Serotonin 5-HT1A Research Articles

Thermal behavior and determination of physicochemical properties of novel candidates for antipsychotic drugs

Treatment of schizophrenia with currently available drugs is often ineffective or results in several adverse reactions. In previous studies focusing on the search for new antipsychotic drugs, we designed and obtained a series of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptor ligands that were pharmacologically evaluated and showed promising antipsychotic activity. Evaluation of ADMET parameters is an important issue in drug development and should be performed at its early stage to avoid developing molecules with poor pharmacokinetics, that are unlikely to enter the market. For this reason, in this work we focused on the assessment of physicochemical parameters of selected compounds from the series we obtained to assess their drug-like potential. The results of thermal analysis showed that most of the tested compounds are thermally stable above 200 °C, with one compound stable up to 190 °C. Permeability through biological membranes assessed in the parallel artificial membrane permeability assay indicated that all tested compounds effectively migrate through biological membranes by means of passive diffusion. The solubility of the tested compounds was determined in PBS, reflecting physiological pH, and 0.01 M HCl, indicating their low to moderate solubility in PBS, which was significantly improved in acidic environment. The lipophilicity of the studied compounds expressed as LogD falls within the range of 1.84–2.80, what suggest that they would show good oral absorption and the ability to cross lipid barriers. The studies were supplemented with in silico prediction of ADMET parameters, which also indicate the probable high drug-likeness of the tested compounds.

Up-to-Date on clinical and preclinical studies of psilocybin therapy

Major Depressive Disorder (MDD) poses a significant global health burden, with 30-40% patients developing resistance to standard clinical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants. In 2016, Carhart-Harris and colleagues reported that psilocybin, the hallucinogenic compound derived from magic mushrooms, exhibits rapid and enduring antidepressant effects in patients with treatment-resistant depression. Subsequent clinical studies have found the therapeutic potential of psilocybin in MDD, depressive episode in bipolar disorder, anorexia, and drug addiction. In 2018 and 2019, the U.S. Food and Drug Administration designated psilocybin as a "breakthrough medicine" for treatment-resistant depression and MDD, respectively. Notably, the side effects of psilocybin are limited to transient and mild issues, such as headache and fatigue, suggesting its safety. In 2023, we published a review on the role of serotonin 5-HT2A receptors in the antidepressant effects of serotonergic psychedelics (Nihon Yakurigaku Zasshi, Volume 158, Issue 3, Page 229-232). Here, we present our study alongside the latest clinical and preclinical research on the antidepressant effects of psilocybin and provide an overview of the potential and issues related to psilocybin therapy.

Revealing a role of brainstem monoaminergic nuclei on the pronociceptive effect of sleep restriction

Sleep disturbances and persistent pain conditions are public health challenges worldwide. Although it is well-known that sleep deficit increases pain sensitivity, the underlying mechanisms remain elusive. We have recently demonstrated the involvement of nucleus accumbens (NAc) and anterior cingulate cortex (ACC) in the pronociceptive effect of sleep restriction. In this study, we found that sleep restriction increases c-Fos expression in NAc and ACC, suggesting hyperactivation of these regions during prolonged wakefulness in male Wistar rats. Blocking adenosine A2A receptors in the NAc or GABAA receptors in the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), or locus coeruleus (LC) effectively mitigated the pronociceptive effect of sleep restriction. In contrast, the blockade of GABAA receptors in each of these nuclei only transiently reduced carrageenan-induced hyperalgesia. Pharmacological activation of dopamine D2, serotonin 5-HT1A and noradrenaline alpha-2 receptors within the ACC also prevented the pronociceptive effect of sleep restriction. While pharmacological inhibition of these same monoaminergic receptors in the ACC restored the pronociceptive effect which had been prevented by the GABAergic disinhibition of the of the VTA, DRN or LC. Overall, these findings suggest that the pronociceptive effect of sleep restriction relies on increased adenosinergic activity on NAc, heightened GABAergic activity in VTA, DRN, and LC, and reduced inhibitory monoaminergic activity on ACC. These findings advance our understanding of the interplay between sleep and pain, shedding light on potential NAc-brainstem-ACC mechanisms that could mediate increased pain sensitivity under conditions of sleep impairment.

Nicotine and fluoxetine alter adolescent dopamine-mediated behaviors via 5-HT1A receptor activation.

Abuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when the distinct neurobiology of adolescent serotonin (5-HT) and dopamine (DA) systems create unique behavioral vulnerabilities to drugs of abuse. Using a pharmacological approach, we modeled the behavioral and neurochemical effects of subchronic (4-day) nicotine (60µg/kg, i.v.) or fluoxetine (1mg/kg, i.v.) exposure in adolescent and adult male rats. Nicotine and fluoxetine significantly enhance quinpirole-induced locomotor activity and initial cocaine self-administration in adolescents, but not adults. These effects were blocked by serotonin 5-HT1A receptor antagonists, WAY-100,635 (100 µg/kg, i.v.) or S-15535 (300 µg/kg, i.v.). Neurochemical and anatomical autoradiographic analysis of 8-OH-DPAT-stimulated [35S]GTPγS reveal that prior exposure to nicotine and fluoxetine results in both overlapping and distinct effects on regional 5-HT1A receptor activity. Both fluoxetine and nicotine enhance adolescent 5-HT1A receptor activity in the primary motor cortex (M1), whereas fluoxetine alone targets prefrontal cortical neurocircuitry and nicotine alone targets the amygdala. Given their different pharmacological profiles, comparison between WAY-100,635 and S-15535 indicates that postsynaptic 5-HT1A receptors mediate the behavioral effects of prior nicotine and fluoxetine exposure. In addition, within the adolescent M1, maladaptive changes in 5-HT signaling and 5-HT1A activity after nicotine or fluoxetine exposure may potentiate hyper-responsiveness to dopaminergic drugs and prime adolescent vulnerability for future substance abuse.

The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, like ketamine, elicit rapid-acting antidepressant activity in the rat chronic mild stress model via cortical mechanisms.

The highly selective 5-HT1A serotonin receptor "biased" agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model with systemic (i.p.) administration. They rapidly (within 1 day) reverse anhedonia (i.e., CMS-induced sucrose consumption deficit), attenuate working memory deficit (novel object recognition: NOR), and decrease anxiety behavior in the elevated-plus maze (EPM). Here, we sought to explore the contribution of prefrontal cortex (PFC) 5-HT1A receptor activation in the RAAD activity of NLX compounds. In male Wistar rats, unilateral PFC microinjections of NLX-204 and NLX-101 (16 µg), like ketamine (10 µg), reproduced the effects of their systemic administration: they reversed CMS-induced sucrose consumption deficit, attenuated anxiety (EPM), and reduced working memory deficits (NOR). In addition, unilateral PFC microinjections of the selective 5-HT1A antagonist, WAY-100,635 (2 µg), attenuated the beneficial effects of systemic NLX-204 and NLX-101 (0.16 mg/kg i.p.) in the sucrose intake and NOR models, indicating that these compounds exert their RAAD activity specifically through activation of PFC 5-HT1A receptors. These data indicate that 5-HT1A receptor biased agonists share with ketamine a common neuroanatomical site for RAAD activity, which can be obtained not only by targeting glutamatergic/NMDA neurotransmission (ketamine's primary mechanism of action) but also by activating 5-HT1A receptors, as is the case for the NLX compounds. The present observations also reinforce the notion that biased agonism at 5-HT1A receptors constitutes a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits and anxiety in depressed patients, without ketamine's troublesome side effects.

Discovery and in vitro Evaluation of Novel Serotonin 5-HT2A Receptor Ligands Identified Through Virtual Screening.

The 5-HT2A receptor is a molecular target of high pharmacological importance. Ligands of this protein, particularly atypical antipsychotics, are useful in the treatment of numerous mental disorders, including schizophrenia and major depressive disorder. Structure-based virtual screening using a 5-HT2A receptor complex was performed to identify novel ligands for the 5-HT2A receptor, serving as potential antidepressants. From the Enamine screening library, containing over 4 million compounds, 48 molecules were selected for subsequent experimental validation. These compounds were tested against the 5-HT2A receptor in radioligand binding assays. From the tested batch, six molecules were identified as ligands of the main molecular target and were forwarded to a more detailed in vitro profiling. This included radioligand binding assays at 5-HT1A, 5-HT7, and D2 receptors and functional studies at 5-HT2A receptors. These compounds were confirmed to show a binding affinity for at least one of the targets tested in vitro. The success rate for the inactive template-based screening reached 17 %, while it was 9 % for the active template-based screening. Similarity and fragment analysis indicated the structural novelty of the identified compounds. Pharmacokinetics for these molecules was determined using in silico approaches.

G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits

G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HT2AR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HT2AR coupling signature in response to different signaling probes, and its physiological consequences by combining computational modeling, in vitro and in vivo experiments with human postmortem brain studies. We show how chemical modification of the endogenous agonist serotonin dramatically impacts the G protein coupling profile of the 5-HT2AR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by Gαq protein activation, whereas psychosis-related behavior is modulated through Gαi1 stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.

Discovery of ITI-333, a Novel Orally Bioavailable Molecule Targeting Multiple Receptors for the Treatment of Pain and Other Disorders.

Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we have designed and synthesized a novel class of tetracyclic pyridopyrroloquinoxalinone derivatives with analgesic properties. The receptor binding profiles and analgesic properties of these tetracyclic compounds were studied. Systematic optimizations of this novel scaffold culminated in the discovery of the clinical candidate, (6bR,10aS)-8-[3-(4-fluorophenoxy)propyl]-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (compound 5, ITI-333), which exhibited potent binding affinity to serotonin 5-HT2A (Ki = 8.3 nM) and μ-opioid receptors (MOR, Ki = 11 nM) and moderate affinity to adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. ITI-333 acts as a 5-HT2A receptor antagonist, a MOR partial agonist, and an adrenergic α1A receptor antagonist. ITI-333 exhibited dose-dependent analgesic effects in rodent models of acute pain. Currently, this investigational new drug is in phase I clinical development.

Psychedelic therapy in depression and substance use disorders.

Psychoactive substances obtained from botanicals have been applied for a wide variety of purposes in the rituals of different cultures for thousands of years. Classical psychedelics from N,N'-dimethyltryptamine, psilocybin, mescaline and various lysergamides cause specific alterations in perception, emotion and cognition by acting through serotonin 5-HT2A receptor activation. Lysergic acid diethylamide, the first famous breakthrough in the field, was discovered by chance by Albert Hoffman in the Zurich Sandoz laboratory in 1943, and studies on its psychoactive effects began to take place in the literature. Studies in this area were blocked after the legislation controlling the use and research of psychedelic drugs came into force in 1967, but since the 1990s, it has started to be a matter of scientific curiosity again by various research groups. In particular, with the crucial reports of psychotherapy-assisted psilocybin applications for life-threatening cancer-related anxiety and depression, a new avenues have been opened in the treatment of psychiatric diseases such as treatment-resistant depression and substance addictions. An increasing number of studies show that psychedelics have a very promising potential in the treatment of neuropsychiatric diseases where the desired efficiency cannot be achieved with conventional treatment methods. In this context, we discuss psychedelic therapy, encompassing its historical development, therapeutic applications and potential treatment effects-especially in depression, trauma disorders and substance use disorders-within the framework of ethical considerations.

Improving dietary patterns in obese mice: Effects on body weight, adiposity, anhedonia-like behavior, pro-BDNF expression and 5-HT system

IntroductionThe excessive fat accumulation in obesity, resulting from an unbalanced diet, can lead to metabolic and neurological disorders and increase the risk of developing anxiety and depression. AimAssess the impact of dietary intervention (DI) on the serotonergic system, brain-derived neurotrophic factor (BDNF) expression and behaviors of obese mice. MethodsMale C57BL/6 mice, 5 weeks old, received a high-fat diet (HFD) for 10 weeks for the induction of obesity. After this period, for 8 weeks, half of these animals received a control diet (CD), group obese (OB) + control diet (OB + CD, n = 10), and another half continued being fed HFD, group obese + HFD (OB + HFD, n = 10). At the end of the eighth week of intervention, behavioral tests were performed (sucrose preference test, open field, novel object recognition, elevated plus maze and tail suspension). Body weight and food intake were assessed weekly. Visceral adiposity, the hippocampal and hypothalamic protein expression of BDNF, 5-HT1A (5-HT1A serotonin receptor) and TPH2 (key enzyme in serotonin synthesis), were evaluated after euthanasia. ResultsThe dietary intervention involved changing from a HFD to a CD over an 8-week period, effectively reduced body weight gain, adiposity, and anhedonia-like behavior. In the OB + HFD group, we saw a lower sucrose preference and shorter traveled distance in the open field, along with increased pro-BDNF expression in the hypothalamus compared to the OB + CD mice. However, the levels of TPH2 and 5-HT1A remained unchanged. ConclusionThe HFD model induced both obesity and anhedonia, but the dietary intervention successfully improved these conditions.

Pharmacoinformational, gerontoinformational and chemoreactomic analysis of the molecule of citrulline malate, carnitine, sulbutiamine and meldonium to identify the molecular mechanisms of antiasthenic action

The pathophysiology of asthenia is very complex and is associated with chronic kidney disease, heart failure, chronic obstructive pulmonary disease, sarcopenia, bacterial and viral pathogens, micronutrient nutritional imbalances, hypothyroidism, etc. Asthenia can occur with excessive (for a given patient) physical, mental or mental stress and adaptation disorders or be iatrogenic in nature (in particular, due to taking medications that contribute to increased loss of vitamins and microelements), incl. due to unwanted drug interactions. The complex nature of the pathophysiology of asthenia necessitates the use of a differentiated approach aimed at eliminating the main cause of asthenia in a given patient. If asthenia is associated primarily with disorders of energy metabolism, then the pathophysiological treatment is the use of nutrients that support intracellular synthesis - such as citrulline, citrulline malate, the main mechanisms of action of which are supporting the urea cycle, increasing the excretion of ammonium ions, reducing the concentration lactate in the blood. The paper presents the results of a comparative pharmacoinformatic and chemoreactomic analysis of citrulline, citrulline malate (CM), carnitine, sulbutiamine and meldonium. The profile of pharmacological effects of citrulline/CM was significantly different from the profiles of other molecules. For citrulline/CM, cholinergic, antidepressant, and lipid-modifying effects have been identified and an antiasthenic effect has been suggested when used in the treatment of Duchenne muscular dystrophy and for disorders of carbohydrate metabolism. Unlike other molecules, CM and carnitine do not contribute to the loss of vitamins and minerals. Inhibition of the CM serotonin 5HT3A receptor may improve vestibulation because blockers of 5-HT3 receptors concentrated in neurons of the vestibular apparatus, improves tests of balance and walking in an experiment in mice. A positive dose-dependent effect of citrulline and CM on the lifespan of a number of model organisms has been shown. Chemoreactomic analysis of molecular receptor proteins indicated new molecular mechanisms of the antiasthenic action of CM: inhibition of serotonin receptors, calcium sensor protein receptors, chemokine receptors, lipopolysaccharides (toll receptors), nociceptin, glutamate, orexin, purines and prostanoids, biosynthesis of NF-kB and TNFα.

PRECLINICAL AND CLINICAL EFFICACY AND SAFETY OF A NOVEL MULTI-TARGET SMALL MOLECULE MT-1207 FOR HYPERTENSION

Objective: To develop a novel multi-target small molecule agent for the treatment of hypertension with potential renal protection. Design and method: Part I (preclinical): MT-1207 was tested in the in vitro and in vivo preclinical models to evaluate mechanisms of action, hypertension efficacy, and renal protection. The in vitro activity of MT-1207 was evaluated in enzyme and radioligand binding assays. In vivo Spontaneously Hypertensive Rats (SHR) and two-kidney two-clip (2K2C) rat models were used to evaluate antihypertensive effects and renal protection of MT-1207. Preclinical safety evaluation of MT-1207 was conducted in rats and dogs following ICH guidelines. Part II (clinical): MT-1207 in clinical phases I and II were completed based on the clinical protocols. Phase Ia was a single center, randomized, double-blind, placebo-controlled, dose escalation study to evaluate safety, tolerability, pharmacokinetic of single oral dose of MT-1207 in healthy adult subjects. Phase Ia doses were 5, 10, 20, 40, 60, 90 mg. Similarly, Phase Ib study was conducted in patients with hypertension at 10 and 20 mg (BID) for 10 days. Clinical phase II was a multi-center, randomized, double-blind, placebo- and active-controlled, multiple-dose study to evaluate safety and pharmacodynamics of MT-1207 in patients with hypertension for 8 weeks. Results: Preclinical (part I): MT-1207 showed potent selective inhibitions of Adrenergic 1alpha and Serotonin (5-HT2A) receptors with IC50 < 1 nM. The efficacy of antihypertension of MT-1207 in SHR model was evident with a well-defined dose-response relationship at 2.5, 5, and 10 mpk. In 2K2C rat model, both blood pressure and serum uric acid decreased post-dose at 4-week and 9-week, indicating antihypertensive effects and potential kidney protection, respectively. Clinical (part II): in Phase I, healthy volunteers had good tolerability at 40 mg and below. Rapid blood pressure decreases were observed 1-2 hr post dose in patients with 10 and 20 mg doses. Results from Phase II (10 and 20 mg (BID)) with placebo and active drug (amlodipine) study will be presented including summary of adverse effects (AE) and efficacy data. Conclusions: Clinical data (phases I and II) demonstrated antihypertensive effects of MT-1207 with mild adverse effects.

Alterations in adolescent brain serotonin (5HT)1A, 5HT2A, and dopamine (D)2 receptor systems in a nonhuman primate model of early life adversity.

Stress affects brain serotonin (5HT) and dopamine (DA) function, and the effectiveness of 5HT and DA to regulate stress and emotional responses. However, our understanding of the long-term impact of early life adversity (ELA) on primate brain monoaminergic systems during adolescence is scarce and inconsistent. Filling this gap in the literature is critical, given that the emergence of psychopathology during adolescence has been related to deficits in these systems. Here, we use a translational nonhuman primate (NHP) model of ELA (infant maltreatment by the mother) to examine the long-term impact of ELA on adolescent 5HT1A, 5HT2A and D2 receptor systems. These receptor systems were chosen based on their involvement in stress/emotional control, as well as reward and reinforcement. Rates of maternal abuse, rejection, and infant's vocalizations were obtained during the first three postnatal months, and hair cortisol concentrations obtained at 6 months postnatal were examined as early predictors of binding potential (BP) values obtained during adolescence using positron emission tomography (PET) imaging. Maltreated animals demonstrated significantly lower 5HT1A receptor BP in prefrontal cortical areas as well as the amygdala and hippocampus, and lower 5HT2A receptor BP in striatal and prefrontal cortical areas. Maltreated animals also demonstrated significantly lower D2 BP in the amygdala. None of the behavioral and neuroendocrine measurements obtained early in life predicted any changes in BP data. Our findings suggest that early caregiving experiences regulate the development of brain 5HT and DA systems in primates, resulting in long-term effects evident during adolescence.

Examination of the effects of vitexin and vitexin-loaded solid lipid nanoparticles on neuropathic pain and possible mechanisms of action

This research aims to investigate the possible antiallodynic and antihyperalgesic effects of pure vitexin and vitexin-loaded solid lipid nanoparticles (SLN) on neuropathic pain and the pathways mediating these effects. Chronic constriction nerve injury was induced in female rats, and the effects of vitexin at the doses of 5, 10, 20, 40 mg/kg were evaluated. Ketanserin, ondansetron, WAY-100635, yohimbine and bicuculin, which are antagonists of receptors on pain pathways. were used to examine the mechanisms of the effects of vitexin. Pure vitexin exhibited antiallodynic activity at all administered doses, whereas antihyperalgesic activity was not observed at 5 mg/kg vitexin dose. SLN formulation was prepared with 5 mg/kg vitexin, the lowest dose. Vitexin-loaded formulation significantly increased antiallodynic and antihyperalgesic effects. Ondansetron, WAY-100635, yohimbine, and bicuculine antagonized the antiallodynic and antihyperalgesic effects of vitexin. So, it was concluded that serotonin (5-hydroxtryptamine, 5-HT) receptor subtypes 5-HT3 and 5-HT1A, alpha-2 adrenergic, and γ-Aminobutyric acid type A (GABA-A) receptors are involved in the antiallodynic and antihyperalgesic activity of vitexin. In conclusion, vitexin and vitexin-loaded formulation have the potential for clinical use in neuropathic pain management, and different pain pathways contributed to this effect. And also, it is thought that vitexin-loaded SLN formulation is more effective than pure vitexin, which will provide an advantage in treatment.

Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists.

Classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) are showing promising results in clinical trials for a range of psychiatric indications, including depression, anxiety, and substance abuse disorder. These compounds are characterized by broad pharmacological activity profiles, and while the acute mind-altering effects can be ascribed to their shared agonist activity at the serotonin 2A receptor (5-HT2AR), their apparent persistent therapeutic effects are yet to be decidedly linked to activity at this receptor. We report herein the discovery of 2,5-dimethoxyphenylpiperidines as a novel class of selective 5-HT2AR agonists and detail the structure-activity investigations leading to the identification of LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with desirable drug-like properties.

Pharmacological fingerprint of antipsychotic drugs at the serotonin 5-HT2A receptor.

The intricate involvement of the serotonin 5-HT2A receptor (5-HT2AR) both in schizophrenia and in the activity of antipsychotic drugs is widely acknowledged. The currently marketed antipsychotic drugs, although effective in managing the symptoms of schizophrenia to a certain extent, are not without their repertoire of serious side effects. There is a need for better therapeutics to treat schizophrenia for which understanding the mechanism of action of the current antipsychotic drugs is imperative. With bioluminescence resonance energy transfer (BRET) assays, we trace the signaling signature of six antipsychotic drugs belonging to three generations at the 5-HT2AR for the entire spectrum of signaling pathways activated by serotonin (5-HT). The antipsychotic drugs display previously unidentified pathway preference at the level of the individual Gα subunits and β-arrestins. In particular, risperidone, clozapine, olanzapine and haloperidol showed G protein-selective inverse agonist activity. In addition, G protein-selective partial agonism was found for aripiprazole and cariprazine. Pathway-specific apparent dissociation constants determined from functional analyses revealed distinct coupling-modulating capacities of the tested antipsychotics at the different 5-HT-activated pathways. Computational analyses of the pharmacological and structural fingerprints support a mechanistically based clustering that recapitulate the clinical classification (typical/first generation, atypical/second generation, third generation) of the antipsychotic drugs. The study provides a new framework to functionally classify antipsychotics that should represent a useful tool for the identification of better and safer neuropsychiatric drugs and allows formulating hypotheses on the links between specific signaling cascades and in the clinical outcomes of the existing drugs.

Use of vortioxetine in treating obsessive-compulsive disorder: a case report

Introduction Obsessive-compulsive disorder (OCD) is a chronic disorder with a wide range of manifestations but primarily intrusive thoughts (obsessions) and/or ritualized actions (compulsions) that can cause a huge distress in patients’ life. First-line treatment for OCD are selective serotonin reuptake inhibitors (SSRIs). Tricyclic antidepressants are used as second-line treatment due to secondary effects. Also antipsychotics such as aripiprazole are approved for treating OCD. Vortioxetine is has 5-HT3, 5-HT7 and 5-HT1D antagonists, 5-HT1B partial agonist and a 5-HT1A agonist and serotonin transporter inhibitor property. It is used in major depressive and anxiety disorders. A male 48 years old patient with an OCD diagnosis since he was 21, was reffered to psychiatry department. Previously, he had no response with SSRIs at full dosage and clomipramine 75mg was effective. At 46 years old, he had an acute myocardial infarction. He also admited not taking the medication regularly due to sexual disfunction and having affective symptoms related to the distress caused by OCD.ObjectivesTo evaluate efficacy of vortioxetine in treating OCD in a patient with contraindications for tricyclic antidepressants and no response to SSRIs.MethodsClomipramine dose was reduced until discontinuation. After one week without treatment, basal scores for Hamilton Scale and Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) were collected. Same data was collected again after 10 weeks treatment.ResultsThe dosage of vortioxetine was progressively titrated until 20mg daily in 3 weeks lapse. Diazepam 5mg was added in case of insomnia or anxiety. Aripiprazole 5mg was added in the third week of treatment as adjunctive treatment due to the recurrence of some intrusive thoughts (discontinued by himself because of akathisia). Finally, the patient reported an improvement in affective and OCD symptoms in the sixth week of treatment that was sustained until the tenth week, when data was recollected. The patient did not refer sexual disfunction.The pre and post results are summarized in tables 1 and 2. Table 1.Hamilton Depresion Rating Scale (0-52)BasalPost 10-week treatment214Dimensional Y-BOCS (0-15)BasalPost 10-week treatmentAggressive-related obsessions and compulsions102Religious-related obsessions and compulsions51Symmetry and order71Pollution and cleaning00Collecting and accumulation20Miscellaneous103ConclusionsVortioxetine might be a promising molecule for treating OCD in patients with contraindications for first and second-line treatments.Disclosure of InterestNone Declared

Potential Serotonin 5-HT2A Receptor Agonist of Psychoactive Components of Silene undulata Aiton: LC-MS/MS, ADMET, and Molecular Docking Studies.

Silene undulata is historically used for inducing vivid and prophetic lucid dreams, but limited information exists on its phytochemical composition and potential pharmacological properties. This study aimed to investigate the phytochemical composition of S. undulata through LC-MS/MS analysis and explore its potential serotonergic activity, which could support and confirm the traditional use of S. undulata as a dream-inducing plant. LC-MS/MS analysis was conducted on S. undulata extract, identifying 51 phytochemicals, including norharman, harmalol, harmaline, harmine, and ibogaine alkaloids. ADMET and Molecular docking investigations were employed to assess the serotonergic potential of these compounds. The analysis revealed the presence of β-carboline alkaloids, such as norharman, harmalol, harmaline, harmine, and ibogaine, within S. undulata extract. ADMET analysis showed that these compounds have a favourable pharmacokinetic properties. In addition, molecular docking investigations showed that harmaline (-8.90 Kcal/mol), harmalol (-8.56 Kcal/mol), and ibogaine (-8.75 Kcal/mol) exhibited binding affinities comparable to the control molecule, LSD (-9.14 Kcal/mol), indicating potential agonistic activity at serotonin 5-HT2A receptor. These findings provide insights into the potential therapeutic benefits of S. undulata, supporting its traditional use as a psychoactive plant. This study investigated the chemical constituents and potential serotonergic agonist activity of S. undulata for the first time. While promising, further research is necessary to uncover additional medicinal properties associated with the identified phytochemical components.

Psychedelics: reconnecting the brain to heal the mind

Natural psychedelics such as magic mushrooms have a long history of human use of at least 7000 years. Their use underwent a resurgence in the 1950/1960s following the synthesis of LSD as a psychedelic and its use as a medicine with powerful therapeutic benefits. But because non-medical use led to massive cultural changes especially in young people, all psychedelics were banned globally in the early 1970s. Over the past 20 years, there has been a resurrection of psychedelic research. This has revealed their common modes of action as agonists (stimulators) of the serotonin 5-HT2A receptor in the brain and that this activity leads to profound alterations in neuro-circuitry, producing a more integrated and flexible pattern of activity. These brain changes found in healthy volunteers predicted utility in mental illnesses such as depression and addiction and subsequent trials revealed this to be true. A single psychedelic trip can lead to very long-lasting improvements in a range of mental illnesses. From these remarkable and consistent positive outcomes, it seems likely that psychedelic therapy will soon become widely approved in western medicine, as it has already been in Australia for treatment-resistant depression.

Serotonin receptor and serotonin transporter expressions in the placental villous tree in gestational diabetes mellitus

BACKGROUND: The serotonergic system during pregnancy plays an important role not only in carbohydrate metabolism, but also in the laying and regulation of the fetoplacental complex, growth and development of the fetus. The study of the expression of placental serotonin 5-HT2A receptor and serotonin transporter (SERT) in gestational diabetes mellitus is foremost for scrutinizing the pathogenesis of perinatal complications, as it may allow for finding new opportunities for their prevention and correction.
 AIM: The aim of this study was to compare the expression patterns of the serotonin 5-HT2A receptor and SERT in placental tissue in gestational diabetes mellitus and in normal pregnancy.
 MATERIALS AND METHODS: This comparative cohort study included pregnant women with gestational diabetes mellitus (n = 6) and patients with normal pregnancy (n = 10). The expression of serotonin 5-HT2A receptor (Abcam, USA) and SERT (Bioss Antibodies, USA) was studied in placenta samples from the both study groups by immunohistochemical method. Morphometric analysis was performed using the VideoTest-Morphology 5.2 program (Videotest Ltd., Russia).
 RESULTS: The relative area of SERT expression in the placenta in gestational diabetes mellitus was higher compared to normal pregnancy (p 0.001). The relative areas of expression of the serotonin 5-HT2A receptor in the placenta did not differ between the study groups (p = 0.5).
 CONCLUSIONS: Higher SERT expression in the placentas of patients with gestational diabetes mellitus compared to those from women with normal pregnancies may reflect the level of tension of compensatory mechanisms in gestational diabetes mellitus and the effect of insulin therapy on these mechanisms.