Pharmacokinetics of Trazodone in Hispaniolan Parrots (Amazona ventralis).

The objective of this study was to establish the pharmacokinetics of a single oral dose of trazodone in the Hispaniolan Amazon parrot (Amazona ventralis). Trazodone is a selective serotonin antagonist and reuptake inhibitor used commonly in both human and veterinary medicine as an antidepressant behavioral modification medicine. A single oral dose of compounded trazodone hydrochloride solution (20 mg/mL) at 50 mg/kg was administered to a total of 7 healthy adult Hispaniolan Amazon parrots. The 7 healthy adult parrots ranged in age from 10 to 15 years and weighed 228 to 323g. Blood was collected at baseline (2 weeks before study) and at 1, 2, 4, 6, 10, and 14 hours post-drug administration. Plasma concentrations of both trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) were measured via liquid chromatography tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was completed. The half-life (t1/2) ± SD of trazodone for the Hispaniolan parrots was 1.89 ± 0.49 hours, and the t1/2 ± SD of mCPP metabolite was 1.9 ± 0.55 hours. Maximum serum drug concentrations, or Cmax (ng/mL), were 738.3 ± 285.3 for trazodone. Times to achieve Cmax (hours) for trazadone and the mCPP metabolite were 1 hour and 2 hours postdosing, respectively. While this study did not establish the behavioral effects of trazodone, no adverse side effects were observed throughout the 48-hour period following drug administration and blood collection. Our results indicate that the oral administration of a 50-mg/kg single dose of trazodone to Hispaniolan parrots may be considered a safe dose. Plasma concentrations are comparable to previously published values in humans, dogs, horses, and pigeons (Columba livia domestica) for up to 14 hours following dosing. This study indicates that further studies are needed to establish the pharmacodynamics and the efficacy of trazodone in the medical management of behavioral problems in psittacine species.

Serotonin and vasovagal syncope.

PURPOSE: The goal of this manuscript was to review the biological and clinical evidence that serotonin neurotransmission might play an important role in the  physiology and treatment of vasovagal syncope. METHODS: The authors reviewed PubMed and handsearches of secondary sources for papers related to the Bezold-Jarisch reflex and serotonin, the plausible involvement of the Bezold-Jarisch reflex in vasovagal syncope, and three lines of clinical evidence involving serotonin and the syncope. RESULTS: The Bezold-Jarisch reflex was first described following the infusion of veratrum alkaloids into animals in the 19th century. The reflex is triggered by serotonin stimulation chemoreceptors and mechanoreceptors in the the left ventricle. The afferent component of the reflex is carried by unmyelinated type C vagal nerve fibers, which results in parasympathetic efferent stimulation that causes bradycardia. The similarity of the combination of hypotension and bradycardia in the Bezold-Jarisch reflex and in vasovagal syncope led to the suggestion that the reflex was the cause of the syndrome.  Three lines of evidence implicate the serotonin 5HT3 receptors in the heart in the reflex. There is genetic and physiologic evidence for the serotonin 5HT1A and 5HT3 receptors and the serotonin reuptake transporter (SERT). Acute blockade of SERT induces vasovagal syncope in humans undergoing head-up tilt table testing, and SERT inhibition reduces hypotension and bradycardia during spinal anaesthesia. Finally, three randomized clinical trials of SERT inhibitors uniformly reported that they significantly reduce the likelihood of vasovagal syncope recurrences. CONCLUSION: Multiple lines of evidence implicate serotonin neurotransmission in the cause of vasovagal syncope.

Insulin resistance, clinical presentation and resistance to selective serotonin and noradrenaline reuptake inhibitors in major depressive disorder.

BACKGROUND: The understanding of mechanisms underlying non-response to antidepressants is limited. The latest data highlights the role of insulin resistance (IR) in major depressive disorder (MDD) pathophysiology, presentation, and treatment efficacy. This work aimed to assess IR in MDD and explore the relationships between IR, MDD presentation and non-response to selective serotonin and noradrenaline reuptake inhibitors (SNRI). METHODS: 67 MDD individuals: 36 responsive (MDD T[+]), 31 non-responsive (MDD T[-]) to SNRI and 30 healthy controls were recruited. The treatment response criteria were: Clinical Global Impression Scale-Improvement score of 1 or 2 after ≥ 8 weeks of treatment. Participants were assessed by physician and self-report tools measuring depression, anhedonia, anxiety, bipolarity, sleep quality. Blood samples were collected to assess fasting glucose and insulin levels and calculate HOMA-IR (homeostasis model assessment of insulin resistance). RESULTS: MDD T[-] vs. MDD T[+] had significantly higher body mass index, insulin levels, and HOMA-IR. MDD T[-] presented higher levels of depressed mood, appetite/weight changes, loss of interest, energy, overall depressive symptoms, and sleep impairment; some evaluations suggested higher anhedonia and anxiety in MDD T[-] vs. MDD T[+]. Insulin and IR were weakly but significantly correlated with the severity of psychomotor symptoms, energy level, thoughts of death/suicide, self-criticism, appetite/weight, depressed mood symptoms, sleep problems. IR was weakly but significantly correlated with anhedonia. CONCLUSION: IR appears to be linked to depressive symptoms characteristic of the "metabolic" MDD subtype, such as psychomotor changes, energy level, anhedonia, sleep problems, appetite/weight changes, state and trait anxiety, sleep quality, and non-response to SNRI.

Potential differences in psychedelic actions based on biological sex.

The resurgence of interest in psychedelics as treatments for psychiatric disorders necessitates a better understanding of potential sex differences in response to these substances. Sex as a biological variable (SABV) has been historically neglected in medical research, posing limits to our understanding of treatment efficacy. Human studies have provided insights into the efficacy of psychedelics across various diagnoses and aspects of cognition, yet sex-specific effects remain unclear, making it difficult to draw strong conclusions about sex-dependent differences in response to psychedelic treatments. Compounding this further, animal studies used to understand biological mechanisms of psychedelics predominantly use one sex and present mixed neurobiological and behavioural outcomes. Studies that do include both sexes often do not investigate sex differences further, which may hinder the translation of findings to the clinic. In reviewing sex differences in responses to psychedelics, we will highlight the direct interaction between estrogen (the most extensively studied steroid hormone) and the serotonin system (central to the mechanism of action of psychedelics), and the potential that estrogen-serotonin interactions may influence the efficacy of psychedelics in female subjects. Estrogen influences serotonin neurotransmission by affecting its synthesis and release, as well as modulating the sensitivity and responsiveness of serotonin receptor subtypes in the brain. This could potentially influence the efficacy of psychedelics in females by modifying their therapeutic efficacy across menstrual cycles and developmental stages. Investigating this interaction in the context of psychedelic research could aid in the advancement of therapeutic outcomes, especially for conditions with sex-specific prevalence.

Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models.

Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, yet available pharmacological treatments are largely ineffective due, in part, to an inadequate understanding of the neurobiological drivers that underpin the condition. The recent resurgence of research into the clinical applications of psychedelic medicine for a range of mental disorders has highlighted the potential for classical psychedelics, including psilocybin, to alleviate symptoms of AN that relate to serotonergic signaling and cognitive inflexibility. Clinical trials using psychedelics in treatment-resistant depression have shown promising outcomes, although these studies are unable to circumvent some methodological biases. The first clinical trial to use psilocybin in patients with AN commenced in 2019, necessitating a better understanding of the neurobiological mechanisms through which psychedelics act. Animal models are beneficial in this respect, allowing for detailed scrutiny of brain function and behavior and the potential to study pharmacology without the confounds of expectancy and bias that are impossible to control for in patient populations. We argue that studies investigating the neurobiological effects of psychedelics in animal models, including the activity-based anorexia (ABA) rodent model, are particularly important to inform clinical applications, including the subpopulations of patients that may benefit most from psychedelic medicine. Appeared originally in Front Neurosci 2020; 14:43.

Neuropathological implication of high blood bilirubin in patients and model rats with depression.

PURPOSE: Elevated bilirubin levels have been associated with major depressive disorder (MDD); however, the exact impact of bilirubin on MDD and the underlying molecular mechanisms remain unclear. Here, we explored the influence of bilirubin on MDD and sought to identify the mechanisms via which bilirubin induces depressive-like behavior. PATIENTS AND METHODS: Forty patients who were diagnosed with MDD and received treatment with selective serotonin reuptake inhibitors (SSRIs) were included, with 43 healthy volunteers serving as controls. Clinical symptoms were evaluated using Hamilton depression rating scale-24 (HAMD-24) and the Hamilton anxiety rating scale. Serum concentrations of total bilirubin (TBIL) and indirect bilirubin (IBIL) were measured at baseline and after treatment using an automated biochemical analyzer. The connection between clinical symptoms and TBIL or IBIL was examined using Pearson correlation. Chronic restraint stress (CRS) was employed to generate a rat model of depression. TBIL, IBIL in rat serum were measured by ELISA. Reactive oxygen species (ROS) contents in rat hippocampal tissues were quantified by flow cytometry. The levels of microglial markers and the extent of neuronal damage in the rat hippocampus were assessed by immunofluorescence and transmission electron microscopy, respectively. RESULTS: Serum TBIL and IBIL levels were higher in patients with MDD than in the healthy controls. After treatment with SSRIs, the serum levels of TBIL and IBIL in MDD patients were significantly reduced. The levels of TBIL and IBIL were associated with HAMD-24 in MDD patients. Compared with the controls, the serum levels of TBIL, IBIL and the hippocampal ROS contents were elevated in CRS-exposed rats. Fluoxetine lowered inflammatory factor levels, mitigated oxidative stress. CONCLUSION: Our findings indicate a possible correlation between elevated serum bilirubin and depressive symptoms. Increases in ROS levels, along with neuronal damage, may represent pathological mechanisms underlying MDD.

Rapid effects of tryptamine psychedelics on perceptual distortions and early visual cortical population receptive fields.

N, N-dimethyltryptamine (DMT) is a psychedelic tryptamine acting on 5-HT2A serotonin receptors, which is associated with intense visual hallucinatory phenomena and perceptual changes such as distortions in visual space. The neural underpinnings of these effects remain unknown. We hypothesised that changes in population receptive field (pRF) properties in the primary visual cortex (V1) might underlie visual perceptual experience. We tested this hypothesis using magnetic resonance imaging (MRI) in a within-subject design. We used a technique called pRF mapping, which measures neural population visual response properties and retinotopic maps in early visual areas. We show that in the presence of visual effects, as documented by the Hallucinogen Rating Scale (HRS), the mean pRF sizes in V1 significantly increase in the peripheral visual field for active condition (inhaled DMT) compared to the control. Eye and head movement differences were absent across conditions. This evidence for short-term effects of DMT in pRF may explain perceptual distortions induced by psychedelics such as field blurring, tunnel vision (peripheral vision becoming blurred while central vision remains sharp) and the enlargement of nearby visual space, particularly at the visual locations surrounding the fovea. Our findings are also consistent with a mechanistic framework whereby gain control of ongoing and evoked activity in the visual cortex is controlled by activation of 5-HT2A receptors.

Key Enzymes of the Serotonergic System - Tryptophan Hydroxylase 2 and Monoamine Oxidase A - In the Brain of Rats Selectively Bred for a Reaction toward Humans: Effects of Benzopentathiepin TC-2153.

At the Institute of Cytology and Genetics (Novosibirsk, Russia) for over 85 generations, gray rats have been selected for high aggression toward humans (aggressive rats) or its complete absence (tame rats). Aggressive rats are an interesting model for studying fear-induced aggression. Benzopentathiepin TC-2153 exerts an antiaggressive effect on aggressive rats and affects the serotonergic system: an important regulator of aggression. The aim of this study was to investigate effects of TC-2153 on key serotonergic-system enzymes - tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) - in the brain of aggressive and tame rats. Either TC-2153 (10 or 20 mg/kg) or vehicle was administered once intraperitoneally to aggressive and tame male rats. TPH2 and MAOA enzymatic activities and mRNA and protein levels were assessed. The selection for high aggression resulted in upregulation of Tph2 mRNA in the midbrain, of the TPH2 protein in the hippocampus, and of proteins TPH2 and MAOA in the hypothalamus, as compared to tame rats. MAO enzymatic activity was higher in the midbrain and hippocampus of aggressive rats while TPH2 activity did not differ between the strains. The single TC-2153 administration decreased TPH2 and MAO activity in the hypothalamus and midbrain, respectively. The drug affected MAOA protein levels in the hypothalamus: upregulated them in aggressive rats and downregulated them in tame ones. Thus, this study shows profound differences in the expression and activity of key serotonergic system enzymes in the brain of rats selectively bred for either highly aggressive behavior toward humans or its absence, and the effects of benzopentathiepin TC-2153 on these enzymes may point to mechanisms of its antiaggressive action.

Early-life manipulation of the serotonergic system exacerbates the harmful effects of sleep deprivation on cognitive functions.

Serotonin is a monoamine neurotransmitter that plays a main role in regulating physiological and cognitive functions. Serotonergic system dysfunction is involved in the etiology of various psychiatric and neurological disorders. Therefore, the present study was designed to investigate the effects of early-life serotonin depletion on cognitive disorders caused by sleep deprivation. Serotonin was depleted by para-chlorophenylalanine (PCPA, 100 mg/kg, s.c.) at postnatal days 10-20, followed by sleep deprivation-induced through the multiple platform apparatus for 24 h at PND 60. After the examination of the novel object recognition and passive avoidance memories, the hippocampi and prefrontal cortex were dissected to examine the brain-derived neurotrophic factor (BDNF) mRNA expression by PCR. Our findings showed that postnatal serotonin depletion and sleep deprivation impaired the novel object recognition and passive avoidance memories and changed the BDNF levels. In the same way, the serotonin depletion in early life before sleep deprivation exacerbated the harmful effects of sleep deprivation on cognitive function and BDNF levels. It can be claimed that the serotonergic system plays a main role in the modulation of sleep and cognitive functions.

Yawning as a Rare Side Effect With Increased Escitalopram Dose: A Case Report.

Yawning is a normal physiological process that occurs naturally in all human beings in different settings, such as hunger, drowsiness, or stress. It is typically harmless, but abnormal yawning can be seen in many medical conditions. In psychiatry, it frequently occurs in disorders like depression, insomnia, and anxiety due to disturbed sleep. It has also been observed as an adverse reaction of some drugs, like escitalopram, a selective serotonin reuptake inhibitor. Escitalopram is a widely prescribed, well-tolerated antidepressant and antianxiety drug that can induce a range of side effects, one of which is excessive yawning. Its excessive occurrence can be distressing for patients, affecting their socio-occupational functioning. Clinically, differentiating yawning induced by escitalopram treatment from that in depression can be a diagnostic hurdle. Awareness and recognition of this lesser known side effect can improve patient outcomes by allowing for timely adjustments and easing the discomfort.

Mitigation and mechanism of low dose linoleic acid on depression caused by disorder of gut microbiome.

OBJECTIVES: Depression is a widely prevalent mental disorder, and nutritional interventions play an increasingly important role in its treatment. In this paper, effects of linoleic acid (LA) on depressive behavior in mice induced by gut microbiome disorders were investigated. METHODS: Fifty C57BL/6J male mice were randomly separated into five groups, control group (CK), ceftriaxone sodium group (CRO), low-dose linoleic acid group (LLA, 1 g/kg), medium-dose linoleic acid group (MLA, 2 g/kg), and high-dose linoleic acid group (HLA, 5 g/kg). In the LLA, MLA, and HLA groups, mice were treated with ceftriaxone sodium (CRO) to induce depressive behaviors, followed by LA administration. Behavioral tests were used to evaluate depressive behavior. High-throughput sequencing and Hematoxylin-eosin (H&E) staining in gut microenvironment were carried out. ELISA kits were used to measure brain inflammatory factors, and 5-hydroxy-tryptamine (5-HT). Gas chromatography and western blot were used to determine fatty acids compositions and the enzymes expression involved in lipid metabolism in brain respectively. RESULTS: The results showed that 10 weeks CRO treatment contribute to depressive behavior, gut microbiome disturbance, and serotonin system disturbance. LLA and MLA improved the depressive-like behavior, and significantly increased the levels of 5-HT1A, 5-HTT and 5-HT in the hippocampus. LLA was found to improve the diversity of gut microbiome and alleviate colon tissue damage. Meantime, LLA increased the content of linoleic acid, improved the expression of FADS2 and COX-2, increased IL-10 levels, and decreased IL-6 levels in the brain. DISCUSSION: LA alleviated depressive behavior in mice by improving the gut microenvironment, regulate fatty acid metabolism, and modulate inflammation.

"Niclosamide: A potential antipruritic agent by modulating serotonin pathway through metabotropic glutamate receptors (mGluRs)".

Pruritus is an uncomfortable sensation induced by various pruritogens, including serotonin. Serotonin, acting as an inflammatory mediator, can activate a histamine-independent pathway. Consequently, many anti-pruritus medications, such as antihistamines, are not effective in adequately relieving patient symptoms. Niclosamide, an anthelmintic drug, has recently demonstrated an affinity for Metabotropic glutamate receptors (mGluRs). mGluRs are a group of receptors activated by glutamate, and they are involved in regulating neuronal excitability. In this study, we utilized mouse models of serotonergic itch and administered different doses of Niclosamide to examine the expression of mGluR1, mGluR5, and 5-HT2. The administration of 5 mg/kg Niclosamide successfully suppressed pruritus in the mice. Additionally, the levels of mGluR1, mGluR5, 5-HT2, and TRPV1 were significantly reduced. These findings suggest that Niclosamide holds promise as a potential antipruritic drug.

Development of a Highly Specific Fluorescent Probe based on Thiol-ene Click Nucleophilic Cascade Reactions for Delving into the Action Mechanism of Serotonin in Depression.

The intrinsic correlation between depression and serotonin (5-HT) is a highly debated topic, with significant implications for the diagnosis, treatment, and advancement of drugs targeting neurological disorders. To address this important question, it is of utmost priority to understand the action mechanism of serotonin in depression through fluorescence imaging studies. However, the development of efficient molecular probes for serotonin is hindered by the lack of responsive sites with high selectivity for serotonin at the present time. Herein, we developed the first highly selective serotonin responsive site, 3-mercaptopropionate, utilizing thiol-ene click cascade nucleophilic reactions. The novel responsive site was then employed to construct the powerful molecular probe SJ-5-HT for imaging the serotonin level changes in the depression cells and brain tissues. Importantly, the imaging studies reveal that the level of serotonin in patients with depression may not be the primary factor, while the ability of neurons in patients with depression to release serotonin appears to be more critical. Additionally, this serotonin release capability correlates strongly with the levels of mTOR (intracellular mammalian target of rapamycin). These discoveries could offer valuable insights into the molecular mechanisms underpinning depression and furnish mTOR as a novel direction for the advancement of antidepressant therapies.

Serotonergic elements in the nervous system of parasite of acipenserid fishes, Acrolichanus auriculatus (Digenea: Allocreadiidae).

The trematode Acrolichanus auriculatus is a widely distributed intestine parasite of acipenserid fishes. For the first time the localization and distribution of the serotonergic nerve elements in A. auriculatus was studied using immunocytochemical method and confocal laser scanning microscopy. The study revealed the presence of biogenic amine, serotonin, in the central and peripheral nervous systems of A. auriculatus, that is in the neurons and neurites of the brain ganglia, brain commissure, the longitudinal nerve cords, and the connective nerve commissures. The innervation of the attachment organs, pharynx, oesophagus and distal regions of the reproductive system by the serotonergic nerve elements is observed. The distribution of serotonergic neurons in A. auriculatus is schematically marked. The comparative analysis of findings obtained in A. auriculatus with those recorded for other digeneans reveals the presence of both conservative and distinctive features in the organization of the serotonergic nervous system in various representatives of trematodes.

New insights into the effects of serotonin on Parkinson's disease and depression through its role in the gastrointestinal tract.

Neuropsychiatric and neurodegenerative disorders are frequently associated with gastrointestinal (GI) co-pathologies. Although the central and enteric nervous systems (CNS and ENS, respectively) have been studied separately, there is increasing interest in factors that may contribute to conditions affecting both systems. There is compelling evidence that serotonin (5-HT) may play an important role in several gut-brain disorders. It is well known that 5-HT is essential for the development and functioning of the CNS. However, most of the body's 5-HT is produced in the GI tract. A deeper understanding of the specific effects of enteric 5-HT on gut-brain disorders may provide the basis for the development of new therapeutic targets. This review summarizes current data focusing on the important role of 5-HT in ENS development and motility, with particular emphasis on novel aspects of 5-HT signaling in conditions where CNS and ENS comorbidities are common, such as Parkinson's disease and depressive disorders.

Early biomarkers in the presymptomatic phase of cognitive impairment: changes in the endocannabinoidome and serotonergic pathways in Alzheimer's-prone mice after mTBI.

BACKGROUND: Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer's disease (AD). METHODS: Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI. RESULTS: We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aß1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma. CONCLUSIONS: Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.

An Unexpected Phenomenon: A Case of Citalopram-Induced Dyskinesia.

Dyskinetic movements are characterized as hyperkinetic, repetitive movements of the extremities, facial, and oral musculature, most associated with prolonged dopamine D2 receptor blockade. In rare instances, dyskinetic movements can be brought on by selective serotonin reuptake inhibitor (SSRI) usage via an indirect D2 blockade mechanism, mimicking the D2 blockade observed with dopamine receptor blocking agents (DRBAs), such as in first-generation antipsychotics. This mimicked D2 blockade by SSRIs is said to be due to increased tonic inhibition by serotonin on dopaminergic neurons in the dopaminergic pathways of the brain, specifically the nigrostriatal pathway. In this case report, we look at a patient with a history of cerebral palsy who developed acute dyskinetic movements after short-term citalopram usage. The objective is to bring attention to the possible extrapyramidal side effects (EPS) of SSRI usage.

Biogenic amines in the testis: sources, receptors and actions.

Biogenic amines are signaling molecules with multiple roles in the central nervous system and in peripheral organs, including the gonads. A series of studies indicated that these molecules, their biosynthetic enzymes and their receptors are present in the testis and that they are involved in the regulation of male reproductive physiology and/or pathology. This mini-review aims to summarize the current knowledge in this field and to pinpoint existing research gaps. We suggest that the widespread clinical use of pharmacological agonists/antagonists of these signaling molecules, calls for new investigations in this area. They are necessary to evaluate the relevance of biogenic amines for human male fertility and infertility, as well as the potential value of at least one of them as an anti-aging compound in the testis.

Prenatal Stress Impacts Foetal Neurodevelopment: Temporal Windows of Gestational Vulnerability.

Prenatal maternal stressors ranging in severity from everyday occurrences/hassles to the experience of traumatic events negatively impact neurodevelopment, increasing the risk for the onset of psychopathology in the offspring. Notably, the timing of prenatal stress exposure plays a critical role in determining the nature and severity of subsequent neurodevelopmental outcomes. In this review, we evaluate the empirical evidence regarding temporal windows of heightened vulnerability to prenatal stress with respect to motor, cognitive, language, and behavioural development in both human and animal studies. We also explore potential temporal windows whereby several mechanisms may mediate prenatal stress-induced neurodevelopmental effects, namely, excessive hypothalamic-pituitary-adrenal axis activity, altered serotonin signalling and sympathetic-adrenal-medullary system, changes in placental function, immune system dysregulation, and alterations of the gut microbiota. While broadly defined developmental windows are apparent for specific psychopathological outcomes, inconsistencies arise when more complex cognitive and behavioural outcomes are considered. Novel approaches to track molecular markers reflective of the underlying aetiologies throughout gestation to identify tractable biomolecular signatures corresponding to critical vulnerability periods are urgently required.

Uncovering the unique characteristics of different groups of 5-HT5AR ligands with reference to their interaction with the target protein.

BACKGROUND: The serotonin 5-HT5A receptor has attracted much more research attention, due to the therapeutic potential of its ligands being increasingly recognized, and the possibilities that lie ahead of these findings. There is a growing body of evidence indicating that these ligands have procognitive, pro-social, and anti-depressant properties, which offers new avenues for the development of treatments that could address socially important conditions related to the malfunctioning of the central nervous system. The aim of our study was to unravel the molecular determinants for 5-HT5AR ligands that govern their activity towards the receptor. METHODS: In response to the need for identification of molecular determinants for 5-HT5AR activity, we prepared a comprehensive collection of 5-HT5AR ligands, carefully gathering literature and patent data. Leveraging molecular modeling techniques, such as pharmacophore hypothesis development, docking, and molecular dynamics simulations enables to gain valuable insights into the specific interactions of 5-HT5AR ligand groups with the receptor. RESULTS: The obtained comprehensive set of 2160 compounds was divided into dozens of subsets, and a pharmacophore model was developed for each group. The results from the docking and molecular dynamics simulations have enabled the identification of crucial ligand-protein interactions that are essential for the compound's activity towards 5-HT5AR. CONCLUSIONS: The findings from the molecular modeling study provide valuable insights that can guide medicinal chemists in the development of new 5-HT5AR ligands. Considering the pharmacological significance of these compounds, they have the potential to become impactful treatments for individuals and communities in the future. Understanding how different crystal/cryo-EM structures of 5-HT5AR affect molecular modeling experiments could have major implications for future computational studies on this receptor.