ondansetron) inhibited the protective effects of YKS. Conclusions: YKS exhibited an anti-allodynic effect, suggesting that YKS may activate 5-HT receptors in the spinal cord, thereby alleviating diabetic neuropathic pain. [ABSTRACT FROM AUTHOR]

Bursaphelenchus mucronatus is the sibling species of B. xylophilus, which causes pine wilt disease. Sex pheromone-mediated mating behavior underlies the development of B. xylophilus populations. The study of the molecular mechanism of sex pheromone receptor genes is vital for the control of B. xylophilus. The pivotal role of the 5-HT receptor ser-1 in Caenorhabditis elegans's mating has been demonstrated, but there is little known in B. mucronatus and B. xylophilus. In our study, the molecular features and biological functions of Bmu-ser-1 are explored. qPCR results showed that Bmu-ser-1 was expressed at all ages, especially at J2 and J4, with significantly high expression. Notably, the expression levels in males were significantly higher than that in females. The results of in situ hybridization suggest that the Bmu-ser-1 gene was expressed at the site of the digestive system during the embryonic stage, the whole body during the J2 stage, and mainly at the end of the germinal primordium during the J3 stage, as well as centrally in the vulva of females and in the gonads and tail of males during the J4 and adult stages. The RNAi results indicate a significant decrease in hatchability and stagnation at the J1 stage after interference. Treated J2 had reduced motility and stunted growth. Males after interference showed mismatch and females showed spawning difficulties. Sexual arousal experiments further validated Bmu-ser-1 as a receptor gene for males receiving female sex pheromones. Collectively, our findings strongly suggest that the Bmu-ser-1 gene has a classical role, the control of nematode growth; and a novel role involved in mating. The study on the molecular mechanisms of growth and reproduction in B. mucronatus could provide a reference for understanding the population expansion and disease epidemics of B. xylophilus. [ABSTRACT FROM AUTHOR]

Abstract Background Yokukansan is a traditional Japanese herbal medicine that is widely administered to individuals of various age groups as an effective drug for anxiety, with few side‐effects. While animal studies have yielded promising results concerning yokukansan's potential in treating anxiety disorders, comprehensive validation has remained incomplete. Moreover, most of the clinical investigations regarding yokukansan have primarily focused on Japanese subjects, and its impact on non‐Asian ethnicities remains unverified. Case Presentation We present the case of a 17‐year‐old Caucasian female with panic disorder (PD). Following her relocation to Japan, she experienced panic attacks due to environmental changes, which subsequently prompted her to visit to our clinic. Various medical examinations revealed no abnormalities, which ruled out the possibility of any physical illness other than PD. Significantly, the administration of yokukansan resulted in a notable reduction in panic attacks, as well as in anticipatory anxiety, accompanied by discernible enhancements in psychosocial functioning and overall quality of life. Furthermore, it is imperative to underscore the fact that no noteworthy adverse events took place. Conclusion Panic attacks and profound anxiety in a Caucasian patient with PD were successfully treated with the use of yokukansan. This case study suggests that yokukansan may be effective in treating PD in Caucasians as well as in Asians. However, to substantiate this preliminary observation, further investigations are required.

In vivo, psilocybin is rapidly dephosphorylated to psilocin which induces psychedelic effects by interacting with the 5-HT2A receptor. Psilocin primarily undergoes glucuronidation or conversion to 4-hydroxyindole-3-acetic acid (4-HIAA). Herein, we investigated psilocybin's metabolic pathways in vitro and in vivo, conducting a thorough analysis of the enzymes involved. Metabolism studies were performed using human liver microsomes (HLM), cytochrome P450 (CYP) enzymes, monoamine oxidase (MAO), and UDP-glucuronosyltransferase (UGT). In vivo, metabolism was examined using male C57BL/6J mice and human plasma samples. Approximately 29% of psilocin was metabolized by HLM, while recombinant CYP2D6 and CYP3A4 enzymes metabolized nearly 100% and 40% of psilocin, respectively. Notably, 4-HIAA and 4-hydroxytryptophol (4-HTP) were detected with HLM but not with recombinant CYPs. MAO-A transformed psilocin into minimal amounts of 4-HIAA and 4-HTP. 4-HTP was only present in vitro. Neither 4-HIAA nor 4-HTP showed relevant interactions at assessed 5-HT receptors. In contrast to in vivo data, UGT1A10 did not extensively metabolize psilocin in vitro. Furthermore, two putative metabolites were observed. N-methyl-4-hydroxytryptamine (norpsilocin) was identified in vitro (CYP2D6) and in mice, while an oxidized metabolite was detected in vitro (CYP2D6) and in humans. However, the CYP2D6 genotype did not influence psilocin plasma concentrations in the investigated study population. In conclusion, MAO-A, CYP2D6, and CYP3A4 are involved in psilocin's metabolism. The discovery of putative norpsilocin in mice and oxidized psilocin in humans further unravels psilocin's metabolism. Despite limitations in replicating phase II metabolism in vitro, these findings hold significance for studying drug-drug interactions and advancing research on psilocybin as a therapeutic agent. [ABSTRACT FROM AUTHOR]

Refractory peripheral neuropathy can occur as a side effect in 60–70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain. [ABSTRACT FROM AUTHOR]

Introduction: Internet addiction disorder (IAD) has grown into public health concern of global proportions. Previous studies have indicated that individuals with IAD may exhibit altered levels of serotonin and dopamine, which are known to play crucial roles in depression, anxiety, impulsivity, and addiction. Therefore, polymorphisms in the receptors that mediate the effects of serotonin and dopamine and affect their functional states as well as their activities are suspect. In this study, we aimed to investigate the association between IAD and rs6313 (T102C) polymorphism in the serotonin 2A receptor (5-HT2A) gene, (HTR2A). Methods: Twenty patients with IAD and twenty healthy controls (HCs) were included in this study. Young's Internet Addiction Test (IAT), Self-Rating Anxiety Scale, Self-Rating Depression Scale, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Barratt Impulse Scale, Pittsburgh Sleep Quality Index (PSQI), and Social Support Rating Scale (SSRS) were used to assess the severity of internet addiction, mental status, impulsive traits, sleep quality, and social support. Genotyping was performed to identify rs6313 polymorphisms in the HTR2A gene of all participants. Results: The frequencies of the C and T alleles of HTR2A T102C were 28% and 72% in the IAD group and 53% and 47% in the HCs group, respectively, indicating that the differences between these two groups were significant. No significant difference was observed in the distribution of the CC, CT, and TT genotypes of HTR2A gene T102C between the IAD and the HCs groups. Additionally, there was no difference in the distribution of the frequencies of the HTR2A gene T102C CC and CT+TT genotypes between the two groups. However, the distribution between the TT and CC+CT genotypes showed an apparent statistical difference in the HTR2A gene T102C between the two groups. Correlation analysis indicated that the IAT score was positively correlated with the Y-BOCS and BIS scores for the CC+CT genotype in patients with IAD. Moreover, the IAT score was positively correlated with the PSQI score in patients with IAD carrying the TT genotype. Conclusion: The present study demonstrates that rs6313 in HTR2A is associated with IAD, and that the T allele of rs6313 in HTR2A may be a risk factor for IAD. [ABSTRACT FROM AUTHOR]

Bursaphelenchus mucronatus is the sibling species of B. xylophilus, which causes pine wilt disease. Sex pheromone-mediated mating behavior underlies the development of B. xylophilus populations. The study of the molecular mechanism of sex pheromone receptor genes is vital for the control of B. xylophilus. The pivotal role of the 5-HT receptor ser-1 in Caenorhabditis elegans’s mating has been demonstrated, but there is little known in B. mucronatus and B. xylophilus. In our study, the molecular features and biological functions of Bmu-ser-1 are explored. qPCR results showed that Bmu-ser-1 was expressed at all ages, especially at J2 and J4, with significantly high expression. Notably, the expression levels in males were significantly higher than that in females. The results of in situ hybridization suggest that the Bmu-ser-1 gene was expressed at the site of the digestive system during the embryonic stage, the whole body during the J2 stage, and mainly at the end of the germinal primordium during the J3 stage, as well as centrally in the vulva of females and in the gonads and tail of males during the J4 and adult stages. The RNAi results indicate a significant decrease in hatchability and stagnation at the J1 stage after interference. Treated J2 had reduced motility and stunted growth. Males after interference showed mismatch and females showed spawning difficulties. Sexual arousal experiments further validated Bmu-ser-1 as a receptor gene for males receiving female sex pheromones. Collectively, our findings strongly suggest that the Bmu-ser-1 gene has a classical role, the control of nematode growth; and a novel role involved in mating. The study on the molecular mechanisms of growth and reproduction in B. mucronatus could provide a reference for understanding the population expansion and disease epidemics of B. xylophilus.

Osteoporosis is a systemic bone disease characterized by an imbalance in the relationship between osteoblasts, osteocytes, and osteoclasts. This imbalance in bone metabolism results in the destruction of the bone’s microstructure and an increase in bone brittleness, thereby increasing the risk of fractures. Osteoporosis has complex causes, one of which is related to the dysregulation of 5-hydroxytryptamine, a neurotransmitter closely associated with bone tissue metabolism. Dysregulation of 5-HT directly or indirectly promotes the occurrence and development of osteoporosis. This paper aims to discuss the regulation of 5-HT by Traditional Chinese Medicine and its impact on bone metabolism, as well as the underlying mechanism of action. The results of this study demonstrate that Traditional Chinese Medicine has the ability to regulate 5-HT, thereby modulating bone metabolism and improving bone loss. These findings provide valuable insights for future osteoporosis treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Serotonin (5-HT) is a highly effective oxytocin widely used in aquaculture. However, the role of 5-HT in mollusks remains unclear. Limited research has been conducted on the structures of 5-HT receptor genes, particularly those associated with ovulatory function. In this study, 5-HT receptors were screened and characterized in the whole genome of Sinonovacula constricta. Some 5-HT-binding receptors had been tentatively identified, and their expression pattern exhibited a circadian rhythm. The findings will contribute to a deeper comprehension of the biological role of 5-HT in bivalve ovulation induction and enhance the investigation into its molecular mechanism. Serotonin (5-HT) is primarily distributed in the gastrointestinal and central nervous systems, where it plays a crucial role in regulating various physiological functions such as digestion, reproduction and establishing animal emotions. 5-HT is an effective oxytocin widely used in molluscan aquaculture, and its physiological functions are performed by binding to corresponding 5-HT receptors (5-HTRs). In this study, seven 5-HTR genes of Sinonovacula constricta (Sc5-HTRs) were identified and analyzed, and they were designated as Sc5-HT1A, Sc5-HT1D, Sc5-HT2-1, Sc5-HT2-2, Sc5-HT2-3, Sc5-HT4 and Sc5-HT6. Phylogenetic analysis showed that the seven Sc5-HTRs were conserved among mollusks, and the Sc5-HTRs were all transmembrane proteins. The seven Sc5-HTR genes were distributed on chromosome 1, 2, 13 and 14. After injecting 5-HT, there was a significant increase in mRNA expression levels of Sc5-HT1A (p < 0.05) and Sc5-HT2-3 (p < 0.01), while Sc5-HT4 decreased significantly (p < 0.01) compared to control groups which might be effective 5-HT receptors. Furthermore, two of the receptors (Sc5-HT2-3 and Sc5-HT4) were expressed in the circadian rhythm patterns, indicating their potential influence on the nocturnal spawning of S. constricta. Overall, these findings provide a theoretical basis for understanding the structures and functions of 5-HTR gene family members, and may facilitate the artificial propagation of mollusks. [ABSTRACT FROM AUTHOR]

The cost of reproduction is the core driver of life history evolution in animals. This paper demonstrates that the cumulative distance moved and the duration of movement of sexually immature abalones, Haliotis discus hannai, kept in various male and female groups, were significantly higher than those of sexually mature individuals, except when kept in mixed cultures of mature males and females. After mixed‐culture, sexually mature males moved significantly further and for a longer duration than mature female abalones, and even more so than mature male abalones of any other group. Examination of the LC‐MS metabolomics of mature males cultured with sexually mature females (AM) and those cultured with sexually immature females (JM) showed that cyclic adenosine monophosphate (cAMP) acted as a differential metabolic biomarker. After 24‐h uninterrupted sampling, the concentration of 5‐HT and the expression levels of the 5‐HT2 and 5‐HT6 receptors in AM were significantly higher than those in JM. After further injection of 5‐HT2 and 5‐HT6 receptor antagonists, the concentrations of cAMP and PKA rose again, but the cumulative movement duration and distance of male abalones decreased significantly, showing that 5‐HT was involved in the regulation of movement behavior of male abalones through the 5‐HT2 and 5‐HT6 receptor‐activated cAMP‐PKA pathways. The results demonstrated a significant increase in the movement endurance of mature male abalones cultured with mature females, providing a theoretical basis for understanding the adaptive life history strategies of abalones and suggesting ways to protect diverse benthic resources for abalones during the reproductive stage. [ABSTRACT FROM AUTHOR]

Fear is characterized by distinct behavioral and physiological responses that are essential for the survival of the human species. Fear conditioning (FC) serves as a valuable model for studying the acquisition, extinction, and expression of fear. The serotonin (5-hydroxytryptamine, 5-HT) system is known to play a significant role in emotional and motivational aspects of human behavior, including fear learning and expression. Accumulating evidence from both animal and human studies suggests that brain regions involved in FC, such as the amygdala, hippocampus, and prefrontal cortex, possess a high density of 5-HT receptors, implicating the crucial involvement of serotonin in aversive learning. Additionally, studies exploring serotonin gene polymorphisms have indicated their potential influence on FC. Therefore, the objective of this work was to review the existing evidence linking 5-HT with fear learning and memory in humans. Through a comprehensive screening of the PubMed and Web of Science databases, 29 relevant studies were included in the final review. These studies investigated the relationship between serotonin and fear learning using drug manipulations or by studying 5-HT-related gene polymorphisms. The results suggest that elevated levels of 5-HT enhance aversive learning, indicating that the modulation of serotonin 5-HT2A receptors regulates the expression of fear responses in humans. Understanding the role of this neurochemical messenger in associative aversive learning can provide insights into psychiatric disorders such as anxiety and post-traumatic stress disorder (PTSD), among others. [ABSTRACT FROM AUTHOR]

Simple Summary: Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae) is a natural predatory enemy insect widely distributed in north China and has been widely used in agricultural practice. Owing to a low daily average temperature from December to February of the following year in greenhouses and the facultative diapause of adult H. axyridis, the application of this ladybird in greenhouses in north China is limited. It is of great importance to regulate its predatory ability to improve its biological control efficiency in greenhouses. The 5-hydroxytryptamine (5-HT) was found to play a regulatory role in the predation of H. axyridis in our previous study, but the 5-HT receptor of H. axyridis has not been clearly identified so far, and its expression characteristics are poorly understood. In this study, the 5-HT receptor gene of H. axyridis was cloned and identified by phylogenetic tree construction and multiple sequence alignments. The expression patterns of each receptor in different developmental stages and tissues were analyzed by quantitative real-time PCR (qRT-PCR). The results showed that H. axyridis expressed four 5-HT receptor subtypes, named 5-HT1AHar, 5-HT1BHar, 5-HT2Har, and 5-HT7Har. All 4 receptors were expressed at high levels in the adult stage, especially in 2-day-old adults, with expression levels of 18.72-fold (male) and 14.21-fold (female) of that in eggs for 5-HT1AHar, 32.27-fold (male) and 83.58-fold (female) of that in eggs for 5-HT1BHar, 36.82-fold (male) and 119.35-fold (female) of that in eggs for 5-HT2Har, and 165.47-fold (male) and 115.59-fold (female) of that in eggs for 5-HT7Har. The level of expression for each receptor gene decreased with the advance of day-age in adults. The levels of expression of 5-HT1BHar, 5-HT2Har, and 5-HT7Har were low at the egg, larval, and pupal stages, and 5-HT1AHar was not expressed in the larval stage. The four receptors were expressed in the nervous system, digestive tract, pectoral muscles, and male and female gonads of adults. The 5-HT1AHar was expressed at a high level in the pectoral muscle (6.75-fold of that in the nervous system), 5-HT1BHar in male gonads (1.02-fold of that in the nervous system) and the nervous system, 5-HT2Har in male gonads (5.74-fold of that in the nervous system), and 5-HT7Har in the digestive tract (1.81-fold of that in the nervous system). The results of this study will lay a foundation for research on the function of the 5-HT receptor by RNA interference in the regulation of predation by H. axyridis. It has been found that 5-hydroxytryptamine (5-HT) modulates the feeding of some insects, and this phenomenon was found in Harmonia axyridis (Pallas) by our previous study. An understanding of the 5-HT system in this beetle is helpful for utilizing 5-HT to modulate its predation to improve biological control efficiency, especially in greenhouses in winter in north China. This is because 5-HT influences diapause in insects by modulating the synthesis and release of prothoracic hormone (PTTH) and, therefore, influences feeding. To elucidate the molecular basis of the H. axyridis 5-HT system, reverse-transcription polymerase chain reaction (RT-PCR), multiple sequence alignment, and phylogenetic tree construction were used to identify the 5-HT receptor in H. axyridis, and quantitative real-time PCR (qRT-PCR) was used to analyze the expression pattern of these receptor genes in different developmental stages and in the nervous system (brain + ventral nerve cord), digestive tract, pectoral muscles, and gonads of the adult ladybird. The results showed that four 5-HT receptors were identified in H. axyridis, named 5-HT1AHar, 5-HT1BHar, 5-HT2Har, and 5-HT7Har. The four receptors were expressed at high levels in the adult stage, especially in 2-day-old adults, with expression levels of 18.72-fold (male) and 14.21-fold (female) of that in eggs for 5-HT1A, 32.27-fold (male) and 83.58-fold (female) of that in eggs for 5-HT1B, 36.82-fold (male) and 119.35-fold (female) of that in eggs for 5-HT2, and 165.47-fold (male) and 115.59-fold (female) of that in eggs for 5-HT7. The level of expression decreased with the advance of day-age in adults. The levels of expression of 5-HT1BHar, 5-HT2Har, and 5-HT7Har were low at the egg, larval, and pupal stages, and 5-HT1AHar was not expressed in the larval stage. The four receptors were expressed in the nervous system, digestive tract, pectoral muscles, and male and female gonads. The 5-HT1AHar was expressed at a high level in the pectoral muscle (6.75-fold of that in the nervous system), 5-HT1BHar in male gonads (1.02-fold of that in the nervous system) and the nervous system, 5-HT2Har in male gonads (5.74-fold of that in the nervous system), and 5-HT7Har in the digestive tract (1.81-fold of that in the nervous system). The results of this study will lay a foundation for research on the function of the 5-HT receptor by RNA interference in the regulation of predation by H. axyridis. [ABSTRACT FROM AUTHOR]

Depression is a mental disorder that affects more than 300 million people worldwide. The medications available for treatment take a long time to exhibit therapeutic results and present several side effects. Furthermore, there is a decrease in the quality of life of people suffering from this affliction. Essential oils are traditionally used to relieve the symptoms of depression due to the properties of the constituents of these oils to cross the blood–brain barrier acting on depression-related biological receptors associated with reduced toxicity and side effects. In addition, compared to traditional drugs, they have several administration forms. This review provides a comprehensive assessment of studies on plants whose essential oil has exhibit antidepressant activity in the past decade and the mechanism of action of the major components and models tested. An additional in silico study was conducted with the frequent compounds in the composition of these essential oils, providing a molecular approach to the mechanism of action that has been reported in the past decade. This review is valuable for the development of potential antidepressant medications in addition to providing a molecular approach to the antidepressant mechanism of action of the major volatile compounds that have been reported in the past decade. [ABSTRACT FROM AUTHOR]

Introduction: Serotonin (5-hydroxytryptamine; 5-HT) and GABA (γ-aminobutyric acid) are involved in the regulation of behaviors in the central nervous system. However, it remains unclear whether they modulate olfaction in the peripheral nervous system, and how they modulate olfaction. Methods and results: One 5-HT receptor sequence (Lmig5-HT2) and one GABA receptor sequence (LmigGABAb) were identified in locust antennae by transcriptome analysis and polymerase chain reaction experiments. In situ hybridization localized Lmig5-HT2 to accessory cells, while LmigGABAb was localized to olfactory receptor neurons (ORNs) in locust chemosensilla. Singleunit electrophysiological recordings combined with RNA interference (RNAi) experiments indicated ORNs of locusts with knockdown of Lmig5-HT2 (ds-Lmig5- HT2) and LmigGABAb (ds-LmigGABAb) to some odors had significantly higher responses than wild-type and control locusts in the dose-dependent responses. Moreover, the gaps between the responses of ORNs of RNAi ones and those of wild-type and ds-GFP enlarged with an increase in concentrations of odors. Discussion: Taken together, our findings suggest that 5-HT, GABA, and their receptors exist in the insect peripheral nervous system and that they may function as negative feedback to ORNs and contribute to a fine-tuning mechanism for olfaction in the peripheral nervous system. [ABSTRACT FROM AUTHOR]

Refractory peripheral neuropathy can occur as a side effect in 60–70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain.

To survive, animals maintain energy homeostasis by seeking out food. Compared to freely feeding animals, food-deprived animals may choose different strategies to balance both energy and nutrition demands, per the metabolic state of the animal. Serotonin mediates internal states, modifies existing neural circuits, and regulates animal feeding behavior, including in humans and fruit flies. However, an in-depth study on the neuromodulatory effects of serotonin on feeding microstructure has been held back for several technical reasons. Firstly, most feeding assays lack the precision of manipulating neuronal activity only when animals start feeding, which does not separate neuronal effects on feeding from foraging and locomotion. Secondly, despite the availability of optogenetic tools, feeding in adult fruit flies has primarily been studied using thermogenetic systems, which are confounded with heat. Thirdly, most feeding assays have used food intake as a measurement, which has a low temporal resolution to dissect feeding at the microstructure level. To circumvent these problems, we utilized OptoPAD assay, which provides the precision of optogenetics to control neural activity contingent on the ongoing feeding behavior. We show that manipulating the serotonin circuit optogenetically affects multiple feeding parameters state-dependently. Food-deprived flies with optogenetically activated and suppressed serotonin systems feed with shorter and longer sip durations and longer and shorter inter-sip intervals, respectively. We further show that serotonin suppresses and enhances feeding via 5-HT1B and 5-HT7 receptors, respectively. [ABSTRACT FROM AUTHOR]

Serotonin (5-HT) is primarily distributed in the gastrointestinal and central nervous systems, where it plays a crucial role in regulating various physiological functions such as digestion, reproduction and establishing animal emotions. 5-HT is an effective oxytocin widely used in molluscan aquaculture, and its physiological functions are performed by binding to corresponding 5-HT receptors (5-HTRs). In this study, seven 5-HTR genes of Sinonovacula constricta (Sc5-HTRs) were identified and analyzed, and they were designated as Sc5-HT1A, Sc5-HT1D, Sc5-HT2-1, Sc5-HT2-2, Sc5-HT2-3, Sc5-HT4 and Sc5-HT6. Phylogenetic analysis showed that the seven Sc5-HTRs were conserved among mollusks, and the Sc5-HTRs were all transmembrane proteins. The seven Sc5-HTR genes were distributed on chromosome 1, 2, 13 and 14. After injecting 5-HT, there was a significant increase in mRNA expression levels of Sc5-HT1A (p < 0.05) and Sc5-HT2-3 (p < 0.01), while Sc5-HT4 decreased significantly (p < 0.01) compared to control groups which might be effective 5-HT receptors. Furthermore, two of the receptors (Sc5-HT2-3 and Sc5-HT4) were expressed in the circadian rhythm patterns, indicating their potential influence on the nocturnal spawning of S. constricta. Overall, these findings provide a theoretical basis for understanding the structures and functions of 5-HTR gene family members, and may facilitate the artificial propagation of mollusks.

To survive, animals maintain energy homeostasis by seeking out food. Compared to freely feeding animals, food-deprived animals may choose different strategies to balance both energy and nutrition demands, per the metabolic state of the animal. Serotonin mediates internal states, modifies existing neural circuits, and regulates animal feeding behavior, including in humans and fruit flies. However, an in-depth study on the neuromodulatory effects of serotonin on feeding microstructure has been held back for several technical reasons. Firstly, most feeding assays lack the precision of manipulating neuronal activity only when animals start feeding, which does not separate neuronal effects on feeding from foraging and locomotion. Secondly, despite the availability of optogenetic tools, feeding in adult fruit flies has primarily been studied using thermogenetic systems, which are confounded with heat. Thirdly, most feeding assays have used food intake as a measurement, which has a low temporal resolution to dissect feeding at the microstructure level. To circumvent these problems, we utilized OptoPAD assay, which provides the precision of optogenetics to control neural activity contingent on the ongoing feeding behavior. We show that manipulating the serotonin circuit optogenetically affects multiple feeding parameters state-dependently. Food-deprived flies with optogenetically activated and suppressed serotonin systems feed with shorter and longer sip durations and longer and shorter inter-sip intervals, respectively. We further show that serotonin suppresses and enhances feeding via 5-HT1B and 5-HT7 receptors, respectively.

Recently, studies have demonstrated that serotonin type 7 receptors (5-HT7) have conflincting effects on neuronal excitability in different brain regions. However, the effect of 5-HT7 on seizures has not been exactly elucidated yet. Therefore, our aim in this study was to investigate the effects of 5-HT7 antagonist SB-269970 on pentylenetetrazole (PTZ) induced fully kindled rats. In the study, 32 adult male Wistar Albino rats (weighing 220–260 g) were used. Rats were injected with PTZ (35 mg/kg) intraperitoneally every other day to generate kindling model. 5-CT (0.1 mg/kg) and SB-269970 (1 mg/kg) were administered 30 min before acute seizure induction with PTZ (35 mg/kg). Seizure stages were determined according to the Racine scale. After electrocorticography (ECoG) recordings of seizure-induced rats were obtained, the animals were sacrificed by decapitation. The hippocampal GABA levels were determined by ELISA kit and the number of c-Fos positive neurons in the hippocampal dentate gyrus (DG), CA1 and CA3 areas were measured by immunohistochemical method. The results showed that SB-269970 reduced the number of spikes, percent seizure duration and duration of generalized tonic-clonic seizures (dGTCS), while increasing the onset time of generalized tonic-clonic seizures (oGTCS). The hippocampal GABA levels were significantly increased in the SB-269970 group compared with the PTZ group. In addition, SB-269970 reduced the number of c-Fos positive cells in hippocampal CA1 area. 5-HT7 antagonist SB-269970 displays anticonvulsant effects on PTZ-induced seizures in fully kindled rats and these effects may be related to GABAergic activity in the hippocampus. [ABSTRACT FROM AUTHOR]

Fear is characterized by distinct behavioral and physiological responses that are essential for the survival of the human species. Fear conditioning (FC) serves as a valuable model for studying the acquisition, extinction, and expression of fear. The serotonin (5-hydroxytryptamine, 5-HT) system is known to play a significant role in emotional and motivational aspects of human behavior, including fear learning and expression. Accumulating evidence from both animal and human studies suggests that brain regions involved in FC, such as the amygdala, hippocampus, and prefrontal cortex, possess a high density of 5-HT receptors, implicating the crucial involvement of serotonin in aversive learning. Additionally, studies exploring serotonin gene polymorphisms have indicated their potential influence on FC. Therefore, the objective of this work was to review the existing evidence linking 5-HT with fear learning and memory in humans. Through a comprehensive screening of the PubMed and Web of Science databases, 29 relevant studies were included in the final review. These studies investigated the relationship between serotonin and fear learning using drug manipulations or by studying 5-HT-related gene polymorphisms. The results suggest that elevated levels of 5-HT enhance aversive learning, indicating that the modulation of serotonin 5-HT2A receptors regulates the expression of fear responses in humans. Understanding the role of this neurochemical messenger in associative aversive learning can provide insights into psychiatric disorders such as anxiety and post-traumatic stress disorder (PTSD), among others.

Most peripheral serotonin (5-HT) is synthesized in enterochromaffin cells, and most circulating 5-HT is stored in platelets. As a monoamine, 5-HT has several functions in various non-neuronal and neuronal systems. In the central nervous system, it functions as a neurotransmitter to modulate feeding behavior and mood. Numerous clinical trials have focused on increasing 5-HT activation in the central nervous system, including those involving anti-obesity drugs currently in the market, although severe side effects on peripheral system can lead to the withdrawal of certain drugs. Recent studies have revealed that both the peripheral and central serotonergic systems play a vital role in diabetes and its complications. This review summarizes the roles of the serotonergic system in blood glucose regulation, diabetic macroangiopathy, diabetic peripheral neuropathy, and diabetic encephalopathy, indicating its potential clinical significance as a therapeutic target for the treatment of diabetes and its complications. [ABSTRACT FROM AUTHOR]

It has been found that 5-hydroxytryptamine (5-HT) modulates the feeding of some insects, and this phenomenon was found in Harmonia axyridis (Pallas) by our previous study. An understanding of the 5-HT system in this beetle is helpful for utilizing 5-HT to modulate its predation to improve biological control efficiency, especially in greenhouses in winter in north China. This is because 5-HT influences diapause in insects by modulating the synthesis and release of prothoracic hormone (PTTH) and, therefore, influences feeding. To elucidate the molecular basis of the H. axyridis 5-HT system, reverse-transcription polymerase chain reaction (RT-PCR), multiple sequence alignment, and phylogenetic tree construction were used to identify the 5-HT receptor in H. axyridis, and quantitative real-time PCR (qRT-PCR) was used to analyze the expression pattern of these receptor genes in different developmental stages and in the nervous system (brain + ventral nerve cord), digestive tract, pectoral muscles, and gonads of the adult ladybird. The results showed that four 5-HT receptors were identified in H. axyridis, named 5-HT1AHar, 5-HT1BHar, 5-HT2Har, and 5-HT7Har. The four receptors were expressed at high levels in the adult stage, especially in 2-day-old adults, with expression levels of 18.72-fold (male) and 14.21-fold (female) of that in eggs for 5-HT1A, 32.27-fold (male) and 83.58-fold (female) of that in eggs for 5-HT1B, 36.82-fold (male) and 119.35-fold (female) of that in eggs for 5-HT2, and 165.47-fold (male) and 115.59-fold (female) of that in eggs for 5-HT7. The level of expression decreased with the advance of day-age in adults. The levels of expression of 5-HT1BHar, 5-HT2Har, and 5-HT7Har were low at the egg, larval, and pupal stages, and 5-HT1AHar was not expressed in the larval stage. The four receptors were expressed in the nervous system, digestive tract, pectoral muscles, and male and female gonads. The 5-HT1AHar was expressed at a high level in the pectoral muscle (6.75-fold of that in the nervous system), 5-HT1BHar in male gonads (1.02-fold of that in the nervous system) and the nervous system, 5-HT2Har in male gonads (5.74-fold of that in the nervous system), and 5-HT7Har in the digestive tract (1.81-fold of that in the nervous system). The results of this study will lay a foundation for research on the function of the 5-HT receptor by RNA interference in the regulation of predation by H. axyridis.

Depression is a mental disorder that affects more than 300 million people worldwide. The medications available for treatment take a long time to exhibit therapeutic results and present several side effects. Furthermore, there is a decrease in the quality of life of people suffering from this affliction. Essential oils are traditionally used to relieve the symptoms of depression due to the properties of the constituents of these oils to cross the blood–brain barrier acting on depression-related biological receptors associated with reduced toxicity and side effects. In addition, compared to traditional drugs, they have several administration forms. This review provides a comprehensive assessment of studies on plants whose essential oil has exhibit antidepressant activity in the past decade and the mechanism of action of the major components and models tested. An additional in silico study was conducted with the frequent compounds in the composition of these essential oils, providing a molecular approach to the mechanism of action that has been reported in the past decade. This review is valuable for the development of potential antidepressant medications in addition to providing a molecular approach to the antidepressant mechanism of action of the major volatile compounds that have been reported in the past decade.

Chronic stress is a major risk factor for psychiatric disorders. However, certain individuals may be at higher risk due to greater stress susceptibility. Elucidating the neurobiology of stress resilience and susceptibility may facilitate the development of novel strategies to prevent and treat stress-related disorders such as depression. Mounting evidence suggests that the serotonin (5-HT) system is a major regulator of stress sensitivity. In this study, we assessed the functions of 5-HT1A and 5-HT2A receptors within the lateral septum (LS) in regulating stress vulnerability. Among a group of male mice exposed to chronic social defeat stress (CSDS), 47.2% were classified as stress-susceptible, and these mice employed more passive coping strategies during the defeat and exhibited more severe anxiety- and depression-like behaviors during the following behavioral tests. These stress-susceptible mice also exhibited elevated neuronal activity in the LS as evidenced by greater c-Fos expression, greater activity of 5-HT neurons in both the dorsal and median raphe nucleus, and downregulated expression of the 5-HT1A receptor in the intermediate LS (LSi). Finally, we found the stress-induced social withdrawal symptoms could be rapidly relieved by LSi administration of 8-OH-DPAT, a 5-HT1A receptor agonist. These results indicate that 5-HT1A receptors within the LSi play an important role in stress vulnerability in mice. Therefore, modulation of stress vulnerable via 5-HT1A receptor activation in the LSi is a potential strategy to treat stress-related psychiatric disorders. • Mice subjected to chronic social defeat stress exhibited resilient or susceptible subtypes. • Enhanced neural activity in the LS were observed in the susceptible mice. • 5-HTergic neurons in the DR and MnR were more activated in the susceptible mice. • 5-HT1A receptor in the LSi were down-regulated in the susceptible mice. • A 5-HT1A receptor agonist rapidly relieved social avoidance symptoms of the susceptible mice. [ABSTRACT FROM AUTHOR]

Dravet Syndrome (DS) is a severe developmental and epileptic encephalopathy. Fenfluramine recently demonstrated to be a highly efficacious and safe treatment option for DS patients. Fenfluramine has been recently approved by the FDA and EMA and is marketed as Fintepla®. DS and the need for additional anticonvulsive treatment options is discussed. The results of three placebo-controlled phase III studies (1 with and 2 without stiripentol) and 2 open label (extension) studies are reviewed. All studies demonstrate a consistent and impressive seizure reduction, confirming the results of two smaller investigator-initiated trials. The mechanism of action of fenfluramine is discussed. Finally, the place of fenfluramine in the future treatment of DS is outlined. Fenfluramine has a potent anticonvulsive effect in DS. Although not yet fully elucidated, the anticonvulsive mechanism of fenfluramine seems to be mainly serotonergic. Fenfluramine is generally well tolerated. A dose reduction is necessary in combination with stiripentol. Considering new competitors, efficacy seems lower for cannabidiol and is comparable with stiripentol. Preclinical studies indicate a disease specific action and possible disease modification in DS. The latter would support the use of fenfluramine above its anticonvulsive effect and needs to be further elaborated. [ABSTRACT FROM AUTHOR]

5‐hydroxytryptamine (5‐HT; serotonin) is traditionally considered as a key mediator implicated in migraine. Multiple 5‐HT receptor subtypes contribute to a variety of region‐specific functional effects. The raphé nuclei control nociceptive inputs by releasing 5‐HT in the brainstem, whereas dural mast cells provide the humoral source of 5‐HT in the meninges. Triptans (5‐HT1B/D agonists) and ditans (5‐HT1F agonists) are the best established 5‐HT anti‐migraine agents. However, activation of meningeal afferents via ionotropic 5‐HT3 receptors results in long‐lasting excitatory drive suggesting a pro‐nociceptive role for these receptors in migraine. Nevertheless, clinical data do not clearly support the applicability of currently available 5‐HT3 antagonists to migraine treatment. The reasons for this might be the presence of 5‐HT3 receptors on inhibitory interneurons dampening the excitatory drive, a lack of 5‐HT3A–E subunit‐selective antagonists and gender/age‐dependent effects. This review is focusing on the controversial role of 5‐HT3 receptors in migraine pathology and related pharmacological perspectives of 5‐HT ligands. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc [ABSTRACT FROM AUTHOR]

Background: Yokukansan is a traditional Japanese herbal medicine that is widely administered to individuals of various age groups as an effective drug for anxiety, with few side-effects. While animal studies have yielded promising results concerning yokukansan 's potential in treating anxiety disorders, comprehensive validation has remained incomplete. Moreover, most of the clinical investigations regarding yokukansan have primarily focused on Japanese subjects, and its impact on non-Asian ethnicities remains unverified., Case Presentation: We present the case of a 17-year-old Caucasian female with panic disorder (PD). Following her relocation to Japan, she experienced panic attacks due to environmental changes, which subsequently prompted her to visit to our clinic. Various medical examinations revealed no abnormalities, which ruled out the possibility of any physical illness other than PD. Significantly, the administration of yokukansan resulted in a notable reduction in panic attacks, as well as in anticipatory anxiety, accompanied by discernible enhancements in psychosocial functioning and overall quality of life. Furthermore, it is imperative to underscore the fact that no noteworthy adverse events took place., Conclusion: Panic attacks and profound anxiety in a Caucasian patient with PD were successfully treated with the use of yokukansan . This case study suggests that yokukansan may be effective in treating PD in Caucasians as well as in Asians. However, to substantiate this preliminary observation, further investigations are required., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Introduction: Internet addiction disorder (IAD) has grown into public health concern of global proportions. Previous studies have indicated that individuals with IAD may exhibit altered levels of serotonin and dopamine, which are known to play crucial roles in depression, anxiety, impulsivity, and addiction. Therefore, polymorphisms in the receptors that mediate the effects of serotonin and dopamine and affect their functional states as well as their activities are suspect. In this study, we aimed to investigate the association between IAD and rs6313 (T102C) polymorphism in the serotonin 2A receptor (5-HT2A) gene, (HTR2A)., Methods: Twenty patients with IAD and twenty healthy controls (HCs) were included in this study. Young's Internet Addiction Test (IAT), Self-Rating Anxiety Scale, Self-Rating Depression Scale, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Barratt Impulse Scale, Pittsburgh Sleep Quality Index (PSQI), and Social Support Rating Scale (SSRS) were used to assess the severity of internet addiction, mental status, impulsive traits, sleep quality, and social support. Genotyping was performed to identify rs6313 polymorphisms in the HTR2A gene of all participants., Results: The frequencies of the C and T alleles of HTR2A T102C were 28% and 72% in the IAD group and 53% and 47% in the HCs group, respectively, indicating that the differences between these two groups were significant. No significant difference was observed in the distribution of the CC, CT, and TT genotypes of HTR2A gene T102C between the IAD and the HCs groups. Additionally, there was no difference in the distribution of the frequencies of the HTR2A gene T102C CC and CT+TT genotypes between the two groups. However, the distribution between the TT and CC+CT genotypes showed an apparent statistical difference in the HTR2A gene T102C between the two groups. Correlation analysis indicated that the IAT score was positively correlated with the Y-BOCS and BIS scores for the CC+CT genotype in patients with IAD. Moreover, the IAT score was positively correlated with the PSQI score in patients with IAD carrying the TT genotype., Conclusion: The present study demonstrates that rs6313 in HTR2A is associated with IAD, and that the T allele of rs6313 in HTR2A may be a risk factor for IAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dai, Zhang, Zhang, Wen, Li and Zhu.)

Osteoporosis is a systemic bone disease characterized by an imbalance in the relationship between osteoblasts, osteocytes, and osteoclasts. This imbalance in bone metabolism results in the destruction of the bone's microstructure and an increase in bone brittleness, thereby increasing the risk of fractures. Osteoporosis has complex causes, one of which is related to the dysregulation of 5-hydroxytryptamine, a neurotransmitter closely associated with bone tissue metabolism. Dysregulation of 5-HT directly or indirectly promotes the occurrence and development of osteoporosis. This paper aims to discuss the regulation of 5-HT by Traditional Chinese Medicine and its impact on bone metabolism, as well as the underlying mechanism of action. The results of this study demonstrate that Traditional Chinese Medicine has the ability to regulate 5-HT, thereby modulating bone metabolism and improving bone loss. These findings provide valuable insights for future osteoporosis treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Wang, Du, Wang, Liu, Li, Zhang and Xu.)

Introduction: Serotonin (5-hydroxytryptamine; 5-HT) and GABA (γ-aminobutyric acid) are involved in the regulation of behaviors in the central nervous system. However, it remains unclear whether they modulate olfaction in the peripheral nervous system, and how they modulate olfaction., Methods and Results: One 5-HT receptor sequence ( Lmig 5-HT2) and one GABA receptor sequence ( Lmig GABAb) were identified in locust antennae by transcriptome analysis and polymerase chain reaction experiments. In situ hybridization localized Lmig 5-HT2 to accessory cells, while Lmig GABAb was localized to olfactory receptor neurons (ORNs) in locust chemosensilla. Single-unit electrophysiological recordings combined with RNA interference (RNAi) experiments indicated ORNs of locusts with knockdown of Lmig 5-HT2 (ds- Lmig 5-HT2) and Lmig GABAb (ds- Lmig GABAb) to some odors had significantly higher responses than wild-type and control locusts in the dose-dependent responses. Moreover, the gaps between the responses of ORNs of RNAi ones and those of wild-type and ds-GFP enlarged with an increase in concentrations of odors., Discussion: Taken together, our findings suggest that 5-HT, GABA, and their receptors exist in the insect peripheral nervous system and that they may function as negative feedback to ORNs and contribute to a fine-tuning mechanism for olfaction in the peripheral nervous system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lv, Xu, Zhang, Yuwen and Zhang.)