Serotonin Research Articles

Arginine vasopressin, ghrelin, 5-hydroxyindoleacetic acid, and substance P do not appear to be reliable biomarkers of nausea in dogs.

To determine if ACTH, cortisol, arginine vasopressin (AVP), ghrelin, 5-hydroxyindoleacetic acid (5-HIAA), and substance P (SP) blood biomarkers associated with nausea in humans have similar associations in dogs. 7 healthy, mixed hound dogs were nausea scored using videotaped observations, and concentrations of ACTH, cortisol, AVP, ghrelin, 5-HIAA, and SP were measured in blood at baseline, after 0.5 mg/kg, IM, morphine administration, and following administration of the treatment drug. Data collection occurred from October 20 through November 24, 2023. Treatments were saline 0.1 mL/kg (S) and propofol 0.5 mg/kg (P1), 1.0 mg/kg (P2), and 1.5 mg/kg (P3) administered IV 20 minutes after morphine administration using a randomized, crossover design with a 7-day washout between treatments. Nausea scores increased at 5 minutes and over time in all treatments. Adrenocorticotropic hormone concentrations were lower in P2 versus P1, P2 versus S, and P3 versus S at the 50-minute time point. At 50 minutes, cortisol concentrations were lower in P3 versus S, P2 versus S, and P3 versus P1. There were no statistically significant differences in AVP, ghrelin, 5-HIAA, or SP concentrations between treatments or over time. AVP, ghrelin, 5-HIAA, and SP did not correlate with nausea signs in dogs. Additionally, propofol, at the subhypnotic doses administered, did not significantly decrease signs of nausea. ACTH and cortisol, but not AVP, ghrelin, 5-HIAA, and SP, concentrations appeared to be associated with signs of nausea in dogs. Propofol was not effective at decreasing signs of nausea at the administered dosages.

Discovery of a Novel Multitarget Analgesic Through an In Vivo-Guided Approach

Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget analgesic with improved pharmacological properties. Methods: An in vivo-guided screening approach was used to discover a new analgesic compound. Compound 29, derived from a novel scaffold inspired by opiranserin and vilazodone pharmacophores, was identified through analog screening in the formalin test. Its efficacy was further evaluated in the spinal nerve ligation (SNL) model of neuropathic pain. Mechanistic studies explored its interaction with neurotransmitter transporters and receptors, while pharmacokinetic and safety assessments were conducted to determine its stability, brain penetration, and potential toxicity. Results: Compound 29 demonstrated high potency in the formalin test, with an ED50 of 0.78 mg/kg in the second phase and a concentration-dependent effect in the first phase. In the SNL model, it produced dose-dependent analgesic effects, increasing withdrawal thresholds by 24% and 45% maximum possible effect (MPE) at 50 and 100 mg/kg, respectively. Mechanistic studies revealed strong triple uptake inhibition, particularly at dopamine (DAT) and serotonin (SERT) transporters, alongside high-affinity 5-HT2A receptor antagonism. Pharmacokinetic analysis indicated enhanced stability and blood–brain barrier permeability. In vitro studies confirmed its nontoxicity to HT-22 cells but revealed potential hERG inhibition and strong CYP3A4 inhibition. Conclusions: Compound 29 is a promising multitarget analgesic with potent efficacy and favorable pharmacokinetics. Ongoing optimization efforts aim to mitigate side effects and enhance its therapeutic profile for clinical application.

Co-evolution of the humoral immune and serotonergic systems in chickens selected for high or low blood antibody titer response to sheep red blood cells.

Serotonin is a potent immunomodulatory neurohormone. Activities of the serotonergic and immune systems are often reported together in poultry studies with unidirectional analyses focused on serotonergic signaling mediating immune response. Considering serotonin's relevance across a range of immune-related poultry topics, elucidation of whether the immune system affects the serotonergic system can provide valuable insights into the bi-directionality of poultry neuroendocrine-immune interactions. The present study sought to determine whether selection for divergence in blood antibody titers to a non-pathogenic antigen coincides with parallel changes in the chicken's serotonergic system over the life of the bird. We utilized generations 49 and 50 male and female White Leghorn chickens (n = 10-12/chickens/line/sex/age) that have been selected long-term for high (HAS) or low (LAS) blood antibody response to intravenous sheep red blood cell injection. Because serotonin is predominantly produced in the gut and acts as an interkingdom signaling molecule, the first experiment sampled cecal tissue and luminal content samples from male and female HAS and LAS chickens at 293 days of age. In the second experiment, cecal tissue and luminal content, as well as plasma, were collected from HAS and LAS chickens at 28 and 56 days of age. Serotonin and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), concentrations were determined in cecal tissue, luminal content, and plasma samples. Immunoglobulins IgA and IgY concentrations were analyzed in cecal luminal content or plasma, respectively. The HAS chickens had lower (p < 0.05) cecal IgA concentrations but higher (p < 0.05) plasma IgY concentrations than LAS chickens, suggesting a compensatory response within the intestinal tract following selection for high or low blood antibody titers. Serotonin and 5-HIAA concentrations in the ceca and plasma diverged (p < 0.05) in a pattern that mirrored ceca IgA and plasma IgY differences according to genetic line. The results from this study demonstrate that evolutionary selection pressure for humoral immune response in chickens causes responses in the serotonergic system at both enteric and systemic levels.

Bangia fusco-purpurea polysaccharide with ultra-high pressure assisted extraction alleviates dyslipidemia in high-fat diet induced mice.

Bangia fusco-purpurea polysaccharide (UBFP) with ultra-high pressure assisted extraction has good in vitro hypolipidemic activity. To be explored as a natural hypolipidemic agent, the alleviation effect of UBFP on in vivo dyslipidemia in high-fat diet (HFD) induced mice was further investigated. Compared with native polysaccharide (BFP), UBFP was better to reduce weight gain, fat accumulation, serum and hepatic lipid abnormalities for HFD induced mice. This might be caused by the factor that UBFP was more effective to improve the diversity and structure of gut microbiota especially with SCFAs-producing bacteria (e.g., Allprevotella and Akkermansia) increased. Moreover, UBFP could up-regulate tryptophan, 5-hydroxyindoleacetic acid, leptin and N-arachidonic acid glutamate levels, and exhibited significant differential enrichment in the pathways of lysine biosynthesis, arginine biosynthesis, and tryptophan metabolism. In addition, UBFP could regulate energy metabolism and enhance fatty acid oxidation by inhibiting PPARγ protein expression and activating AMPK and ACC signaling pathways. Overall, with ultra-high pressure assisted extraction, UBFP possessed better function of regulating lipid homeostasis, which resulted from the altered structure of polysaccharides, improved intestinal flora and metabolites. The findings can lay the theoretical foundation for the design and development of desirable polysaccharides on regulating lipid homeostasis through ultra-high pressure modification.

The metabolic and cardiovascular effects of amphetamine are partially mediated by the central melanocortin system.

Amphetamine (AMPH) exerts metabolic and cardiovascular effects. The central melanocortin system is a key regulator of both metabolic and cardiovascular functions. Here, we show that the melanocortin system partially mediates AMPH-induced anorexia, energy expenditure, tachycardia, and hypertension. AMPH increased α-melanocyte stimulating hormone (αMSH) secretion from the hypothalamus, elevated blood pressure and heart rate (HR), increased brown adipose tissue (BAT) thermogenesis, and reduced both food intake (FI) and body weight (BW). In melanocortin 4 receptor-deficient (MC4R knockout [KO]) mice, metabolic and cardiovascular effects of AMPH were significantly attenuated. Antagonism of serotonergic and noradrenergic neurotransmitter systems attenuated AMPH-induced αMSH secretion as well as AMPH-induced metabolic and cardiovascular effects. We propose that AMPH increases serotonergic activation of proopiomelanocortin (POMC) neurons and reduces the noradrenergic inhibition of POMC neurons, thereby disinhibiting them. Together, these presynaptic mechanisms result in increased POMC activity, increased αMSH secretion, and increased activation of MC4R pathways that regulate both the metabolic and cardiovascular systems.

Machine Learning Tool for New Selective Serotonin and Serotonin–Norepinephrine Reuptake Inhibitors

Depression, a serious mood disorder, affects about 5% of the population. Currently, there are two groups of antidepressants that are the first-line treatment for depressive disorder: selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors. The aim of the study was to develop Quantitative Structure–Activity Relationship (QSAR) models for serotonin (SERT) and norepinephrine (NET) transporters to predict the affinity and inhibition potential of new molecules. Models were developed using the Automated Machine Learning tool Mljar based on 80% of the dataset according to 10-fold cross-validation and externally validated on the remaining 20% of data. The molecular representation featured two-dimensional Mordred descriptors. For each model, Shapley additive explanations analysis was performed to clarify the influence of the descriptors on the models’ predictions. Based on the final QSAR models, the following results were obtained: NET and pIC50 value RMSEtest = 0.678, R2test = 0.640; NET and pKi RMSEtest = 0.590, R2test = 0.709; SERT and pIC50 RMSEtest = 0.645, R2test = 0.678; SERT and pKi value RMSEtest = 0.540, R2test = 0.828. QSAR models for serotonin and norepinephrine transporters have been made available in a new module of the SerotoninAI application to enhance usability for scientists.

Multi-omics dissection of metabolic dysregulation associated with immune recovery in people living with HIV-1

BackgroundDespite the success of antiretroviral therapy (ART) in suppressing HIV-1 replication, some people living with HIV-1 (PLWH) fail to achieve an optimal recovery of CD4 T cells, and precise metabolic regulation underlying immune recovery remained poorly understood.MethodsIn this cross-sectional study, mass spectrometry was used for quantitative analysis of plasma metabolome and lipidome in 24 treatment-naïve PLWH (TNs), 33 immunological responders (IRs), 35 immunological non-responders (INRs), and 16 healthy controls (HCs). The data were analyzed using the Mann–Whitney U-test, Kruskal–Wallis test, Spearman correlation, and LASSO regression analysis.ResultsSignificant metabolic dysregulation was observed in TNs, IRs and INRs compared to HCs. In TNs, metabolomic analysis revealed increased levels of 3-hydroxyoctanoic acid, 3-oxododecanoic acid, 5-hydroxy-L-tryptophan, 5-hydroxyindoleacetic acid, L-kynurenine, oleoylcarnitine, and pseudouridine that were positively correlated with CD8 T cell activation and inflammation-related markers, and decreased levels of phosphorylcholine, ribothymidine, and thymine that were negatively correlated. Notably, 3-hydroxyoctanoic acid and thymine were consistently associated with CD4 T cell counts and inflammation-related markers in PLWH, regardless of ART. Pathway analysis uncovered the biosynthesis of unsaturated fatty acids as the major dysregulated pathway in TNs, IRs, and INRs, while primary bile acid biosynthesis was the dysregulated pathway specifically in INRs. Lipidomic analysis indicated higher plasma triacylglycerols, free fatty acids, ceramide, and monosialodihexosyl gangliosides (GM3) in TNs, IRs, and INRs compared to HCs. Pathway enrichment and differential correlation analyses underscore perturbed systemic lipid metabolism in treatment response to ART, possibly mediated by host-commensal metabolic interactions. Ultimately, we identified two panels, one consisting of 9 metabolites and another of 8 lipids, that can effectively distinguish INRs from IRs.ConclusionsMetabolic aberrations induced by chronic HIV-1 infection persist and do not recover with ART. Abnormal primary bile acid biosynthesis pathway and levels of DHA-containing lipids are closely associated with CD4 T cell recovery. These finding provide new intervention targets to achieve better immune recovery in PLWH.

Real-Time 5-Hydroxyindoleacetic Acid Monitoring in Guinea Pig Brain Using a Molecular Imprinted Polymer-Based Galvanic Redox Potentiometric Sensor.

5-Hydroxyindoleacetic acid (5-HIAA), a vital metabolite of serotonin (5-HT), is crucial for understanding metabolic pathways and is implicated in various mental disorders. In situ monitoring of 5-HIAA is challenging due to the lack of affinity ligands and issues with electrochemical fouling. We present an advanced sensing approach that integrates customizable molecular imprinting polymer (MIP) with self-driven galvanic redox potentiometry (GRP) for precise, real-time in vivo monitoring of 5-HIAA. The sensor, featuring pyrrole as the functional monomer in the MIP on the micrometer-sized bipolar carbon fiber electrodes, exhibited nanomolar sensitivity and superior selectivity for 5-HIAA over biosynthetic pathway analogs like 5-hydroxytryptophan (5-HTP) and serotonin. The MIPGRP sensor demonstrated excellent reversibility and resistance to fouling, enabling continuous monitoring in live guinea pig brains. We observed that intraperitoneal 5-HTP injection increases brain 5-HIAA levels, which is amplified up to 8-fold with Carbidopa pretreatment, providing deeper insights into the serotonergic signaling pathway. This work underscores the MIPGRP sensor's potential as a versatile and reliable tool for advancing neuroscience research.

Social group size alters social behavior and dopaminergic and serotonergic systems

ABSTRACT Social behavior is affected by social structure type, but how neural function changes with social type remains unclear. We investigated whether social group size affects social behaviors based on dopamine (DA) and serotonin (5-HT) systems. Four-week-old male mice were housed under different social group sizes: one, two, four, and eight mice per cage (1mpc, 2mpc, 4mpc, 8mpc, respectively). After 4 weeks, social preference, social interaction, and forced swim tests were performed to test sociability and anxiety, respectively, followed by analysis of DA and 5-HT and their metabolites (3,4-dihydroxyphenylacetic acid [DOPAC], 3-methoxytyramine [3-MT], norepinephrine, and 5-hydroxyindoleacetic acid [5-HIAA]). Social interactions and anxious behavior decreased with increased social group size. DA, 3-MT, and 5-HT levels decreased with increasing social group size, whereas DOPAC and 5-HIAA levels increased in the extended mesocorticolimbic system, including the dorsal striatum. Moreover, the increased social group size resulted in increased DOPAC/DA and 5-HIAA/5-HT ratios, accompanied by a decrease in the 3-MT/DA ratio within the extended mesocorticolimbic system. Linear regression analysis also revealed that social group size affects DA and 5-HT turnover. These suggest that social group size may influence behavior and monoamine levels, potentially contributing to DA- and 5-HT-related psychiatric disorders.

Lactobacillus fermentum 016 Alleviates Mice Colitis by Modulating Oxidative Stress, Gut Microbiota, and Microbial Metabolism

Ulcerative colitis (UC) is a chronic and progressive inflammatory gastrointestinal disease closely associated with gut microbiota dysbiosis and metabolic homeostasis disruption. Although targeted microbial therapies are an emerging intervention strategy for inflammatory bowel disease (IBD), the mechanisms by which specific probiotics, such as Lactobacillus fermentum 016 (LF), alleviate UC remain unclear. The current study evaluated the effects of LF supplementation on gut health in a basal model using C57BL/6 mice. Subsequently, the preventive effects and mechanisms of LF supplementation on DSS-induced UC were systematically investigated. According to our findings, LF supplementation revealed immunoregulatory capabilities with significantly altered gut the composition of microbiota and metabolic activities, particularly enhancing tryptophan metabolism. In the UC model, LF supplementation effectively mitigated weight loss, increased the disease activity index (DAI), and alleviated diarrhea, rectal bleeding, and colon shortening. Moreover, it reduced colonic pathological damage and histological injury scores. LF intervention improved antioxidant markers and intestinal mucosal barrier function with the activation of the Nrf2–Keap1 signaling pathway and regulation of systemic inflammatory markers, i.e., IL-1β, IL-6, TNF-α, IFN-γ, IL-4, and IL-10. Importantly, LF supplementation reversed metabolic disturbances by significantly increasing the abundance of beneficial genera (e.g., g_Dubosiella, g_Faecalibaculum, g_Odoribacter, g_Candidatus_saccharimonas, g_Roseburia, and g_Eubacterium_xylanophilum_group) and elevating tryptophan metabolites (e.g., melatonin, kynurenic acid, 3-indoleacetic acid, 5-methoxytryptophan, and 5-hydroxyindoleacetic acid). In conclusion, Lactobacillus fermentum 016 exhibits potential for regulating gut microbiota homeostasis, enhancing tryptophan metabolism, and alleviating UC, providing critical insights for developing probiotic-based precision therapeutic strategies for IBD.

Comparative Study on Sedative and Hypnotic Effects of Crude and Parched Semen Ziziphi Spinosae: Integration of Network Pharmacology and In Vivo Pharmacological Evaluation.

This study aimed to investigate the medicinal properties of SZS before and after processing and provide novel insights into its potential for treating insomnia. This study employed the network pharmacology platform to gather information on the chemical composition of SZS, human targets, genes, molecular networks, and pathways associated with insomnia treatment using SZS. Liquid chromatography-tandem mass spectrometry (LC-MS/ MS) was utilized to analyze the chemical profiles of crude SZS, parched SZS, and their combined decoction. The effects of different SZS products on p-chlorophenylalanine-induced insomnia mice were evaluated through pentobarbital-induced sleep tests, behavioral analyses, examination of brain tissue-related mRNA levels, and measurement of plasma neurotransmitters, aiming to explore the sedative and hypnotic effects of various SZS products. SZS was found to contain a total of 47 genes, including 22 target genes associated with insomnia. These genes may contribute to the sedative and hypnotic effects through 9 related pathways and 69 biological processes. The active components of SZS remained consistent before and after processing. Jujuboside B was found in higher concentrations in crude SZS, while jujuboside A was more abundant in parched SZS. Additionally, SZS exhibited reduced locomotor activity in mice, enhanced the hypnotic effect of pentobarbital sodium, and decreased the levels of acetylcholinesterase, α-1B adrenergic receptor, and solute carrier family 6 member 4 mRNA in the cortex and hippocampus of mice. The levels of acetylcholine, choline acetyltransferase, 5-hydroxyindoleacetic acid, and glutamate in plasma increased, with the hypnotic effect being proportional to the dosage of the drug. SZS demonstrates sedative and hypnotic effects, potentially mediated by its influence on neurotransmitter levels and related receptors within the central nervous system. There was a slight variation in regulatory capabilities before and after SZS processing, with the combined decoction of crude and parched SZS exhibiting a more pronounced effect, particularly at higher dosages.

Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder.

Memory and emotion are especially vulnerable to psychiatric disorders such as post-traumatic stress disorder (PTSD), which is linked to disruptions in serotonin (5-HT) metabolism. Over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (KYN) metabolic pathway, which generates a variety of bioactive molecules. Dysregulation of KYN metabolism, particularly low levels of kynurenic acid (KYNA), appears to be linked to neuropsychiatric disorders. The majority of KYNA is produced by the aadat (kat2) gene-encoded mitochondrial kynurenine aminotransferase (KAT) isotype 2. Little is known about the consequences of deleting the KYN enzyme gene. In CRISPR/Cas9-induced aadat knockout (kat2-/-) mice, we examined the effects on emotion, memory, motor function, Trp and its metabolite levels, enzyme activities in the plasma and urine of 8-week-old males compared to wild-type mice. Transgenic mice showed more depressive-like behaviors in the forced swim test, but not in the tail suspension, anxiety, or memory tests. They also had fewer center field and corner entries, shorter walking distances, and fewer jumping counts in the open field test. Plasma metabolite levels are generally consistent with those of urine: antioxidant KYNs, 5-hydroxyindoleacetic acid, and indole-3-acetic acid levels were lower; enzyme activities in KATs, kynureninase, and monoamine oxidase/aldehyde dehydrogenase were lower, but kynurenine 3-monooxygenase was higher; and oxidative stress and excitotoxicity indices were higher. Transgenic mice displayed depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits, coupled with a decrease in KYNA, a shift of Trp metabolism toward the KYN-3-hydroxykynurenine pathway, and a partial decrease in the gut microbial Trp-indole pathway metabolite. This is the first evidence that deleting the aadat gene induces depression-like behaviors uniquely linked to experiences of despair, which appear to be associated with excitatory neurotoxic and oxidative stresses. This may lead to the development of a double-hit preclinical model in despair-based depression, a better understanding of these complex conditions, and more effective therapeutic strategies by elucidating the relationship between Trp metabolism and PTSD pathogenesis.

Persistent large-scale changes in alternative splicing in prefrontal cortical neuron types following psychedelic exposure.

Psychedelics engage the serotonergic system as potent neuromodulators, increasing neuroplasticity in humans and rodents. Persistent changes in cognitive flexibility, emotional regulation, and social cognition are thought to underlie the therapeutic effects of psychedelics. However, the underlying molecular and cellular basis of psychedelic-induced plasticity remains unclear. Here, we identify persistent, cell type-specific alternative splicing changes in the mouse medial prefrontal cortex (mPFC) induced by a single dose of psychedelics. Combining deep RiboTag sequencing and bioinformatics, we find that a single dose of psychedelics modestly alters gene expression while dramatically shifting patterns of alternative splicing lasting at least a month. We connect our functional enrichment and alternative splicing analysis with changes in the extracellular matrix, synaptic physiology, and intrinsic physiology in parvalbumin interneurons days to a week after psychedelic treatment. Our dataset is an essential resource for understanding the persistent, cell type-specific effects of psychedelics on cortical cell types and functions.

Simultaneous Quantification of Biogenic Amines and their Metabolites in Mice Tissue by Combining Ultraviolet and Integrated Pulsed Amperometric Detectors.

We developed a reversed-phased high-performance liquid chromatographic method combining ultraviolet detection and integrated pulsed amperometric detection for the simultaneous quantification of dopamine, 5-hydroxyindolacetic acid, homovanillic acid, serotonin, 3,4-dihydroxyphenylacetic acid, norepinephrine and epinephrine. All target components were completely separated in a C18 column with isocratic elution of 5% acetonitrile solution containing 8mM HClO4 and 0.20mM 1-octanesulfonic acid as an ion pairing reagent. This method showed limits of detection of 0.03-0.1ng and limits of quantification of 0.10-0.3ng with linear regression coefficients of 0.9998-1.0000. All inter-day and intra-day precision values were below 9.58%, and the average recoveries were 93.71-109.82% for mouse striatum samples. The mean levels of the seven components in striatal brain tissue in a mouse model of Parkinson's disease decreased by 2-12 times compared to those of a control group. In particular, the decrease in dopamine, 5-hydroxyindolacetic acid and 3,4-dihydroxyphenylacetic acid was statistically significant (P < 0.05). Orthogonal partial least squares discriminant analysis confirmed that the seven components are useful biomarkers. The significance of the developed method lies in its ability to simultaneously analyze seven biogenic amines related to Parkinson's disease by combining two detectors, offering a simple and cost-effective approach for clinical and biological labs.

Venlafaxine-induced serotonin syndrome causing bilateral cerebral strokes: a case report

A 21-year-old Caucasian woman was admitted to our neurologic intermediate care unit after attempting suicide by ingesting an estimated 15 g venlafaxine (Trevilor retard®), adding up to a serum concentration of approximately 17,943 μg/l. Brain magnetic resonance imaging (MRI) revealed bilateral cortical restricted-diffusion patterns, indicating ischemic lesions. We report a case of venlafaxine-induced serotonin syndrome most likely cumulating in diffuse artery vasospasm due to an autonomic effect mediated by the serotonergic and adrenergic systems, causing myocardial and cerebral injuries. The serotonin syndrome was treated symptomatically by administering fluids and benzodiazepines and managing the hyperthermia using paracetamol; also, medication with venlafaxine was stopped, and the hypoglycemia was treated. After 6 days, our patient was discharged to the psychiatric facility with no remaining neurologic deficit. The case report provides evidence of ischemic stroke as a rare adverse event of venlafaxine intoxication. Furthermore, we aim to increase awareness of hypoglycemia and epileptic seizures as complications of venlafaxine intoxication. In addition, we demonstrate important pitfalls in the diagnostic procedure and propose a treatment regimen for the underlying serotonin syndrome.

The impact of borneolum on Citalopram hydrobromide pharmacokinetics and serotonin levels in the hypothalamus of conscious rats

Borneolum (BO) is an effectiveness adjuvant in facilitating the transportation of central nervous system drugs to the brain by opening the blood-brain barrier (BBB). Citalopram hydrobromide (CIT-HBr), a widely prescribed serotonin (5-HT) reuptake inhibitor, restricts the efficacy due to the BBB, resulting in slow onset and systemic side effects. Enhancing CIT-HBr’s efficacy through BO appears to be a promising approach. However, one of BO’s mechanisms involves increasing 5-HT. Therefore, evaluating the combined medication’s efficacy and safety is crucial. Using brain microdialysis techniques, after administering CIT-HBr (2 mg/kg) and BO (30 mg/kg) through intragastric administration, Cmax and AUC0-t of CIT-HBr significantly increase. Additionally, the ratio of 5-hydroxyindoleacetic acid to 5-HT markedly decreases, indicating a more efficient enhancement of CIT-HBr and 5-HT in the hypothalamus of conscious rats due to BO (p < 0.05). Nevertheless, it is necessary to investigate whether BO exacerbates the side effects of CIT-HBr associated with ‘serotonin syndrome’.

Therapeutic Strategies Targeting the Serotonergic System and Circadian Rhythm in Alzheimer's Disease Treatment

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, circadian rhythm disturbances, and loss of serotonergic function. While there is no cure for AD, emerging research suggests that targeting the serotonergic system and circadian rhythms may offer novel therapeutic avenues. Serotonin, a key neurotransmitter involved in regulating mood, cognition, and circadian rhythms, plays a critical role in maintaining brain function. However, serotonin levels decline with age and are further reduced in AD, exacerbating circadian disruptions and contributing to the disease's progression. This review explores the connection between the serotonergic system and circadian rhythm regulation in AD, examining the impact of serotonin depletion on the suprachiasmatic nucleus and its influence on amyloid-beta accumulation and tau pathology. Additionally, the potential therapeutic benefits of serotonin-targeted treatments, such as selective serotonin reuptake inhibitors and melatonin supplementation, are discussed. Restoring circadian and serotonergic balance may help delay AD onset and mitigate symptoms, though further research is needed to fully understand these mechanisms and develop effective interventions

Genetic and neurobiological aspects of psychosis in major neurocognitive disorder.

Psychiatric symptoms are frequent in neurocognitive disorders and dementias. Psychotic symptoms, mainly hallucinations and delusions, may appear in up to 50% of cases, influencing morbidity and mortality. Genetic, neurobiological, and environmental factors are involved in their onset. We conducted a narrative review of primary articles developed in humans that analyzed the genetic and neurobiological basis of psychosis in dementias. Evidence suggests that there are genetic risk variants for presenting psychosis in dementia. How genetic variants are related to schizophrenia, dementia, and other neurodegenerative disorders is under discussion. Candidate gene studies have found and genetic variants are associated with psychosis in dementia while genome-wide association studies have shown variants located in y . Epigenetic studies are scarce but have detected differences in the methylome of people with dementia and psychosis. On the other hand, alterations of the cholinergic, serotonergic, dopaminergic, and gabaergic neurotransmitter systems and the excitatory-inhibitory balance have been described in dementia. From a functional and anatomical point of view, there are alterations in several regions, mainly in the frontal area and other sensory processing and integration areas. Finally, we describe the influence of cognitive alterations in the genesis and maintenance of delusions and discuss the phenomenological overlap with confabulations. Multiple genetic, neurobiological, structural, and cognitive factors influence the occurrence of delusions and hallucinations in persons with dementia. Further research is needed to understand the pathophysiology of psychosis in dementias. This approach would support the understanding of psychosis as a transdiagnostic entity.

Pain and Perception: Exploring Psychedelics as Novel Therapeutic Agents in Chronic Pain Management.

Chronic pain affects approximately 1.5billion people worldwide, representing the leading cause of disability and a significant financial burden on healthcare systems. Conventional treatments, such as opioids and non-steroidal anti-inflammatory drugs, are frequently linked to adverse effects, including dependency and gastrointestinal issues, and often offer limited long-term relief. This review explores the potential of psychedelics, including psilocybin, LSD, and ketamine, as alternative therapeutic agents in chronic pain management. These substances modulate pain perception through actions on serotonergic and glutamatergic systems and may promote neuroplasticity, offering novel pathways for pain relief. Specifically, the review details the pharmacologic actions of psychedelics, their effects on chronic pain syndromes such as cancer pain, migraines, and neuropathic pain, and their clinical implications. The safety profiles, patient responses, and analgesic properties of these compounds are examined, highlighting the need for further research to validate their efficacy and optimize their therapeutic use in pain management.

Brainstem serotonin amplifies nociceptive transmission in a mouse model of Parkinson’s disease

Parkinson’s disease arises from the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as akinesia, rigidity, and tremor at rest. The non-motor component of Parkinson’s disease includes increased neuropathic pain, the prevalence of which is 4 to 5 times higher than the general rate. By studying a mouse model of Parkinson’s disease induced by 6-hydroxydopamine, we assessed the impact of dopamine depletion on pain modulation. Mice exhibited mechanical hypersensitivity associated with hyperexcitability of neurons in the dorsal horn of the spinal cord (DHSC). Serotonin (5-HT) levels increased in the spinal cord, correlating with reduced tyrosine hydroxylase (TH) immunoreactivity in the nucleus raphe magnus (NRM) and increased excitability of 5-HT neurons. Selective optogenetic inhibition of 5-HT neurons attenuated mechanical hypersensitivity and reduced DHSC hyperexcitability. In addition, the blockade of 5-HT2A and 5-HT3 receptors reduced mechanical hypersensitivity. These results reveal, for the first time, that PD-like dopamine depletion triggers spinal-mediated mechanical hypersensitivity, associated with serotonergic hyperactivity in the NRM, opening up new therapeutic avenues for Parkinson’s disease-associated pain targeting the serotonergic systems.