Central Serotonin Research Articles

Hyperphenylalaninemia and serotonin deficiency in Dnajc12-deficient mice

Serotonin exerts numerous neurological and physiological actions in the brain and in the periphery. It is generated by two different tryptophan hydroxylase enzymes, TPH1 and TPH2, in the periphery and in the brain, respectively, which are members of the aromatic amino acid hydroxylase (AAAH) family together with phenylalanine hydroxylase (PAH), degrading phenylalanine, and tyrosine hydroxylase (TH), generating dopamine. In this study, we show that the co-chaperone DNAJC12 is downregulated in serotonergic neurons in the brain of mice lacking TPH2 and thereby central serotonin. DNAJC12 has been described to regulate the stability of PAH and mutations in its gene cause hyperphenylalaninemia and neurological symptoms in patients. We show that DNAJC12 also binds and stabilizes TPH1 and TPH2 in transfected cells. In order to clarify the importance of DNAJC12 in the regulation of neurotransmitter synthesis and phenylalanine degradation in vivo, we generated DNAJC12-deficient mice. These mice show reduced levels and activity of PAH, TPH2, and TPH1 in liver, brain, and pineal gland, respectively, and experience hyperphenylalaninemia and central and peripheral serotonin deficiency. These data support a pivotal role of DNAJC12 in the regulation of AAAH and thereby in neurotransmitter synthesis and phenylalanine homeostasis.

Serotonin circuits act cooperatively with pathophysiology of opioid use disorder

Opioid abuse and its negative effect have become a critical epidemic, putting our health and society in jeopardy. Opioids are effective treatment for pain, but at risk for developing associated health threatening impacts including the euphoria associated relapsing effects, persistent occurrence with addictive and withdrawal symptoms, and consequent respiratory depression and apnea. The opioid use disorder (OUD), represented as those recurring phases of symptoms, is initiated with mediation of opioid receptor signaling pathway and subsequent neurocircuitry transformation with homeostatic and motivational change. It has been imperative to establish modulatory mechanisms and alternative treatments to mitigate OUD. This review deals with central serotonin (5-HT) system as a cooperative mediator with OUD-related neural processing. We briefly introduce molecular base of opioid receptors and available research tools in mouse models and examine OUD-phase dependent circuit mechanisms, including pain, addiction, and respiratory depression. We interrogate the potential neural roles of 5-HT in OUD-related symptoms including 5-HT toxicity and pathophysiology and discuss potential availability of 5-HT-related agents as a neuromodulatory therapeutic interacting with opioid mediated neural mechanisms and the OUD-related symptoms.

Features of Stress-Induced Changes in Heart Rate Variability During Blockade of Central and Stimulation of Peripheral Serotonin and Dopamine Receptors in Rats.

The dynamics of heart rate variability (HRV) during acute stress was studied in male nonlinear rats that received single injection of serotonin (200 μg/kg) or dopamine (60 μg/kg), regular (4-fold) injections of central serotonin receptor blockers (ketanserin and granisetron, 0.1 mg/kg each) or central dopamine receptor blockers (0.1 mg/kg SCH-23390 and 10 mg/kg sulpiride), as well as a combination of central receptor blockers with the administration of serotonin or dopamine, respectively. During stress against the background of serotonin receptors blockade, a weak tachycardia, low stress index, high rhythm variability, especially in the low-frequency range were recorded; against the background of dopamine receptors blockade, increased reactivity to stress at high HR, an initial increase in the stress index, and a decrease in rhythm variability, followed by an increase in the proportion of very low frequency waves in the spectrum were revealed. Serotonin and dopamine, by stimulating peripheral receptors, predominantly weakened stress-induced changes in HRV (especially serotonin), but in combination with blockade of the corresponding central receptors contributed to maintaining tachycardia, reduced rhythm variability, and potentiated the effects of blockers in relation to stress induced changes in the wave structure of the HRV spectrum. We believe that central and peripheral serotoninergic and dopaminergic structures are involved in the formation of HRV by modulating the activity of components of the autonomous and central circuits of HR regulation, respectively.

Sinisan Alleviates Stress-Induced Intestinal Dysfunction and Depressive-like Behaviors in Mice with Irritable Bowel Syndrome by Enhancing the Intestinal Barrier and Modulating Central 5-Hydroxytryptamine

Irritable bowel syndrome (IBS) is a common chronic functional bowel disorder and is strongly associated with an increased risk of depression and anxiety. The brain–gut axis plays an important role in the pathophysiologic changes in IBS, yet effective treatments for IBS are still lacking. Sinisan, originating from the Treatise on Typhoid Fever by the medical sage Zhang Zhongjing, is a classic formula in the Eight Methods of Traditional Chinese Medicine (TCM) that focuses on dispersing the liver and regulating the spleen, relieving depression and transmitting evils, and has been widely used in the treatment of liver-depression and spleen-deficiency, diarrhea, and related liver and stomach disorders. However, the therapeutic effect of sinisan in IBS has not been clarified. The aim of this study was to investigate the effects of sinisan on stress-induced intestinal dysfunction and depressive behavior in IBS mice. We established a diarrhea-predominant irritable bowel syndrome (IBS-D) mouse model using a 4% acetic acid enema combined with restraint stress, and analyzed the results using behavioral tests, relevant test kits, hematoxylin-eosin (HE) staining, immunofluorescence (IF), Western blot (WB), and quantitative fluorescence polymerase chain reaction (qRT-PCR). The results showed that sinisan administration significantly alleviated intestinal dysfunction and depressive-like behaviors in IBS-D mice, improved mild colonic inflammation and intestinal mucosal permeability, up-regulated the expression of tight junction proteins ZO-1 and occludin. Sinisan significantly alleviated intestinal dysfunction and depressive-like behaviors in IBS-D mice by decreasing the expression of TNF-α, promoting the expression of tight junction proteins (occludin, ZO-1) expression, and inhibiting the Tlr4/Myd88 signaling pathway, thereby attenuating the inflammatory response, protecting the intestinal barrier, and alleviating symptoms in the IBS-D mouse model. Taken together, sinisan may ameliorate intestinal inflammation and the intestinal barrier by regulating 5-HT expression and the Tlr4/Myd88 pathway, thereby alleviating stress-induced intestinal dysfunction and depressive behaviors in IBS-D mice.

Serotonin drives aggression and social behaviors of laboratory male mice in a semi-natural environment.

Aggression is an adaptive social behavior crucial for the stability and prosperity of social groups. When uncontrolled, aggression leads to pathological violence that disrupts group structure and individual wellbeing. The comorbidity of uncontrolled aggression across different psychopathologies makes it a potential endophenotype of mental disorders with the same neurobiological substrates. Serotonin plays a critical role in regulating impulsive and aggressive behaviors. Mice lacking in brain serotonin, due to the ablation of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in serotonin synthesis, could serve as a potential model for studying pathological aggression. Home cage monitoring allows for the continuous observation and quantification of social and non-social behaviors in group-housed, freely-moving mice. Using an ethological approach, we investigated the impact of central serotonin ablation on the everyday expression of social and non-social behaviors and their correlations in undisturbed, group-living Tph2-deficient and wildtype mice. By training a machine learning algorithm on behavioral time series, "allogrooming", "struggling at feeder", and "eating" emerged as key behaviors dissociating one genotype from the other. Although Tph2-deficient mice exhibited characteristics of pathological aggression and reduced communication compared to wildtype animals, they still demonstrated affiliative huddle behaviors to normal levels. Altogether, such a distinct and dynamic phenotype of Tph2-deficient mice influenced the group's structure and the subsequent development of its hierarchical organization. These aspects were analyzed using social network analysis and the Glicko rating methods. This study demonstrates the importance of the ethological approach for understanding the global impact of pathological aggression on various aspects of life, both at the individual and group levels. Home cage monitoring allows the observation of the natural behaviors of mice in a semi-natural habitat, providing an accurate representation of real-world phenomena and pathological mechanisms. The results of this study provide insights into the neurobiological substrate of pathological aggression and its potential role in complex brain disorders.

Role of the circadian nuclear receptor REV-ERBα in dorsal raphe serotonin synthesis in mood regulation

Affective disorders are frequently associated with disrupted circadian rhythms. The existence of rhythmic secretion of central serotonin (5-hydroxytryptamine, 5-HT) pattern has been reported; however, the functional mechanism underlying the circadian control of 5-HTergic mood regulation remains largely unknown. Here, we investigate the role of the circadian nuclear receptor REV-ERBα in regulating tryptophan hydroxylase 2 (Tph2), the rate-limiting enzyme of 5-HT synthesis. We demonstrate that the REV-ERBα expressed in dorsal raphe (DR) 5-HTergic neurons functionally competes with PET-1—a nuclear activator crucial for 5-HTergic neuron development. In mice, genetic ablation of DR 5-HTergic REV-ERBα increases Tph2 expression, leading to elevated DR 5-HT levels and reduced depression-like behaviors at dusk. Further, pharmacological manipulation of the mice DR REV-ERBα activity increases DR 5-HT levels and affects despair-related behaviors. Our findings provide valuable insights into the molecular and cellular link between the circadian rhythm and the mood-controlling DR 5-HTergic systems.

Direct serotonin release in humans shapes aversive learning and inhibition

The role of serotonin in human behaviour is informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes, notably selective serotonin reuptake inhibitors. Here we use a now-accessible approach to directly increase synaptic serotonin in humans (a selective serotonin releasing agent) and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques, including reinforcement learning and drift diffusion modelling, explain participant behaviour at baseline and after week-long intervention. Reinforcement learning models reveal that increasing synaptic serotonin reduces sensitivity for outcomes in aversive contexts. Furthermore, increasing synaptic serotonin enhances behavioural inhibition, and shifts bias towards impulse control during exposure to aversive emotional probes. These effects are seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increasing synaptic serotonin on human behaviour, underlining its role in guiding decision-making within aversive and more neutral contexts, and offering implications for longstanding theories of central serotonin function.

Agouti-Induced Anxiety-Like Behavior Is Mediated by Central Serotonergic Pathways in Zebrafish.

Overexpression of the agouti-signaling protein (asip1), an endogenous melanocortin antagonist, under the control of a constitutive promoter in zebrafish [Tg(Xla.Eef1a1:Cau.Asip1]iim4] (asip1-Tg) increases food intake by reducing sensitivity of the central satiety systems and abolish circadian activity rhythms. The phenotype also shows increased linear growth and body weight, yet no enhanced aggressiveness in dyadic fights is observed. In fact, asip1-Tg animals choose to flee to safer areas rather than face a potential threat, thus suggesting a potential anxiety-like behavior (ALB). Standard behavioral tests, i.e., the open field test (OFT), the novel object test (NOT), and the novel tank dive test (NTDT), were used to investigate thigmotaxis and ALB in male and female zebrafish. Results showed that the asip1-Tg strain exhibited severe ALB in every test, mainly characterized by pronounced freezing behavior and increased linear and angular swimming velocities. asip1-Tg animals exhibited low central serotonin (5-HT) and dopamine (DA) levels and high turnover rates, thus suggesting that central monoaminergic pathways might mediate melanocortin antagonist-induced ALB. Accordingly, the treatment of asip1-Tg animals with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), reversed the ALB phenotype in NTDT as well as 5-HT turnover. Genomic and anatomical data further supported neuronal interaction between melanocortinergic and serotonergic systems. These results suggest that inhibition of the melanocortin system by ubiquitous overexpression of endogenous antagonist has an anxiogenic effect mediated by serotonergic transmission.

Neuroleptic malignant syndrome and serotonin syndrome: a comparative bibliometric analysis

ObjectiveThis study aimed to analyze and map scientific literature on Neuroleptic Malignant Syndrome (NMS) and Serotonin Syndrome (SS) from prestigious, internationally indexed journals. The objective was to identify key topics, impactful articles, prominent journals, research output, growth patterns, hotspots, and leading countries in the field, providing valuable insights for scholars, medical students, and international funding agencies.MethodsA systematic search strategy was implemented in the PubMed MeSH database using specific keywords for NMS and SS. The search was conducted in the Scopus database, renowned for its extensive coverage of scholarly publications. Inclusion criteria comprised articles published from 1950 to December 31st, 2022, restricted to journal research and review articles written in English. Data were analyzed using Microsoft Excel for descriptive analysis, and VOSviewer was employed for bibliometric mapping.ResultsThe search yielded 1150 articles on NMS and 587 on SS, with the majority being case reports. Growth patterns revealed a surge in NMS research between 1981 and 1991, while SS research increased notably between 1993 and 1997. Active countries and journals differed between NMS and SS, with psychiatry journals predominating for NMS and pharmacology/toxicology journals for SS. Authorship analysis indicated higher multi-authored articles for NMS. Top impactful articles focused on review articles and pathogenic mechanisms. Research hotspots included antipsychotics and catatonia for NMS, while SS highlighted drug interactions and specific medications like linezolid and tramadol.ConclusionsNMS and SS represent rare but life-threatening conditions, requiring detailed clinical and scientific understanding. Differential diagnosis and management necessitate caution in prescribing medications affecting central serotonin or dopamine systems, with awareness of potential drug interactions. International diagnostic tools and genetic screening tests may aid in safe diagnosis and prevention. Reporting rare cases and utilizing bibliometric analysis enhance knowledge dissemination and research exploration in the field of rare drug-induced medical conditions.

Interaction of serotonin/GLP-1 circuitry in a dual preclinical model for psychiatric disorders and metabolic dysfunction

Isolation of rodents throughout adolescence is known to induce many behavioral abnormalities which resemble neuropsychiatric disorders. Separately, this paradigm has also been shown to induce long-term metabolic changes consistent with a pre-diabetic state. Here, we investigate changes in central serotonin (5-HT) and glucagon-like peptide 1 (GLP-1) neurobiology that dually accompany behavioral and metabolic outcomes following social isolation stress throughout adolescence. We find that adolescent-isolation mice exhibit elevated blood glucose levels, impaired peripheral insulin signaling, altered pancreatic function, and fattier body composition without changes in bodyweight. These mice further exhibited disruptions in sleep and enhanced nociception. Using bulk and spatial transcriptomic techniques, we observe broad changes in neural 5-HT, GLP-1, and appetitive circuits. We find 5-HT neurons of adolescent-isolation mice to be more excitable, transcribe fewer copies of Glp1r (mRNA; GLP-1 receptor), and demonstrate resistance to the inhibitory effects of the GLP-1R agonist semaglutide on action potential thresholds. Surprisingly, we find that administration of semaglutide, commonly prescribed to treat metabolic syndrome, induced deficits in social interaction in group-housed mice and rescued social deficits in isolated mice. Overall, we find that central 5-HT circuitry may simultaneously influence mental well-being and metabolic health in this model, via interactions with GLP-1 and proopiomelanocortin circuitry.

Poor Decision Making and Sociability Impairment Following Central Serotonin Reduction in Inducible TPH2-Knockdown Rats.

Serotonin is an essential neuromodulator for mental health and animals' socio-cognitive abilities. However, we previously found that a constitutive depletion of central serotonin did not impair rat cognitive abilities in stand-alone tests. Here, we investigated how a mild and acute decrease in brain serotonin would affect rats' cognitive abilities. Using a novel rat model of inducible serotonin depletion via the genetic knockdown of tryptophan hydroxylase 2 (TPH2), we achieved a 20% decrease in serotonin levels in the hypothalamus after three weeks of non-invasive oral doxycycline administration. Decision making, cognitive flexibility, and social recognition memory were tested in low-serotonin (Tph2-kd) and control rats. Our results showed that the Tph2-kd rats were more prone to choose disadvantageously in the long term (poor decision making) in the Rat Gambling Task and that only the low-serotonin poor decision makers were more sensitive to probabilistic discounting and had poorer social recognition memory than other low-serotonin and control individuals. Flexibility was unaffected by the acute brain serotonin reduction. Poor social recognition memory was the most central characteristic of the behavioral network of low-serotonin poor decision makers, suggesting a key role of social recognition in the expression of their profile. The acute decrease in brain serotonin appeared to specifically amplify the cognitive impairments of the subgroup of individuals also identified as poor decision makers in the population. This study highlights the great opportunity the Tph2-kd rat model offers to study inter-individual susceptibilities to develop cognitive impairment following mild variations of brain serotonin in otherwise healthy individuals. These transgenic and differential approaches together could be critical for the identification of translational markers and vulnerabilities in the development of mental disorders.

Loss of Htr1B Leads to a Failure in the Neonate Autoresuscitation Reflex

Sudden Infant Death Syndrome (SIDS) is the leading cause of death in infants under the age of 1, with an unknown etiology, that takes the lives of 3,400 infants per year in the US alone. Interestingly, SIDS cases show males predominance (60%), however this sexual disparity in is not fully understood. SIDS is believed to follow a triple risk hypothesis model where the infant has an innate vulnerability, is at a critical developmental period, and is challenged with an exogenous stressor. A leading hypothesis indicates many SIDS cases are mechanistically driven by a failure in the autoresuscitation reflex. The autoresuscitation reflex is a series of gasps that occur to revitalize normal cardiorespiratory function when an infant falls into a hypoxic coma, characterized by an apnea and bradycardia, due to severe hypoxic conditions (i.e., rebreathing while sleeping in face down or with the face blocked). Although the cause of failure in the autoresuscitation reflex for SIDS remains unknown, post-mortem studies have found abnormalities related to the central serotonin (5-HT) neurotransmitter system, including several 5-HT receptors (5-HTr’s). Follow up studies in animal models show that 5-HT system perturbations result in a significant survival decrease in neonatal animals during anoxic (3% CO2/balance N2) gas challenges that test the autoresuscitation function, including pharmacological receptor manipulations. Furthermore, adult animal studies report that 5-HT receptor stimulation alters various respiratory parameters (i.e., tidal volume, respiratory rate, gasping). What remains to be understood is the cellular and molecular mechanisms through which 5-HT plays a role in the autoresuscitation reflex and how those mechanism may be disrupted in SIDS. We hypothesize that Htr1B is required for successful autoresuscitation. To test this hypothesis, we utilized an automated closed loop robotic platform for neonate cardio-respiratory measurements ( Looper) to assay P7 Htr1B loss of function mice for their abilities to survive repeated anoxic gas challenges testing the autoresuscitation reflex. Using Looper, we find that the loss of Htr1B decreases survival to repeated anoxic challenges compared to wild type (WT) controls in both male and female mice. Additionally, a subset of male heterozygous Htr1B mice survive fewer challenges compared to WT mice, whereas others survive a similar number of challenges as WT mice; a phenotype not observed in female mice. Our data supports the hypothesis that modulations to the serotonin system via Htr1B is important in eliciting the autoresuscitation response. Future studies aim to investigate additional respiratory parameters from respiratory trace data, in addition to recovery parameters, and functionally mapping out where in the brainstem and what neuronal populations require the expression of this receptor for the autoresuscitation reflex. R01 HL161142. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dextromethorphan moderates reward deficiency associated with central serotonin transporter availability in 3,4-methylenedioxy-methamphetamine-treated animals.

The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats. Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[ 18 F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT. MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction. Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[ 18 F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.

Rhabdomyolysis and Neuroleptic Malignant Syndrome in a Postrenal Transplant Patient: Is Desidustat a Culprit?

We report a case of a 46-year-old female – a postrenal transplant patient, having developed rhabdomyolysis and neuroleptic malignant syndrome (NMS), after 2.5 months of desidustat initiation – for anemia. Post renal transplant anemia (PTA) is common among renal transplant recipients. Apart from treating it with iron supplements, folic acid, andrecombinant human erythropoietin (EPO), novel agents like hypoxia-inducible factor–prolyl hydroxylase domain (HIF–PHI) are also used, with a very few studies available on its efficacy and safety in PTA patients. Anemia occurring in the first 6 months is called early PTA – occurring most commonly due to iron deficiency, while anemia occurring after 6 months is called late PTA – associated with impaired graft function. The optimal target of hemoglobin in transplant recipients is 12.5–13 gm/dl, which is higher than targets in chronic kidney disease patients. NMS is a life-threatening emergency – mainly seen in patients on antipsychotic medications. It needs to be differentiated from other closely related conditions such as central nervous system infections (meningitis and encephalitis), tetanus, heatstroke, serotonin syndrome, and thyrotoxicosis. Desidustat is an oral HIF–PHI that stimulates erythropoiesis by preventing EPO degradation. Its adverse effects include high blood pressure, myocardial infarction, heart failure, high potassium, and dizziness; however, there is only one case report of rhabdomyolysis associated with desidustat, and none of NMS. It is, therefore, important to be aware of this potential severe side effect of the drug that was not known earlier so that practicing physicians can be vigilant of the same.

Peripheral peroxisomal β-oxidation engages neuronal serotonin signaling to drive stress-induced aversive memory in C. elegans

Physiological dysfunction confers negative valence to coincidental sensory cues to induce the formation of aversive associative memory. How peripheral tissue stress engages neuromodulatory mechanisms to form aversive memory is poorly understood. Here, we show that in the nematode C.elegans, mitochondrial disruption induces aversive memory through peroxisomal β-oxidation genes in non-neural tissues, including pmp-4/very-long-chain fatty acid transporter, dhs-28/3-hydroxylacyl-CoA dehydrogenase, and daf-22/3-ketoacyl-CoA thiolase. Upregulation of peroxisomal β-oxidation genes under mitochondrial stress requires the nuclear hormone receptor NHR-49. Importantly, the memory-promoting function ofperoxisomal β-oxidation is independent of its canonical role in pheromone production. Peripheral signals derived from the peroxisomes target NSM, a critical neuron for memory formation under stress, to upregulate serotonin synthesis and remodel evoked responses to sensory cues. Our genetic, transcriptomic, and metabolomic approaches establish peroxisomal lipid signaling as a crucial mechanism that connects peripheral mitochondrial stress to central serotonin neuromodulation in aversive memory formation.

Correlation between serum tryptophan metabolism and treatment efficacy of dapoxetine in patients with premature ejaculation: A pilot study.

Primary premature ejaculation (PPE) is a common male neurobiological disorder. Currently, there is consensus that the impairment in central serotonin (5-HT) neurotransmission constitutes a key pathogenic factor in PPE. Selective serotonin reuptake inhibitors (SSRIs) serve as the primary pharmacological intervention; however, a comprehensive elucidation of their mechanism of action remains incomplete. Owing to significant individual variability in efficacy, SSRIs exhibit a high discontinuation rate. Hence, there is an urgent need to address the selection of SSRIs for PPE treatment. This study aims to investigate the characteristics of tryptophan (TRP) metabolism in patients with PPE and to assess its influence on the efficacy of SSRIs. The exploratory study included a total of 16 patients with PPE and 16 control subjects who were healthy men without any sexual dysfunction. Upon enrollment in the study, all participants underwent a thorough medical history review and physical examination. Subsequently, their serum levels of TRP, its metabolites, large neutral amino acids (LNAAs), and metabolite ratios were assessed using a liquid chromatography-mass spectrometry (LC-MS) assay. After a period of 4weeks of dapoxetine treatment, all patients with PPE underwent reassessment using the Premature Ejaculation Diagnostic Tool (PEDT) score and intravaginal ejaculatory latency time (IELT) test. The ratio of serum TRP to other LNAAs (TRP/LNAAs) in patients with PPE was found to be significantly lower compared to the control group (P<0.05). Conversely, the ratio of kynurenine to TRP (KYN/TRP) was observed to be significantly higher in the PPE patients compared to the control group (P<0.05). Including the serum TRP/LNAAs ratio and KYN/TRP ratio in the prediction model yielded the highest prediction efficiency for PPE. There was a significant negative correlation between the ratio of TRP/LNAAs before the treatment and the IELT after 4weeks of the treatment. Additionally, there was a significant positive correlation observed between the ratio of TRP/LNAAs before the treatment and the PEDT score after 4weeks of the treatment. This study demonstrates that the reduction in the TRP/LNAAs ratio and the elevation of the KYN/TRP ratio are significant characteristics associated with PPE. These findings suggest that diminished tryptophan availability in the brain and the activation of the kynurenine (KYN) pathway may play a role in the pathogenesis of PPE. The TRP/LNAAs ratio has potential as a reliable indicator of central serotonin (5-HT) levels. Considering the TRP/LNAAs ratio when selecting SSRIs for the treatment of PPE may enhance the response rate of this medication.

Strain in the Midbrain: Impact of Traumatic Brain Injury on the Central Serotonin System.

Traumatic brain injury (TBI) is a pervasive public health crisis that severely impacts the quality of life of affected individuals. Like peripheral forms of trauma, TBI results from extraordinarily heterogeneous environmental forces being imparted on the cranial space, resulting in heterogeneous disease pathologies. This has made therapies for TBI notoriously difficult to develop, and currently, there are no FDA-approved pharmacotherapies specifically for the acute or chronic treatment of TBI. TBI is associated with changes in cognition and can precipitate the onset of debilitating psychiatric disorders like major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Complicating these effects of TBI, FDA-approved pharmacotherapies utilized to treat these disorders often fail to reach the desired level of efficacy in the context of neurotrauma. Although a complicated association, decades of work have linked central serotonin (5-HT) neurotransmission as being involved in the etiology of a myriad of neuropsychiatric disorders, including MDD and GAD. 5-HT is a biogenic monoamine neurotransmitter that is highly conserved across scales of biology. Though the majority of 5-HT is isolated to peripheral sites such as the gastrointestinal (GI) tract, 5-HT neurotransmission within the CNS exerts exquisite control over diverse biological functions, including sleep, appetite and respiration, while simultaneously establishing normal mood, perception, and attention. Although several key studies have begun to elucidate how various forms of neurotrauma impact central 5-HT neurotransmission, a full determination of precisely how TBI disrupts the highly regulated dynamics of 5-HT neuron function and/or 5-HT neurotransmission has yet to be conceptually or experimentally resolved. The purpose of the current review is, therefore, to integrate the disparate bodies of 5-HT and TBI research and synthesize insight into how new combinatorial research regarding 5-HT neurotransmission and TBI may offer an informed perspective into the nature of TBI-induced neuropsychiatric complications.

From dysbiosis to neuropathologies: Toxic effects of glyphosate in zebrafish

Glyphosate, a globally prevalent herbicide known for its selective inhibition of the shikimate pathway in plants, is now implicated in physiological effects on humans and animals, probably due to its impacts in their gut microbiomes which possess the shikimate pathway. In this study, we investigate the effects of environmentally relevant concentrations of glyphosate on the gut microbiota, neurotransmitter levels, and anxiety in zebrafish. Our findings demonstrate that glyphosate exposure leads to dysbiosis in the zebrafish gut, alterations in central and peripheral serotonin levels, increased dopamine levels in the brain, and notable changes in anxiety and social behavior. While the dysbiosis can be attributed to glyphosate's antimicrobial properties, the observed effects on neurotransmitter levels leading to the reported induction of oxidative stress in the brain indicate a novel and significant mode of action for glyphosate, namely the impairment of the microbiome-gut-axis. While further investigations are necessary to determine the relevance of this mechanism in humans, our findings shed light on the potential explanation for the contradictory reports on the safety of glyphosate for consumers.

Prevalence and Correlates of Serotonin Syndrome in Real-World Inpatients.

Serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction due to an increased central and peripheral serotonin activity, which usually presents as a triad of behavioral changes, neuromuscular excitability, and autonomic instability. Probably SS is often misdiagnosed, and its symptoms are mistaken for psychiatric symptoms or general medical issues: the true incidence of SS is not clear, and literature concerning potential risk factors is scarce. Our aims were to examine the prevalence of SS in a naturalistic sample of hospitalized patients and to evaluate potential factors related to the risk of developing the condition. The sample included 133 patients being treated with serotonergic medications admitted to the psychiatric inpatient unit of the San Luigi Gonzaga Hospital. All patients received a medical examination (including a neurological examination) within 24 hours of admission. Serotonin syndrome was diagnosed according to Hunter Criteria. Sixteen patients (12%) were diagnosed with SS. In the subgroup of subjects with SS, we found a higher rate of male patients when compared with subjects with no SS (62.5% vs 33.3%, P = 0.023). SS probably is an underestimated condition, which should be carefully assessed in patients on serotonergic medications. Male gender was the only factor found to be significantly related to a higher risk of developing SS. Further studies on larger samples are needed, to gain more information on possible risk factors and to identify subjects more prone to developing SS, given the potential risk for patients' health.

Mutuality of thyroid hormones and psychiatric disorders

Abnormalities in thyroid function may induce affective, anxious, psychotic, and cognitive disorders and are a potential marker for assessing suicidal risk in patients suffering from psychiatric disorders. This retrospective, cross-sectional, electronic, and data-based study, comprising 118 adult psychiatric patients, aimed to establish differences in the concentrations of total T3, T4, and thyroid-stimulating hormone among patients diagnosed with common psychiatric disorders. The analysis encompassed the levels of these hormones in patients who had attempted suicide and those who had not. Lower values of total T3 were observed in patients with depressive disorder compared to patients with psychotic and bipolar disorder, as well as the control group. Furthermore, lower total T3 values were observed in patients who had reported a suicide attempt in their lives compared to participants who had not attempted suicide. These findings suggest a potential link between thyroid hormones and the regulation of central serotonin activity. The study underscores the importance of routinely assessing thyroid function in clinical practice to facilitate early detection of suicidality and the prevention of suicide.