Serotonin 1A Research Articles

Consistent evidence that brain serotonin 2A receptor binding is positively associated with personality-based risk markers of depression.

Using [18F]altanserin, a serotonin 2A receptor (5-HT2AR) antagonist Positron Emission Tomography (PET) tracer, a positive association between cortical 5-HT2AR binding and the inward-directed facets of neuroticism has been demonstrated in healthy individuals. Psilocybin, a 5-HT2AR agonist, shows promise for the treatment of depression, reducing neuroticism and mood symptoms potentially via hypothalamic-pituitary-adrenal (HPA) modulation. 5-HT2AR and neuroticism are both modulated by HPA axis function. In this study, we examined whether the association between 5-HT2AR binding and the inward facets of neuroticism can be replicated in an independent healthy cohort using the new 5-HT2AR agonist tracer [11C]Cimbi-36, and if their association is moderated by cortisol awakening response (CAR), an index of HPA axis function. If so, this could advance mechanistic insights into interventions that target the 5-HT2AR and reduce neuroticism. Eighty healthy volunteers underwent [11C]Cimbi-36 PET scans and completed the NEO personality inventory (NEO-PI-R) for the assessment of neuroticism. Salivary samples were available for determination of CAR in 70 of the participants. Using linear latent variable models, we evaluated the association between 5-HT2AR binding and inward facets of neuroticism, namely depression, anxiety, self-consciousness and vulnerability to stress, and whether CAR moderated this association. The study confirms the positive association between 5-HT2AR binding and the inward facets of neuroticism (β = 0.01, 95% CI = [0.0005: 0.02], P = 0.04), and this association is independent of CAR (P = 0.33). The findings prompt consideration of whether novel interventions such as psilocybin that actively targets 5-HT2AR and causes changes in personality could be particularly beneficial if implemented as a targeted approach based on neuroticism profiles.

Neurochemical characterization of 5-HT2AR partial agonists with simultaneous PET-MRI.

Understanding neuromodulatory effects of serotonin 2A receptor (5-HT2AR) agonists with diverse pharmacological profiles is relevant to advancing psychedelic-related drug applications. We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) to examine partial agonists with varying 5-HT2AR affinities and selectivity profiles: psilocybin (30, 60, and 90 µg/kg), lisuride (5 µg/kg), and 25CN-NBOH (15 µg/kg). Receptor occupancy was assessed with [11C]MDL-100907 PET, and cerebral blood volume (CBV) changes were measured with phMRI. Mixed partial agonists psilocybin and lisuride evoked biphasic CBV responses, whereas the selective 25CN-NBOH produced monophasic CBV increases. Cortical occupancy for psilocybin plateaued at 60 µg/kg (32%), whereas a lower dose of lisuride (5 µg/kg) resulted in similar occupancy (31%). Administration of 25CN-NBOH resulted in lower occupancy (7%) but larger changes in CBV compared to psilocybin and lisuride. The associations between CBV and 5-HT2AR occupancy appear linear for lisuride and 25CN-NBOH, but not for psilocybin. We speculate that the temporal and spatial differences in hemodynamic responses of the three agonists could stem from mixed affinity profiles. This work provides an understanding of pharmacological impacts of mixed serotonergic agonists being pursued as therapeutics for psychiatric conditions, offering valuable insights for future drug applications and development strategies.

Sex-stratified association of variants in the Serotonin 1A receptor gene with acute crisis pain among African American sickle cell disease patients

Patients with sickle cell disease (SCD) suffer from pain in their daily lives. Both the acute and chronic pain phenotypes of this disease exhibit high variability, making pain management a challenge. The underlying reasons for the phenotypic variability are poorly understood. Given the importance of serotonergic neurotransmission in pain signaling, we aimed to explore the role of variants in the 5-HT1A receptor gene (HTR1A) on pain variability in SCD. Four variants (rs6449693, rs878567, rs6294, and rs10042486) in HTR1A were genotyped in a cohort of 131 African Americans with SCD. Acute and chronic pain were measured by the acute care utilization and the McGill Pain Questionnaire, respectively. Association analyses were performed for three genetic models (additive, dominant, and recessive). Three variants (rs6449693, rs6294, and rs10042486) in HTR1A showed significant association with crisis pain in both the additive and dominant models. While the G allele of rs6449693 and the C allele of rs10042486 associated with lower acute crisis pain, the T allele of rs6294 associated with increased acute crisis pain. Sex-stratified analyses revealed that the associations of these three variants with acute pain were significant only in males, and not in females. Furthermore, the A allele rs878567 that did not reach statistical significance in the overall cohort, showed a significant association with lower crisis pain in males. As the first study to explore the role of HTR1A variants in sickle cell pain, we identified that four variants across the gene are associated with acute crisis pain in SCD in a sex-stratified manner.

The Use of Classic Psychedelics for Depressive and Anxiety-Spectrum Disorders

Abstract Following a decades-long decline in psychedelic research resulting from social, political, and legislative factors, there has been greatly renewed interest in these compounds' ability to treat psychiatric disorders. Classic psychedelics, encompassing both natural and synthetic psychoactive compounds, are characterized by their action as agonists or partial agonists of serotonin 5-hydroxytryptamine 2A receptors. In this comprehensive review, we summarize the latest clinical trials of classic psychedelics on depression and anxiety, attending to the patient demographics and methodology of each study. Overall, studies published since 2020 affirm the potential for classic psychedelics to treat major depressive disorder, treatment-resistant depression, bipolar II, and anxiety-spectrum disorders. However, findings are limited by short follow-up durations and nonstandard dosing and study designs. Given that many of the studies identified were post hoc analyses or follow-up studies from a select few parent studies, it is recommended that more original research be undertaken, with more diverse and larger sample sizes, standardized methodologies including blinding assessment, and long-term follow-up to identify duration of benefits and adverse reactions. It is also important to consider the role of psychological support and the therapeutic alliance in the psychedelic treatment of psychiatric disorders.

Isolation of psychedelic-responsive neurons underlying anxiolytic behavioral states.

Psychedelics hold promise as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell types beyond just those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type-specific mechanisms underlying psychedelic-induced behavioral states.

5-HT2AR and its implication on anti-depression therapy development

Abstract. Major depression disorder (MDD) affects a big population and causes disability and productivity loss worldwide. Yet, fast-onset, powerful cure with minor side effects is scant. Therefore, there is an urging need to examine the biological bases for MDD treatment to design novel antidepressants. The serotonin system in the brain has long been a hot spot for research in this field, leading to accumulating biochemical discoveries of specific serotonin receptors. In this review, we briefly summarized the serotonin hypothesis of MDD, then focused on the implication of serotonin 2A receptor (5-HT2AR) in MDD therapy. Latest genomic evidence of 5-HT2AR gene variations related to MDD was presented. 5-HT2AR antagonists and agonists with antidepressive effects and their possible mechanisms of action was discussed. Based on current understanding of the 5-HT2ARs involvement in MDD therapy, we enumerated several future directions for developing applicable 5-HT2AR-targeting MDD treatment.

Psilocin, the Psychoactive Metabolite of Psilocybin, Modulates Select Neuroimmune Functions of Microglial Cells in a 5-HT2 Receptor-Dependent Manner.

Neuroinflammation that is caused by microglia, the main immune cells of the brain, contributes to neurodegenerative diseases. Psychedelics, including psilocybin and lysergic acid diethylamide (LSD), possess certain anti-inflammatory properties and, therefore, should be considered as drug candidates for treating neuroinflammatory pathologies. When ingested, psilocybin is rapidly dephosphorylated to yield psilocin, which crosses the blood-brain barrier and exerts psychotropic activity by interacting with the 5-hydroxytryptamine 2A receptors (5-HT2ARs) on neurons. Since microglia express all three 5-HT2R isoforms, we hypothesized that, by interacting with these receptors, psilocin beneficially modulates select neuroimmune functions of microglia. We used microglia-like cell lines to demonstrate that psilocin, at non-toxic concentrations, did not affect the secretion of tumor necrosis factor (TNF) by immune-stimulated microglial cells, but significantly inhibited their phagocytic activity, the release of reactive oxygen species (ROS), and nitric oxide (NO) production. The inhibitory activity of psilocin on the latter two functions was similar to that of two selective 5-HT2R agonists, namely, 25I-NBOH and Ro60-0175. The role of this subfamily of receptors was further demonstrated by the application of 5-HT2R antagonists cyproheptadine and risperidone. Psilocin should be considered a novel drug candidate that might be effective in treating neuroimmune disorders, such as neurodegenerative diseases, where reactive microglia are significant contributors.

Abnormal functional lateralization and cooperation in bipolar disorder are associated with neurotransmitter and cellular profiles

BackgroundHemispheric lateralization and cooperation are essential for efficient brain function, and aberrations in both have been found in psychiatric disorders such as schizophrenia. This study investigated alterations in hemispheric lateralization and cooperation among patients with bipolar disorder (BD) and associations with neurotransmitter and cell-type density distributions to identify potential molecular and cellular pathomechanisms. MethodsSixty-seven BD patients and 127 healthy controls (HCs) were examined by resting-state functional MRI (rs-fMRI). Whole-brain maps of the autonomy index (AI) and connectivity between functionally homotopic voxels (CFH) were constructed to reveal BD-specific changes in brain functional lateralization and interhemispheric cooperation, respectively. Spatial associations of regional AI and CFH abnormalities with neurotransmitter and cell-type density distributions were examined by correlation analyses. ResultsBipolar disorder patients exhibited higher AI values in left superior parietal gyrus, cerebellar right Crus I, and cerebellar right Crus II, and these regional abnormalities were associated with the relative densities (proportions) of oligodendrocyte precursor cells and microglia. Patients also exhibited lower CFH values in right inferior parietal gyrus, bilateral middle occipital gyrus, left postcentral gyrus, and bilateral cerebellar crus II, and these regional abnormalities were associated with the densities of serotonin 1A and dopamine D2 receptors, oligodendrocyte precursor cells, astrocytes, and neurons. ConclusionsThese findings indicate that abnormal functional lateralization and cooperation in BD with potential molecular and cellular basis.

Effects of a Serotonergic Psychedelic on the Lipid Bilayer.

Serotonergic psychedelics, known for their hallucinogenic effects, have attracted interest due to their ability to enhance neuronal plasticity and potential therapeutic benefits. Although psychedelic-enhanced neuroplasticity is believed to require activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs), serotonin itself is less effective in promoting such plasticity. Also, the psychoplastogenic effects of these molecules correlate with their lipophilicity, leading to suggestions that they act by influencing the intracellular receptors. However, their lipophilicity also implies that a significant quantity of lipids is accumulated in the lipid bilayer, potentially altering the physical properties of the membrane. Here, we probe whether the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) can affect the properties of artificial lipid bilayers and if that can potentially affect processes such as membrane fusion. Solid-state NMR spectroscopy shows that the DOI strongly induces disorder in the lipid acyl chains. Atomic force microscopy shows that it can shrink the ordered domains in a biphasic lipid bilayer and can reduce the force needed to form nanopores in the membrane. Fluorescence correlation spectroscopy shows that DOI can promote vesicle association, and total internal fluorescence microscopy shows that it enhances vesicle fusion to a supported lipid bilayer. While serotonin has also recently been shown to cause similar effects, DOI is more than two orders of magnitude more potent in evoking these. Our results suggest that the receptor-independent effects of serotonergic psychedelics on lipid membranes may contribute to their biological actions, especially those that require significant membrane remodeling, such as neuronal plasticity.

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats.

Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT2AR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT2AR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT2AR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 h prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT2AR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 h later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, Il17ra. Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including Il17a, and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.

Association between 5-HTR1A gene C-1019G polymorphism and antidepressant response in patients with major depressive disorder: A meta-analysis.

Major depressive disorder (MDD) is a substantial global health concern, and its treatment is complicated by the variability in individual response to antidepressants. To consolidate research and clarify the impact of genetic variation on MDD treatment outcomes. Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search across PubMed, EMBASE, Web of Science, and the Cochrane Library was conducted without date restrictions, utilizing key terms related to MDD, serotonin 1A receptor polymorphism (5-HTR1A), C-1019G polymorphism, and antidepressant response. Studies meeting inclusion criteria were thoroughly screened, and quality assessed using the Newcastle-Ottawa Scale. Statistical analyses, including χ 2 and I² values, were used to evaluate heterogeneity and fixed-effect or random-effect models were applied accordingly. The initial search yielded 1216 articles, with 11 studies meeting criteria for inclusion. Analysis of various genetic models showed no significant association between the 5-HTR1A C-1019G polymorphism and antidepressant efficacy. The heterogeneity was low to moderate, and no publication bias was detected through funnel plot symmetry and Egger's and Begg's tests. This meta-analysis does not support a significant association between the 5-HTR1A C-1019G polymorphism and the efficacy of antidepressant treatment in MDD. The findings call for further research with larger cohorts to substantiate these results and enhance the understanding of antidepressant pharmacogenetics.

Sex-specific and developmental effects of early life adversity on stress reactivity are rescued by postnatal knockdown of 5-HT1A autoreceptors.

Early Life Adversity (ELA) predisposes to stress hypersensitivity in adulthood, but neurobiological mechanisms that protect from the enduring effects of ELA are poorly understood. Serotonin 1A (5HT1A) autoreceptors in the raphé nuclei regulate adult stress vulnerability, but whether 5HT1A could be targeted to prevent ELA effects on susceptibility to future stressors is unknown. Here, we exposed mice with postnatal knockdown of 5HT1A autoreceptors to the limited bedding and nesting model of ELA from postnatal day (P)3-10 and tested behavioral, neuroendocrine, neurogenic, and neuroinflammatory responses to an acute swim stress in male and female mice in adolescence (P35) and in adulthood (P56). In females, ELA decreased raphé 5HT neuron activity in adulthood and increased passive coping with the acute swim stress, corticosterone levels, neuronal activity, and corticotropin-releasing factor (CRF) levels in the paraventricular nucleus (PVN) of the hypothalamus. ELA also reduced neurogenesis in the ventral dentate gyrus (vDG) of the hippocampus, an important mediator of individual differences in stress susceptibility, and increased microglia activation in the PVN and vDG. These effects of ELA were specific to females and manifested predominantly in adulthood, but not earlier on in adolescence. Postnatal knockdown of 5HT1A autoreceptors prevented these effects of ELA on 5HT neuron activity, stress reactivity, neurogenesis, and neuroinflammation in adult female mice. Our findings demonstrate that ELA induces long-lasting and sex-specific impairments in the serotonin system, stress reactivity, and vDG function, and identify 5HT1A autoreceptors as potential targets to prevent these enduring effects of ELA.

Snapshot of 5-HT 2A receptor activation in the mouse brain via IP 1 detection.

The distinct subjective effects that define psychedelics such as LSD, psilocybin or DOI as drug class are causally linked to activation of the serotonin 2A receptor (5-HT 2A R). However, some aspects of 5-HT 2A R pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from non-psychedelic 5-HT 2A R agonists. We developed an ex vivo platform to obtain snapshots of drug-mediated 5-HT 2A R engagement of the canonical G q/11 pathway in native tissue. This non-radioactive methodology captures the pharmacokinetic and pharmacodynamic events leading up to changes in inositol monophosphate (IP 1 ) in the mouse brain. The specificity of this method was assessed by comparing IP 1 levels in homogenates from the frontal cortex in DOI-treated wild-type and 5-HT 2A R-KO animals compared to other brain regions, namely striatum and cerebellum. Furthermore, we encountered that head-twitch response (HTR) counts and IP 1 in the frontal cortex were correlated. We observed that IP 1 levels in frontal cortex homogenates from mice treated with LSD and lisuride vary in magnitude, consistent with LSD's 5-HT 2A R agonism and psychedelic nature, and lisuride's lack thereof. MDMA evoked an increase of IP 1 signal in the frontal cortex that were not matched by the serotonin precursor 5-HTP or the serotonin reuptake inhibitor fluoxetine. We attribute differences in the readout primarily to the indirect stimulation of 5-HT 2A R by MDMA via serotonin release from its presynaptic terminals. This methodology enables capturing a snapshot of IP 1 turnover in the mouse brain that can provide mechanistic insights in the study of psychedelics and other serotonergic agents pharmacodynamics.

Incidence and risk factors of antidepressant withdrawal symptoms: a meta-analysis and systematic review.

Antidepressants are among the most extensively prescribed psychotropic drugs worldwide. Discontinuation induced withdrawal symptoms have been reported for almost all antidepressants. The incidence of antidepressant withdrawal syndrome (AWS) and other characteristics remain unknown. We searched the PubMed, Embase, PsycINFO, MEDLINE, CINAHL, and Cochrane Central Register of Controlled Trials databases from inception to December 31, 2023. Randomized double-blinded trials, longitudinal or cross-sectional studies that reported the incidence and other characteristics of antidepressant withdrawal symptoms were included. The pooled incidence of AWS was calculated by a random effects model. We included 35 studies, of which 2 studies just provided incidence of specific withdrawal symptoms, and 4 studies only described other characteristics. The pooled incidence of AWS from all available studies was 42.9%, from 11 RCTs was 44.4%, in studies in which the treatment duration was mostly 8-12 weeks, which usually appear within 2 weeks, and were generally measured for <4 weeks. The incidence in selective serotonin-norepinephrine reuptake inhibitors was the lowest (29.7%), followed by selective serotonin reuptake inhibitors (45.6%) and tricyclic antidepressants (59.7%), without significant differences (p = 0.221). Treatment duration showed a dose-response to the incidence of AWS (6-12 W: 35.1%, 12-24 W: 42.7%, >24 W: 51.4%). The half-life did not show such a simple dose-dependent relationship. The pooled estimate was robust regardless whether withdrawal symptoms were measured in RCTs or observational studies (including face-to-face and online survey studies). Tapering the dose reduced the incidence of AWS compared with abrupt stoppage (34.5% vs 42.5%), without a significant difference (p = 0.484). Risk factors for withdrawal symptoms included being female, younger, experiencing adverse effects early in treatment, taking higher doses or longer duration of medication, abrupt cessation of drugs, and those with a lower clearance of drugs or with serotonin 1A receptor gene variation. The findings suggest the incidence of AWS are common and some clinical characteristics and risk factors which can help clinicians identify who is at greater risk of experiencing AWS. Discontinuation studies on long-term antidepressant users with long follow-up periods are required in the future.

PET Imaging of the Serotonin 1A Receptor in Major Depressive Disorder: Hierarchical Multivariate Analysis of [11C]WAY100635 Overcomes Outcome Measure Discrepancies

Abstract The serotonin 1A receptor has been linked to both the pathophysiology of major depressive disorder (MDD) and the antidepressant action of serotonin reuptake inhibitors. Most PET studies of the serotonin 1A receptor in MDD used the receptor antagonist radioligand, [carbonyl-11C]WAY100635; however the interpretation of the combined results has been contentious owing to reports of higher or lower binding in MDD with different outcome measures. The reasons for these divergent results originate from several sources, including properties of the radiotracer itself, which complicate its quantification and interpretation; as well as from previously reported differences between MDD and healthy volunteers in both reference tissue binding and plasma free fraction, which are typically assumed not to differ. Recently, we have developed two novel hierarchical multivariate methods which we validated for the quantification and analysis of [11C]WAY100635, which show better accuracy and inferential efficiency compared to standard analysis approaches. Importantly, these new methods should theoretically be more resilient to many of the factors thought to have caused the discrepancies observed in previous studies. We sought to apply these methods in the largest [11C]WAY100635 sample to date, consisting of 160 individuals, including 103 MDD patients, of whom 50 were not-recently-medicated and 53 were antidepressant-exposed, as well as 57 healthy volunteers. While the outcome measure discrepancies were substantial using conventional univariate analysis, our multivariate analysis techniques instead yielded highly consistent results across PET outcome measures and across pharmacokinetic models, with all approaches showing higher serotonin 1A autoreceptor binding potential in the raphe nuclei of not-recently-medicated MDD patients relative to both healthy volunteers and antidepressant-exposed MDD patients. Moreover, with the additional precision of estimates afforded by this approach, we can show that while binding is also higher in projection areas in this group, these group differences are approximately half of those in the raphe nuclei, which are statistically distinguishable from one another. These results are consistent with the biological role of the serotonin 1A autoreceptor in the raphe nuclei in regulating serotonin neuron firing and release, and with preclinical and clinical evidence of deficient serotonin activity in MDD due to over expression of autoreceptors resulting from genetic and/or epigenetic effects. These results are also consistent with downregulation of autoreceptors as a mechanism of action of selective serotonin reuptake inhibitors. In summary, the results using multivariate analysis approaches therefore demonstrate both face and convergent validity, and may serve to provide a resolution and consensus interpretation for the disparate results of previous studies examining the serotonin 1A receptor in MDD.

Estimating molecular properties, drug-likeness, cardiotoxic risk, liability profile, and molecular docking study to characterize binding process of key phyto-compounds against serotonin 5-HT2A receptor

Abstract Nowadays, the physiopathological and molecular mechanisms of multiple diseases have been identified, thus helping scientists to provide a clear answer, especially to those ambiguities related to chronic illnesses. This has been accomplished in part through the contribution of a key discipline known as bioinformatics. In this study, the bioinformatics approach was applied on four compounds identified in Centaurea tougourensis, using two axes of research: an in silico study to predict the molecular characteristics, medicinal chemistry attributes as well as the possible cardiotoxicity and adverse liability profile of these compounds. In this context, four compounds were selected and named, respectively, 2,5-monoformal-l-rhamnitol (compound 1), cholest-7-en-3.beta.,5.alpha.-diol-6.alpha.-benzoate (compound 2), 7,8-epoxylanostan-11-ol, 3-acetoxy- (compound 3), and 1H-pyrrole-2,5-dione, 3-ethyl-4-methyl- (compound 4). The second part looked into molecular docking, which objective was to evaluate the possible binding affinity between these compounds and the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor. Results indicated that compounds 1 and 4 were respecting Pfizer and giant Glaxo-SmithKline rules, while compounds 2 and 3 exhibited an optimal medicinal chemistry evolution 18 score. The structural and molecular features of almost all tested compounds could be considered optimal, indicating that these phyto-compounds may possess drug-likeness capacity. However, only compounds 1 and 4 could be considered non-cardiotoxic, but with a level of confidence more pronounced for compound 1 (80%). In addition, these four biocompounds could preferentially interact with G protein-coupled receptor, ion channel, transporters, and nuclear receptors. However, the heat map was less pronounced for compound 2. Data also indicated that these four compounds could possibly interact with serotonin 5-HT2A receptor, but in an antagonistic way. This research proved once again that plants could be crucial precursors of pharmaceutical substances, which could be helpful to enrich the international pharmacopoeia.

Flavonoids from mulberry leaves exhibit sleep-improving effects via regulating GABA and 5-HT receptors

Ethnopharmacological relevanceMulberry leaf (Folium Mori) is a dried leaf of the dicotyledonous mulberry tree and is a homologous food and medicine. Treating insomnia with it is a common practice in traditional Chinese medicine. But still, its potential sleep-improving mechanism remains to be elucidated. Aim of reviewPotential bioactive components and mechanisms of the sleep-improving effect of purified flavone from mulberry leaves (MLF) were explored through in vivo experiments, network pharmacology analysis, and molecular experimental validation. Materials and methodsThe mice model was established by pentobarbital sodium induction to evaluate the sleep-improving effect of MLF. The MLF's chemical composition was identified through a liquid chromatograph quadrupole time-of-flight mass spectrometer (Q-TOF LC/MS) to elucidate its sleep-improving active ingredient. At last, the underlying mechanism of MLF's sleep-improving effect was elucidated through neurotransmitter detection (ELISA), network pharmacology analysis, and molecular experimental validation (quantitative real-time PCR and western blotting). ResultsMLF could dramatically reduce sleep latency by 35%, prolong sleep duration by 123%, and increase the sleep rate of mice through increasing γ-aminobutyric acid (GABA) and serotonin (5-HT) release in serum, hypothalamus, and hippocampus. Q-TOF LC/MS identified 17 flavonoid components in MLF. Network pharmacological analysis suggested that the key sleep-improving active ingredients in MLF might be quercetin, kaempferol, morin, and delphinidin. The key path for MLF to improve sleep might be the tryptophan metabolism and neuroactive ligand-receptor interaction, and the key targets might be gamma-aminobutyric acid type A receptor subunit alpha2 Gene (GABRA2) and serotonin 1A (5-HT1A) receptors. ConclusionsMLF has shown significant sleep-improving effects in mice and may take effect through regulating the GABA and 5-HT receptors.

The serotonin 1A receptor promoter polymorphism, rs6295, is associated with morphofunctional features

Introduction. The tendency to weight gain is influenced by many genetic and environmental factors (nutrition, level of physical activity, social well-being, etc.), as well as complex interactions of these factors. Studying the genetic factors of obesity can help in developing individual strategies for the prevention and treatment of this common disease. One of the most important hereditary factors is the neurotransmitter systems gene polymorphism, (including the serotonin system gene polymorphism). The aim of the investigation is to study the associations of single nucleotide polymorphism of the rs6295 locus of the serotonin receptor gene 1A HTR1A with morphofunctional features and body weight gain. Material and methods. The study used the materials of a comprehensive anthropogenetic examination of 386 men and 418 women aged 17 to 30 years. More than 20 morphofunctional indicators were measured using the traditional anthropometric method. The material for genetic analysis was genomic DNA isolated from buccal epithelium. The reliability of intergroup differences was assessed using the Mann-Whitney criterion, while canonical discriminant analysis was used to study intergroup variability. Results. For the first time, a significant correlation was shown between the polymorphism of the serotonin receptor type 1 gene HTR1A and morphofunctional features: individuals with the G/G genotype with greater body weight have lower (compared to carriers of the C/C and C/G genotypes) values of the indicators of the level of metabolic processes and specific metabolism. Conclusion. The statistically significant obtained results may be used in the development of individual strategies for the prevention and treatment of obesity, and also allow us to supplement the information on the association of serotonin system gene polymorphism with morphofunctional features and contribute to expanding our understanding of the human physique features formation and their relationships with hereditary predisposition.

Mapping brain activity and neurotransmitters pre-cigarette smoking evolution: A study of male subjects

BackgroundThe impact of tobacco smoking on global health persists and it is essential to understand the progression of addiction and the involvement of neurotransmitters. MethodsThis study assessed 47 participants with tobacco use disorder (TUD) categorized based on changes in Fagerström Test for Nicotine Dependence (FTND) scores over 6 years: progressive TUD (pTUD), regressive TUD (rTUD), and stable TUD (sTUD). Additionally, 35 healthy controls were included. Resting-state functional magnetic resonance imaging was used to evaluate brain regional homogeneity (ReHo) and correlations with neurotransmitter distributions using JuSpace. ResultsSignificant differences in ReHo were observed among pTUD, rTUD, sTUD, and controls. After strict Bonferroni correction, rTUD exhibited increased ReHo in the dorsolateral superior frontal gyrus compared to sTUD (p < 0.001) and controls (p < 0.001). Both pTUD (p < 0.001) and rTUD (p < 0.001) showed decreased ReHo in the superior temporal gyrus compared to sTUD. sTUD had increased ReHo in the supramarginal gyrus compared to all other groups (p < 0.001, p < 0.001, p = 0.002, separately). The strongest association, which survived rigorous Bonferroni correction, was between the ReHo changes in rTUD compared to sTUD and neurotransmitter distribution. This includes 5-hydroxytryptamine receptor 2A (p = 0.001), gamma-aminobutyric acid type A receptor (p < 0.001), norepinephrine transporter (p < 0.001), and N-Methyl-D-Aspartate (p = 0.002). ConclusionsThis study provides insights into how smoking behaviors correlate with alterations in brain activity and neurotransmitter function. By elucidating these neural links to tobacco use disorder progression, our findings contribute to a deeper understanding of smoking's neurological impact and potentially inform more targeted therapeutic strategies.

124 - The serotonin 2A receptor is involved in the hypersensitivity of bladder afferent neurons in cyclophosphamide-induced cystitis

124 - The serotonin 2A receptor is involved in the hypersensitivity of bladder afferent neurons in cyclophosphamide-induced cystitis