5-HT1A Receptor Research Articles

Prazosin and cyproheptadine in combination in the treatment of alcohol use disorder: A randomized, double-blind, placebo-controlled trial.

Pre-clinical studies suggest that the simultaneous blockade of the α1b and 5HT2A receptors may be effective in reducing alcohol consumption. This study aimed to assess the efficacy and safety of prazosin (α1b blocker) and cyproheptadine (5HT2A blocker) combination in decreasing total alcohol consumption (TAC) in alcohol use disorder (AUD). This was a double-blind, parallel group, placebo-controlled, Phase 2, randomized clinical trial conducted in 32 addiction treatment centres in France. A total of 108 men and 46 women with severe AUD took part. Participants were randomly assigned to one of the following 3-month treatments: (1) low-dose group (LDG) receiving 8mg cyproheptadine and 5mg prazosin extended-release (ER) formulation daily; (2) high-dose group (HDG) receiving 12 mg cyproheptadine and 10mg prazosin ER daily; and (3) placebo group (PG) receiving placebo of cyproheptadine and prazosin ER. A total of 154 patients were randomized: 54 in the PG, 54 in the LDG and 46 in the HDG. The primary outcome was TAC change from baseline to month 3. A significant main treatment effect in the change in TAC was found in the intent-to-treat population (P = 0.039). The HDG and LDG showed a benefit in the change in TAC from baseline to month 3 compared with PG: -23.6g/day, P = 0.016, Cohen's d = -0.44; -18.4g/day, P = 0.048 (Bonferroni correction P < 0.025), Cohen's d = -0.36. In a subgroup of very high-risk drinking-level participants (> 100 g/day of pure alcohol for men and > 60 g/day for women), the difference between the HDG and the PG in the primary outcome was -29.8g/day (P = 0.031, Cohen's d = -0.51). The high and low doses were well-tolerated with a similar safety profile. A randomized controlled trial of treatment of severe alcohol use disorder with a cyproheptadine-prazosin combination for 3months reduced drinking by more than 23 g per day compared with placebo. A higher dose combination was associated with a larger magnitude of drinking reduction than a lower dose combination while showing similar safety profile.

5-HT 2A and 5-HT 2C receptor antagonism differentially modulate reinforcement learning and cognitive flexibility: behavioural and computational evidence

RationaleCognitive flexibility, the ability to adapt behaviour in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive–compulsive disorder and major depressive disorder. Evidence suggests that flexibility, which can be operationalised using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behaviour and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown.ObjectivesWe investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on flexibility and underlying RL mechanisms.MethodsThirty-six male Lister hooded rats were trained on a touchscreen visual discrimination and reversal task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to task choice data to extract RL parameters, including a novel model designed specifically for this task.Results5-HT2AR antagonism impaired reversal learning only after an initial perseverative phase, during a period of random choice and then new learning. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate (i.e. negative feedback) at high and low doses. The low dose also decreased reinforcement sensitivity (beta) and increased stimulus and side stickiness (i.e., the tendency to repeat a choice regardless of outcome). 5-HT2CR antagonism also decreased beta, but reduced side stickiness.ConclusionsThese data indicate that 5-HT2A and 5-HT2CRs both modulate different aspects of flexibility, with 5-HT2ARs modulating learning from negative feedback as measured using RL parameters and 5-HT2CRs for learning from positive feedback assessed through conventional measures.

Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist.

Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.

Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor

Psilocybin, and its metabolite psilocin, induces psychedelic effects through activation of the 5-HT2A receptor. Psilocybin has been proposed as a treatment for depression and anxiety but sometimes induces anxiety in humans. An understanding of mechanisms underlying the anxiety response will help to better develop therapeutic prospects of psychedelics. In the current study, psilocybin induced an acute increase in anxiety in behavioral paradigms in mice. Importantly, pharmacological blocking of the 5-HT2A receptor attenuates psilocybin-induced head twitch response, a behavioral proxy for the psychedelic response, but does not rescue psilocybin's effect on anxiety-related behavior. Phosphopeptide analysis in the amygdala uncovered signal transduction pathways that are dependent or independent of the 5-HT2A receptor. Furthermore, presynaptic proteins are specifically involved in psilocybin-induced acute anxiety. These insights into how psilocybin may induce short-term anxiety are important for understanding how psilocybin may best be used in the clinical framework.

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia.

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.

The Secure Therapeutic Effects of Recently Developed Antipsychotic Drugs and Updated Neural Networks in Schizophrenia

Introduction:: Schizophrenia and schizoaffective disorder are treated in most cases with antipsychotic drugs of the second generation. These drugs block dopaminergic and serotonergic receptors, i.e., D2 and 5-HT2A receptors, and cause different adverse effects, for example, movement disturbances of the extrapyramidal system and adverse effects of vital parameters and of the heart. These drugs treat positive symptoms in schizophrenia and, to a lesser extent, negative symptoms. This review presents the development of newer antipsychotic drugs. Methods/Material:: References were taken from PubMed after using the following keywords: schizophrenia, schizoaffective disorder, antipsychotic drug, neurotransmitter and neuropeptide. Among these newer antipsychotic drugs are cariprazine, brexipiprazole and lumateperone, which exert a partial agonistic effect at D2 and 5-HT2A receptors, pimavanserin, a 5-HT2A receptor antagonist which treats negative symptoms in schizophrenia as add-on therapy, olanzapine combined with samidorphan, which reduces weight gain, and M4 or M1 receptor agonists, for example, xanomeline with an antipsychotic effect combined with trospium, an anticholinergic drug. Neural networks were updated in order to deduce the antipsychotic mechanism of action of newer antipsychotic drugs, especially xanomeline. Results:: The newer antipsychotic drugs cariprazine, brexipiprazole and lumateperone show antipsychotic, antimanic and anti-depressive effects, however, the efficacy on psychotic symptoms in long-term treatment has not yet been examined. Pimavanserin reduces negative symptoms in schizophrenia as an additional pharmacotherapy to treat this disorder. Olanzapine combined with samidorphan exerts good antipsychotic effects and reduces weight gain. The new antipsychotic drug xanomeline, the antipsychotic effect of which is quite different from the antidopaminergic effect, treats positive and negative symptoms in schizophrenia. Its mechanism of action was deduced from the neural networks presented. The long-term efficacy should still be examined. Conclusion:: This review is focused on newer antipsychotic drugs. The long-term efficacy of cariprazine, brexipiprazole and lumateperone in the treatment of schizophrenia should be examined further. Neural networks in the brain areas involved in schizophrenia should be examined and updated furthermore. Newer antipsychotic drugs ,for example, xanomeline, an M4 or M1 receptor agonist, which has been combined with trospium, an anticholinergic drug, the mechanism of action of which can be derived from the neural network suggested in this review.

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.

Aripiprazole induced reversible ptosis anda oromandibular dystonia

Introduction Aripiprazole is an atypical antipsychotic orally indicated for the treatment of schizophrenia, bipolar I, major depressive disorder. It is also indicated as an injection for agitation associated with schizophrenia or bipolar mania. Aripiprazole exerts its effects through agonism of dopaminergic and 5-HT1A receptors and antagonism of alpha-adrenergic and 5-HT2A receptors (Cosi et al., 2006). Ptosis is known as the drooping of the upper eyelid, and the patient usually presents with the complaint of the defect in vision and cosmesis (Shahzad &amp; Siccardi, 2023). Orofacial dyskinesia and oromandibular dystonia are uncommon neurological disorders with involuntary, mainly choreic (dance-like) movements, or excessive, involuntary and sustained or repetitive muscle contractions that may involve the face, lips, tongue, and/or jaw (Bakke, 2016).ObjectivesThe aim of this study is to present a case of ptosis and orofacial spasm, which are neurological side effects that may be very rare side effects of aripiprazole.MethodsThe 22-year-old woman was referred to the psychiatric service via the emergency service, due to thoughts of harming herself and irritability. The patient was planned to be hospitalized due to decreased sleep, increased speech, and persecution delusions for the last days. After the patient stayed in the service for 25 days, the patient was prescribed olanzapine 10 mg for discharge. At the follow-up appointment, it was learned that the patient had gained weight due to olanzapine and was switched to aripiprazole on 4th of July. The patient’s aripiprazole dose was gradually increased to 10 mg/day. The patient’s relatives gradually noticed drooping eyelids, involuntary oral movements, and impaired speech due to aripiprazole. Cranial MRI and cranial MRI angiography performed to rule out organic pathologies resulted normal. Accordingly, the aripiprazole dose was reduced to 5 mg/day by his mother, and at the last follow-up appointment on August 4, aripiprazole was stopped and paliperidone was started, and the neurological symptoms completely resolved 4 days later.Results Since aripiprazole is frequently used in the field of psychiatry, its side effects are often wondered about. Extrapyramidal system side effects of antipsychotics are more common than ptosis. And In terms of the incidence of various extrapyramidal side effects, overall, no significant effects of age, sex, mean dose, study duration, or measuring method could be demonstrated. It is very important to distinguish between organic pathology and drug side effects, especially since ptosis accompanies neuromuscular diseases, ischemic, demyelinating brain lesions and intracranial aneurysms.ConclusionsAs a result, patients who are started on antipsychotics should be closely watched for side effects to increase patient comfort and drug compliance. Also organic pathologies must be excluded before making a final decision that it is a drug side effect.Disclosure of InterestNone Declared

The Impact of Psychotropics on Sexuality: A Literature Review

IntroductionSexual dysfunctions related to psychotropic drugs are among the most distressing adverse effects and can lead to non-adherence to treatment.ObjectivesTo elucidate the mechanisms of psychotropic-induced sexual dysfunctions and to suggest strategies for their management.Methods Literature review based on the keywords “psychotropics,” “sexuality,” and “sexual dysfunction”.ResultsPsychotropic medications can impact sexuality either directly or indirectly. The direct effect is primarily due to a decrease in the mesocortical dopaminergic atmosphere, either by blocking D2 receptors or by stimulating 5HT2A receptors. D2 receptor blockade in the tubero-infundibular pathway triggers an increase in prolactin secretion, which can subsequently lead to erection problems, decreased libido, and difficulties achieving orgasm. Action in the nigrostriatal pathway may result in an extrapyramidal syndrome, which can, in turn, hinder intimate physical relations. The indirect effect can also be caused by metabolic complications, which are significant risk factors for sexual dysfunction, as they can lead to male hypogonadism and a negative self-image.Therapeutic strategies suggest either reducing doses (if the patient’s condition allows), changing the drug, or adding an adjunctive medication. Aripiprazole, being a partial agonist of D2 and 5-HT1A receptors and an antagonist of D3 and 5-HT2A receptors, appears to cause fewer sexual dysfunctions and can reduce hyperprolactinemia when added to other antipsychotics.ConclusionsHealthcare professionals must proactively gather information on sexuality given its impact on quality of life and treatment adherence. Prioritizing this dimension of well-being demonstrates a respectful approach toward the patient and establishes the foundation for a strong therapeutic alliance.Disclosure of InterestNone Declared

Side effects and cognitive benefits of buspirone: A systematic review and meta-analysis

Buspirone, a 5-hydroxytryptamine 1A (5-HT1A) receptor agonist, has been investigated for its use in various diseases. However, knowledge about its side effects and potential cognitive benefits in different conditions is limited. Cognitive impairment is also a prevalent symptom in many diseases, yet effective treatments are still lacking. Therefore, to explore the potential side effects of buspirone and the possible cognitive benefits of buspirone, we conducted a comprehensive search of several databases, including PubMed, Embase, Web of Science, Cochrane Review, Cochrane Trial, and ClinicalTrials.gov, to identify eligible randomized clinical trials. Our primary outcome measures included both side effects (adverse events) and cognitive benefits. For continuous variables, we utilized effect size with a 95% confidence interval (CI), whereas for dichotomous variables, we used odds ratios (OR) with a 95% CI. In total, 16 studies were included in this analysis, with 13 studies reporting on buspirone's side effects and 4 studies focusing on cognitive tasks. In terms of side effects, buspirone exhibited a higher rate of dizziness (OR = 4.66, 95% CI: 2.07–10.47), constipation (OR = 4.11, 95% CI: 1.34–12.55), and gastric distress (OR = 1.97, 95% CI: 1.03–3.78) than the placebo group. Regarding cognitive functions, buspirone showed significant benefits (g = 0.20, 95% CI: 0.06–0.34) while the placebo did not. Subgroup analysis indicated superior performance in visual learning and memory (g = 0.49, 95% CI: 0.21–0.78), logical reasoning (g = 0.42, 95% CI: 0.14–0.71), and attention (g = 0.37, 95% CI: 0.13–0.61) when compared to placebo. Our findings indicated that participants in the buspirone group experienced side effects of dizziness, constipation, and gastric distress in different diseases. Despite these adverse events, however, buspirone demonstrated significant cognitive benefits, particularly in the domains of visual learning and memory, logical reasoning, and attention.

The potential of 5-methoxy-N,N-dimethyltryptamine in the treatment of alcohol use disorder: A first look at therapeutic mechanisms of action.

Alcohol use disorder (AUD) remains one of the most prevalent psychiatric disorders worldwide with high economic costs. Current treatment options show modest efficacy and relapse rates are high. Furthermore, there are increases in the treatment gap and few new medications have been approved in the past 20 years. Recently, psychedelic-assisted therapy with psilocybin and lysergic acid diethylamide has garnered significant attention in the treatment of AUD. Yet, they require significant amounts of therapist input due to prolonged subjective effects (~4-12 h) leading to high costs and impeding implementation. Accordingly, there is an increasing interest in the rapid and short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). This paper offers a first look at potential therapeutic mechanisms for AUD by reviewing the current literature on 5-MeO-DMT. Primarily, 5-MeO-DMT is able to induce mystical experiences and ego-dissolution together with increases in psychological flexibility and mindfulness. This could decrease AUD symptoms through the alleviation of psychiatric mood-related comorbidities consistent with the negative reinforcement and self-medication paradigms. In addition, preliminary evidence indicates that 5-MeO-DMT modulates neural oscillations that might subserve ego-dissolution (increases in gamma), psychological flexibility and mindfulness (increases in theta), and the reorganization of executive control networks (increases in coherence across frequencies) that could improve emotion regulation and inhibition. Finally, animal studies show that 5-MeO-DMT is characterized by neuroplasticity, anti-inflammation, 5-HT2A receptor agonism, and downregulation of metabotropic glutamate receptor 5 with clinical implications for AUD and psychiatric mood-related comorbidities. The paper concludes with several recommendations for future research to establish the purported therapeutic mechanisms of action.

Functional connectivity subtypes of MDD and their associations with gene expression profile, neurotransmitter, and cognition

IntroductionThere’s large heterogeneity present in major depressive disorder (MDD) and controversial evidence on alterations of brain functional connectivity (FC), making it hard to elucidate the neurobiological basis of MDD. Subtyping is one promising solution to characterize this heterogeneity.ObjectivesTo identify neurophysiological subtypes of MDD based on FC derived from resting-state functional magnetic resonance imaging using large multisite data and investigate the differences in genetic mechanisms and neurotransmitter basis of FC alterations, and the differences of FC-related cognition between each subtype.MethodsConsensus clustering of FC patterns was applied to a population of 829 MDD patients from REST-Meta-MDD database after data cleaning and image quality control. Gene transcriptomic data derived from Allen Human Brain Atlas and neurotransmitter receptor/transporter density data acquired by using neuromap toolbox were used to characterize the molecular mechanism underlying each FC-based subtype by identifying the gene set and neurotransmitters/transporters showing high spatial similarity with the profiles of FC alterations between each subtype and 770 healthy controls. The FC-related cognition in each subtype was also selected by lasso regression.ResultsTwo stable neurophysiological MDD subtypes were found and labeled as hypoconnectivity (n=527) and hyperconnectivity (n=299) characterized by the FC differences in each subtype relative to controls, respectively. The two subtypes did not differ in age, sex, and scores of Hamilton Depression/Anxiety Scale.The genes related to FC alterations were enriched in ion transmembrane transport, synaptic transmission/organization, axon development, and regulation of neurotransmitter level for both subtypes, but specifically enriched in glial cell differentiation for hypoconnectivity subtype, while enriched in regulation of presynaptic membrane and regulation of neuron differentiation for hyperconnectivity subtype.FC alterations were associated with the density of 5-HT2a receptor in both subtypes. For hyperconnectivity subtype, FC alterations were also correlated with the density of norepinephrine transporter, glutamate receptor, GABA receptor, 5-HT1b receptor, and cannabinoid receptor.Both subtypes showed correlations between FC and categorization, motor inhibition, and localization. The FC in hypoconnectivity subtype correlated with response inhibition, selective attention, face recognition, sleep, empathy, expertise, uncertainty, and anticipation, while that was related to inference, speech perception, and reward anticipation in hyperconnectivity subtype.ConclusionsOur findings suggested the presence of two neuroimaging subtypes of MDD characterized by hypo or hyper-connectivity. The two subtypes had both shared and distinct genetic mechanisms, neurotransmitter receptor/transporter profiles, and cognition types.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.

Neonatal nociceptive stimulation results in pain sensitization, reduction of hippocampal 5-HT1A receptor, and p-CREB expression in adult female rats

Painful invasive procedures are often performed on newborns admitted to intensive care units (ICU). The acute and long-term effects caused by these stimuli can be investigated in animal models, such as newborn rats. Previous studies have shown that animals subjected to nociceptive stimuli in the neonatal period show sex-specific behavioral changes such as signs of anxiety or depression. Under the same conditions, neonatal stimuli also provoke an increase in the rate of neurogenesis and cell activation in the hippocampal dentate gyrus. So, this study aims to identify the possible roles of central monoamines, receptor expression (5-HT1A), and signaling factors (p-CREB) underlying the long-term effects of neonatal nociceptive stimulation. For this, noxious stimulation was induced by intra-plantar injection of Complete Freund´s adjuvant (CFA) on the postnatal day 1 (P1) or 8 (P8). Control animals were not stimulated. On P75 the behavioral tests were conducted (hotplate and elevated plus maze), followed by sacrifice and molecular studies. Our results showed that neonatal nociceptive stimulation alters pain sensitization specially in females, while stimulation on P1 increases pain threshold, P8-stimulated animals respond with reduced pain threshold (P < 0.001). Hippocampal expression of 5-HT1A receptor and p-CREB were reduced in P8 F group (P < 0.001) in opposition to the increased utilization rate of dopamine and serotonin in this group (P < 0.05). This study shows sex- and age-specific responses of signaling pathways within the hippocampus accompanied by altered behavioral repertoire, at long-term after neonatal painful stimulation.

Simultaneous Recording of Remote Domain Dynamics in Membrane Proteins Using the Double-Labeled DXB/DXT Technique.

Protein dynamics play important roles in biological functions, which accompany allosteric structure changes. Diffracted X-ray blinking (DXB) uses monochromatic X-rays and nanocrystal probes. The intramolecular motion of target proteins is analyzed from the intensity changes in detector signals at the diffraction rings. In contrast, diffracted X-ray tracking (DXT) elucidates molecular dynamics by analyzing the trajectories of Laue spots. In this study, we have developed a dual-labeling technique for DXB and DXT, allowing the simultaneous observation of motions at different domains in proteins. We identified zinc oxide (ZnO) crystals as promising candidates for the second labeling probes due to their excellent diffraction patterns, high chemical stability, and favorable binding properties with proteins. The diffraction spots from the ZnO crystals are sufficiently separated from those of gold, enabling independent motion analysis at different domains. Dual-labeling DXB was employed for the motion analysis of the 5-HT2A receptor in living cells. Simultaneous motion recording of the N-terminus and the second extracellular loop demonstrated ligand-induced motion suppression at both domains. The dual-labeling DXT technique demonstrated a capsaicin-induced peak shift in the two-dimensional motion maps at the N-terminus of the TRPV1 protein, but the peak shift was not obvious in the C-terminus. The capsaicin-induced motion modulation was recovered by the addition of the competitive inhibitor AMG9810.

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.&#x0D; 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.&#x0D; 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).&#x0D; 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).&#x0D; 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.

Serotonin Signaling in Hippocampus during Initial Cocaine Abstinence Drives Persistent Drug Seeking.

The initiation of abstinence after chronic drug self-administration is stressful. Cocaine-seeking behavior on the first day of the absence of the expected drug (Extinction Day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampal cornu ammonis 1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior and that dorsal raphe (DR) serotonin (5-HT) input to CA1 may be involved. We inhibited 5-HT1A/1B receptors (WAY-100635 plus GR-127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2 weeks later. We also inhibited 5-HT1A or 5-HT1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in the persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT1A/1B signaling, in CA1 decreased drug seeking on ED1 and decreased cocaine seeking 2 weeks later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug seeking during abstinence. In addition, 5-HT1B antagonism alone transiently decreased drug-associated memory performance when given prior to a CPP test, whereas similar antagonism of 5-HT1A alone had no such effect but blocked CPP retrieval on a test 24 h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augment recall of the drug-associated context and drug seeking via 5-HT1B receptors and prevent consolidation of the updated nondrug context via 5-HT1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence.

Intranasal delivery of shRNA to knockdown the 5HT-2A receptor enhances memory and alleviates anxiety

Short-hairpin RNAs (shRNA), targeting knockdown of specific genes, hold enormous promise for precision-based therapeutics to treat numerous neurodegenerative disorders. However, whether shRNA constructed molecules can modify neuronal circuits underlying certain behaviors has not been explored. We designed shRNA to knockdown the human HTR2A gene in vitro using iPSC-differentiated neurons. Multi-electrode array (MEA) results showed that the knockdown of the 5HT-2A mRNA and receptor protein led to a decrease in spontaneous electrical activity. In vivo, intranasal delivery of AAV9 vectors containing shRNA resulted in a decrease in anxiety-like behavior in mice and a significant improvement in memory in both mice (104%) and rats (92%) compared to vehicle-treated animals. Our demonstration of a non-invasive shRNA delivery platform that can bypass the blood–brain barrier has broad implications for treating numerous neurological mental disorders. Specifically, targeting the HTR2A gene presents a novel therapeutic approach for treating chronic anxiety and age-related cognitive decline.