Serotonin Receptor Research Articles

Cariprazine in Psychiatry: A Comprehensive Review of Efficacy, Safety, and Therapeutic Potential.

This article provides a comprehensive review of recent developments regarding a new atypical antipsychotic drug - cariprazine - considering the mechanism of action, efficacy, safety, and promising therapeutic option for various psychiatric disorders, including schizophrenia and bipolar disorder, therapy of addictions, and treatment in the pediatric population. Its distinct pharmacological profile, characterized by partial agonism at dopamine D2 and D3 receptors, as well as serotonin receptors - 5HT1A with a preference for the D3 receptor - sets it apart from other antipsychotics. The unique mechanism of action contributes to cariprazine's positive impact on negative symptoms in schizophrenia and an antidepressant effect. Its relatively low risk of adverse effects, such as sedation, metabolic issues, and hypotension, enhances its tolerability. In bipolar affective disorder, cariprazine exhibits effectiveness in managing both depressive and manic episodes. Ongoing research in pediatric populations suggests potential benefits in schizophrenia, bipolar I disorder, and autism spectrum disorder, but further research is necessary to establish safety and efficacy. Moreover, cariprazine shows promise in addiction therapy, particularly with coexisting psychiatric disorders. Continued research and clinical exploration may discover additional insights, broadening its use in diverse patient populations. This article aims to review the role of cariprazine, a dopamine D2/D3 and serotonin 5-HT1A receptor partial agonist, in the management of psychotic illnesses, including schizophrenia, bipolar disorder, addiction therapy, and pediatric treatment.

CCNP Innovations in Neuropsychopharmacology Award: The psychopharmacology of psychedelics: where the brain meets spirituality.

For 3000 years, psychedelics have been used in religious contexts to enhance spiritual thinking, well-being, and a sense of community. In the last few years, a renaissance in the use of psychedelic drugs for mental disorders has occurred in Western society; consequently, a pressing scientific need to elucidate the intricate mechanisms underlying their actions has arisen. Psychedelics mainly bind to serotonin (5-HT) receptors, particularly 5-HT2A receptors, but may also bind to other receptors. Unlike conventional psychotropic drugs used in psychiatry, psychedelics introduce a distinctive complexity. They not only engage in receptor activation, but also exert influence over specific neural circuits, thereby facilitating transformative cognitive experiences and fostering what many have identified as a spiritual contemplation or mystical experience. This comprehensive review describes clinical studies that have examined the propensity of psychedelics to enhance spiritual, mystical, and transcendent cognitive states. This multifaceted nature, encompassing diverse components and paradigms, necessitates careful consideration during the investigation of psychedelic mechanisms of action to avoid oversimplification. The present review endeavours to elucidate the mechanisms underlying the actions of 2 principal psychedelic substances, psilocybin and lysergic acid diethylamide (LSD), with a focus on monoamine and glutamate receptor mechanisms; molecular aspects, such as neuroplasticity and epigenetics; as well as the impact of psychedelics on brain circuits, including the default mode network and the cortico-striato-thalamo-cortical network. Given their distinctive and intricate mechanisms of action, psychedelics necessitate a novel conceptual framework in psychiatry, offering insight into the treatment of mental health disorders and facilitating the integration of the realms of brain, mind, and spirituality.

Prevention of postoperative nausea and vomiting after cesarean delivery under neuraxial anesthesia and postpartum analgesia in Japan: A cross-sectional study.

This study aims to investigate the clinical practice of physicians working in obstetric setting toward postoperative nausea and vomiting (PONV) in parturients undergoing cesarean delivery (CD) with neuraxial anesthesia. We conducted this online survey to all active members of the Japan Society of Obstetric Anesthesiology and Perinatology (JSOAP), where leads academic society in obstetric anesthesia in Japan. The questionnaire was developed using the Delphi method. The survey included questions about routine practices for PONV prevention, the use of neuraxial opioids, optimal practices, and perceived obstacles. The email sent three times every 2 weeks as a reminder. A total of 1046 e-mails were sent, and 307 JSOAP members responded to the survey (29.3%). More than half of responders (62.7%) used neuraxial opioids with intrathecal morphine being the most frequent. They had a higher rate of multimodal PONV prophylaxis compared with who did not use neuraxial opioids for postoperative analgesia (19.9% vs 6.7%). Metoclopramide was the commonest medication for PONV prevention, and there was a significant difference in the use of 5-hydroxytryptamine receptor antagonists (19.9% vs. 8.6%, p = 0.012). We observed that 80% of physicians reported the routine administration of prophylaxis for PONV for CD. Among these, 20% indicated the use of two or more agents. Conversely, in the cohort not administering neuraxial opioids, only 6.7% reported the use of two or more agents. The online survey showed that the physicians using neuraxial opioids for CD had a higher proportion of multimodal PONV management involving two or more agents.

PSD-95 Protein: A Promising Therapeutic Target in Chronic Pain.

Chronic pain, as a social public health problem, has a serious impact on the quality of patients' life. Currently, the main drugs used to treat chronic pain are opioids, antipyretic, and nonsteroidal anti-inflammatory drugs (NSAIDs). But the obvious side effects limit their use, so it is urgent to find new therapeutic targets. Postsynaptic density (PSD)-95 protein plays an important role in the occurrence and development of chronic pain. The over-expression of the PSD-95 protein and its interaction with other proteins are closelyrelated to the chronic pain. Besides, the PSD-95-related drugs that inhibit the expression of PSD-95 as well as the interaction with other protein have been proved to treat chronic pain significantly. In conclusion, although more deep studies are needed in the future, these studies indicate that PSD-95 and the related proteins, such as NMDA receptor (NMDAR) subunit 2B (GluN2B), AMPA receptor (AMPAR), calmodulin-dependent protein kinase II (CaMKII), 5-hydroxytryptamine 2A receptor (5-HT2AR), and neuronal nitric oxide synthase (nNOS), are the promising therapeutic targets for chronicpain.

Experimental Validation of the Neurotrophic Factor-α1 Binding Site on the Serotonin Receptor 1E (HTR1E) Responsible for β-Arrestin Activation and Subsequent Neuroprotection.

Stress, such as neuroexcitotoxicity and oxidative stress, as well as traumatic brain injury, will result in neurodegeneration. Deciphering the mechanisms underlying neuronal cell death will facilitate the development of drugs that can promote neuronal survival and repair through neurogenesis. Many growth and trophic factors, including transforming growth factors (TGFs), insulin-like growth factors (IGFs), epidermal growth factor (EGF), fibroblast growth factor 2 (FGF2), and brain-derived neurotrophic factor (BDNF), are known to play a role in neuroprotection and neurogenesis. Neurotrophic factor-α1 (NF-α1), also known as carboxypeptidase E (CPE), has been shown experimentally to have neuroprotective activity, acting extracellularly, independent of its intracellular enzymatic function in prohormone processing. We previously reported experiments and molecular dynamics (MD) simulations showing that a 200 amino acid segment of NF-α1/CPE interacts with the serotonin receptor 1E (HTR1E) to protect human neurons against oxidative and neuroexcitotoxic stress via β-arrestin and extracellular signal-regulated kinase (ERK) signaling. We report here validation of our previously predicted binding site with a series of 16 carboxypeptidase E (CPE) mutants, identifying 3 mutants that substantially decrease the binding to HTR1E. We then carried out pERK studies to show that these 3 mutants also dramatically reduce β-arrestin activation. This was followed by MD simulations of 8 selected mutants, finding that the same 3 most dramatically reduced binding of the mutated CPE to 5-HTR1E. Then, we examined the binding of β-arrestin to these 3 (after phosphorylating the intracellular Ser and Thr) and found that the predicted binding decreased dramatically. Then, we examined the predicted activation of the β-arrestin by these 3 and found a dramatic decrease, just as in the pERK experiments. We consider that these experiments and simulations fully validate the predicted binding site for CPE, identifying the key amino acid residues critical for binding and biological activity. This provides the target for experiments and in silico computational screening to identify small molecules to replace the CPE protein as novel drugs to protect human neurons against oxidative/neuroexcitotoxic stress via β-arrestin/ERK signaling.

The interplay of serotonin 5-HT1A and 5-HT7 receptors in chronic stress.

Serotonin regulates multiple physiological and pathological processes in the brain, including mood and cognition. The serotonin receptors 5-HT1AR (also known as HTR1A) and 5-HT7R (also known as HTR7) have emerged as key players in stress-related disorders, particularly depression. These receptors can form heterodimers, which influence their functions. Here, we explored the developmental dynamics of 5-HT1AR and 5-HT7R expression and validated heterodimerization levels in the brain of control and stressed mice. In control animals, we found that there was an increase in 5-HT1AR expression over 5-HT7R in the prefrontal cortex (PFC) and hippocampus during development. Using a chronic unpredictable stress as a depression model, we found an increase in 5-HT7R expression exclusively in the PFC of resilient animals, whereas no changes in 5-HT1AR expression between control and anhedonic mice were obtained. Quantitative in situ analysis of heterodimerization revealed the PFC as the region exhibiting the highest abundance of 5-HT1AR-5-HT7R heterodimers. More importantly, upon chronic stress, the amount of heterodimers was significantly reduced only in PFC of anhedonic mice, whereas it was not affected in resilient animals. These results suggest an important role of brain-region-specific 5-HT1AR-5-HT7R heterodimerization for establishing depressive-like behaviour and for development of resiliency.

226 Serotonin stimulates relaxation in ovine saphenous vein precontracted with ergovaline

Abstract The predominant ergot alkaloid found in wild type endophyte-infected tall fescue grass is ergovaline. Ergovaline is a potent vasoconstrictor in livestock that consume it. Previous research has shown that ergovaline can bind serotonin (5-HT) receptors and blood vessels exposed to ergovaline become unresponsive to subsequent 5-HT exposure. Serotonin can stimulate vascular contraction or relaxation depending on the receptor subtype targeted. The objective of this experiment was to evaluate 5HT as vasorelaxant in the ovine saphenous artery and vein that were precontracted with ergovaline. Blood vessels were collected from mixed breed market rams (n = 7) at slaughter, cleaned of surrounding adipose and connective tissue, sliced into 2-mm cross-sections, and mounted in a multimyograph. Artery and vein cross-sections were equilibrated to 1 g tension in continuously gassed (95% O2/5% CO2) Krebs-Henseleit buffer (pH 7.4; 37.5 °C) for 90 min, precontracted with 1.0 μM ergovaline (in a tall fescue seed extract) for 30 min, exposed to increasing concentrations of 5-HT that ranged from 1 x 10-9 to 1 x 10-4 M for a 5-min interval. Response data were normalized to the 1.0 μM ergovaline response and were analyzed as a completely randomized design in SAS. The saphenous vein was larger in diameter blood vessel than the saphenous artery. Both vessel types contracted in response to exposure to 1 μM ergovaline. The saphenous artery had a much lower maximal response to ergovaline than did the vein (P < 0.05) that could be attributed to the size difference. The lateral saphenous vein relaxed to increasing concentrations of 5-HT (P < 0.05) with 87 % relaxation occurring by 1 x 10-6 M 5-HT. Conversely, the lateral saphenous artery contracted in response to increasing concentrations of 5-HT (P < 0.05) resulting in a 43% increase from the ergovaline response by the 1 x 10-4 M addition. This response did not become significant in the artery until 1 x 10-5 M 5-HT compared with 1 x 10-8 M for the vein. This resulted in a 50% effective concentration for 5-HT in the artery of 4.5 compared with 8.1 M for the vein (P < 0.05). The differing responses across vessels are likely a result of different receptor populations and this should be verified in future research. This is the first reported observation of stimulated relaxation of a blood vessel constricted ergovaline. Additional research is needed to understand the mechanism of how 5HT can be used to stimulate vasorelaxation in livestock suffering from ergot alkaloid-induced vasoconstriction.

Recent Development of Zolmitriptan Formulation in Migraine Therapy: Production, Metabolism and Pharmaceutical Aspects.

The triptans class of pharmaceuticals, which was created to treat acute migraine, is made up of indole-containing drugs that bind to a subset (1B/1D) of 5-hydroxytryptamine receptors and are agonists of serotonin receptors. At the moment, naratriptan, eletriptan, zolmitriptan, rizatriptan, almotriptan, and frovatriptan are the seven types of triptans available on the market. Among these are the FDA-approved triptans, Zolmitriptan and Sumatriptan, which are selective serotonin (5-hydroxytryptamine) agonists. Zolmitriptan, a synthetic tryptamine derivative and a well-known member of the triptan family, is available as an orally disintegrating tablet, nasal spray, and tablet. There are melt formulations of rizatriptan and zolmitriptan available on the market that are easier to use and absorb, comparable to regular pills. Recently, the FDA approved zolmitriptan, a medication with tolerability comparable to sumatriptan. Whereas zolmitriptan is only available as an oral melt or tablet, sumatriptan is available as a nasal spray, oral preparation, or self-injectable kit. The only known antimigraine drugs that were widely utilized before the triptan period were ergotamine and dihydroergotamine. However, zolmitriptan binds to plasma proteins only 25% of the time because of significant first-pass degradation. Researchers have looked into fresh ideas for solving this issue and innovations to overcome its pharmacokinetic difficulties. This article emphasizes the role of zolmitriptan in the treatment of migraines, highlighting its pharmacological properties, production, metabolism, and structural features.

B - 61 Psilocybin as a First-Line Treatment of ADHD in Adult Populations

Abstract Objectives The first line for symptom management of attention deficit hyperactivity disorder (ADHD) is a class of medications that act on dopamine and noradrenaline receptors, which leads to symptom reduction at the cost of significant side effects. These side effects have led to community searching for alternative methods that manage ADHD symptoms in adults that lead to less side effects. Microdosing Psilocybin has emerged as a course of treatment that could provide benefits for those who may experience serious side effects to stimulant medication. Method This literature review was conducted using search terms such as, ADHD attention deficit hyperactivity disorder, psychedelic treatment, stimulant treatment of ADHD, naturalistic treatment of ADHD, 5-HT, neural plasticity. Journals that reported about the benefits and concerns of Psilocybin use for ADHD are Neurochemistry International, American College of Neuropharmacology, European Psychology, Movement and Nutrition in Health and Disease, Journal of Psychopharmacology, and Psychiatry Research. Results Research shows that not only does microdosing Psilocybin have less adverse effects than stimulant medications when being used to treat ADHD, but it also leads to an alternative method that focuses on serotonin receptors when other avenues are unsuccessful. Conclusions This poster illustrates the alternative use of Psilocybin for treatment in ADHD and highlights neurological underpinnings that may lead to explaining success. Limitations of stimulant medications are also reviewed.

Postprandial metabolomics analysis reveals disordered serotonin metabolism in post-bariatric hypoglycemia.

Bariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1 to 3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin. To identify mediators of disordered metabolism in PBH, we analyzed plasma metabolome in fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH (n = 13), asymptomatic post-RYGB (n = 10), and non-surgical controls (n = 8). In the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone beta-hydroxybutyrate were increased by 30% to 80% in PBH vs. asymptomatic. Conversely, multiple amino acids (BCAA, tryptophan) and polyunsaturated lipids were reduced by 20% to 50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced by 2- to 10-fold in PBH in fasting state. Postprandially, plasma serotonin was uniquely increased by 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin. Together these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target. NIH grant R01 DK121995, NIH grant P30 DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP grant 2018/22111-2.

Serotonergic modulation of swallowing in a complete fly vagus nerve connectome

How the body interacts with the brain to perform vital life functions, such as feeding, is a fundamental issue in physiology and neuroscience. Here, we use a whole-animal scanning transmission electron microscopy volume of Drosophila to map the neuronal circuits that connect the entire enteric nervous system to the brain via the insect vagus nerve at synaptic resolution. We identify a gut-brain feedback loop in which Piezo-expressing mechanosensory neurons in the esophagus convey food passage information to a cluster of six serotonergic neurons in the brain. Together with information on food value, these central serotonergic neurons enhance the activity of serotonin receptor 7-expressing motor neurons that drive swallowing. This elemental circuit architecture includes an axo-axonic synaptic connection from the glutamatergic motor neurons innervating the esophageal muscles onto the mechanosensory neurons that signal to the serotonergic neurons. Our analysis elucidates a neuromodulatory sensory-motor system in which ongoing motor activity is strengthened through serotonin upon completion of a biologically meaningful action, and it may represent an ancient form of motor learning.

Proteome and Metabolome Profiling of Anticoagulant Disorders Induced by Familial Protein S Deficiency.

Protein S deficiency (PSD) is an autosomal dominant disorder characterized by congenital thrombophilia. Studies on PSD are limited yet, resulting in a lack of clarity about molecular changes during abnormal coagulation. Proteomics and metabolomics analyses were conducted on the plasma of PSD patients based on liquid and gas chromatography-mass spectrometry (LC- and GC-MS). Differential proteins and metabolites of PSD were then filtered by univariate statistical analysis and subjected to network analysis using the ingenuity pathway analysis (IPA) platform. The proteome and metabolome of PSD were obviously disturbed, and the biological pathway of coagulation and complement cascades was the most affected. During PSD, overall levels of anticoagulant protein decreased and negative regulation of thrombin production was reduced, causing the formation of fibrin clots and platelet aggregation. Furthermore, 9 differential proteins correlated significantly with protein S, comprising A2M, AGT, APOE, FGG, GPLD1, IGHV1-69, CFHR5, CPN2, and CA1. The biological networks suggested that the pathways of acute phase response, FXR/RXR activation, serotonin receptor signaling, and p70S6K signaling were associated with PSD, indicating an interaction disorder of inflammatory immune and lipid metabolism. The findings may contribute to knowledge of available functional molecules and biological pathways of familial PSD and help with treatment improvement. Data are available via ProteomeXchange with identifier PXD055111 and MetaboLights with reference number MTBLS2653.

Environmental fluoxetine promotes skin cell proliferation and wound healing

This study investigates the effects of environmentally-relevant concentrations of fluoxetine (FLX, commercial name: Prozac) on wound healing. Pollution of water systems with pharmaceutical and personal care products, including antidepressants such as FLX and other selective serotonin reuptake inhibitors, is a growing environmental concern. Environmentally-relevant FLX concentrations are known to impact physiological functions and behaviour of aquatic animals, however, the effects of exposure on humans are currently unknown. Using a combination of human skin biopsies and a human keratinocyte cell line, we show that exposure to environmental FLX promotes wound closure. We show dose-dependent increases in wound closure with FLX concentrations from 125 ng/l. Using several –omics and pharmaceutical approaches, we demonstrate that the mechanisms underlying enhanced wound closure are increased cell proliferation and serotonin signalling. Transcriptomic analysis revealed 350 differentially expressed genes after exposure. Downregulated genes were enriched in pathways related to mitochondrial function and metabolism, while upregulated genes were associated with cell proliferation and tissue morphogenesis. Kinase profiling showed altered phosphorylation of kinases linked to the MAPK pathway. Consistent with this, phosphoproteomic analyses identified 235 differentially phosphorylated proteins after exposure, with enriched GO terms related to cell cycle, division, and protein biosynthesis. Treatment of skin biopsies and keratinocytes with ketanserin, a serotonin receptor antagonist, reversed the increase in wound closure observed upon exposure. These findings collectively show that exposure to environmental FLX promotes wound healing through modulating serotonin signalling, gene expression and protein phosphorylation, leading to enhanced cell proliferation. Our results justify a transition from the study of behavioural effects of environmental FLX in aquatic animals to the investigation of effects of exposure on wound healing in aquatic and terrestrial animals, including direct impacts on human health.

Mental disorders of the depressive and anxiety spectrum in neuroendocrine tumors: prevalence, pathogenesis, clinical particulars

Neuroendocrine tumors (NETs) are a heterogeneous group of slowly progressing tumors from neuroendocrine cells able to secrete biologically active substances. The most striking clinical manifestation of functioning NETs is the carcinoid syndrome, which is caused by serotonin overproduction and is most often associated with hot flashes, diarrhea, and abdominal pain. The prevalence of depressive and anxiety spectrum disorders in NETs patients can amount to 30–50%. The development of depressive and anxiety spectrum disorders in NETs can occur both through a nosogenic mechanism facilitated by a long pre-diagnostic stage, the presence of a serious disease with severe somatic symptoms and resulting significant decrease in quality of life. The mental disorders may be a result of somatogenic factors, which include an imbalance of significant mediators in the central nervous system (in particular, serotonin), as well as chronic inflammation and abnormalities of the body's immune defense. In the treatment of patients with NETs and verified anxiety and depressive disorders, special attention is paid to the safety of prescribing the first-line therapy, the selective serotonin reuptake inhibitors. The side effects of these agents are related to the activity of serotonin receptor agonists in the gut, which results in diarrhea and increased gastrointestinal motility, the symptoms similar to the carcinoid syndrome manifestations. The accumulated evidence allows concluding on the relative safety of serotoninergic antidepressants in NETs patients, but does not exclude some groups of patients with an increased risk of complications related to an additional effect on serotonin metabolism. Current knowledge on the prevalence, pathogenesis and treatment of depressive and anxiety spectrum disorders, comorbid to NETs, are limited and contradictory. Therefore, further studies with a larger patient samples are required to identify key factors of the pathophysiology and manifestation of mental disorders in NETs patients, which would generally facilitate the optimization of their treatment.

Mesocorticolimbic and Cardiometabolic Diseases-Two Faces of the Same Coin?

The risk behaviors underlying the most prevalent chronic noncommunicable diseases (NCDs) encompass alcohol misuse, unhealthy diets, smoking and sedentary lifestyle behaviors. These are all linked to the altered function of the mesocorticolimbic (MCL) system. As the mesocorticolimbic circuit is central to the reward pathway and is involved in risk behaviors and mental disorders, we set out to test the hypothesis that these pathologies may be approached therapeutically as a group. To address these questions, the identification of novel targets by exploiting knowledge-based, network-based and disease similarity algorithms in two major Thomson Reuters databases (MetaBase™, a database of manually annotated protein interactions and biological pathways, and IntegritySM, a unique knowledge solution integrating biological, chemical and pharmacological data) was performed. Each approach scored proteins from a particular approach-specific standpoint, followed by integration of the scores by machine learning techniques yielding an integrated score for final target prioritization. Machine learning identified characteristic patterns of the already known targets (control targets) with high accuracy (area under curve of the receiver operator curve was ~93%). The analysis resulted in a prioritized list of 250 targets for MCL disorders, many of which are well established targets for the mesocorticolimbic circuit e.g., dopamine receptors, monoamino oxidases and serotonin receptors, whereas emerging targets included DPP4, PPARG, NOS1, ACE, ARB1, CREB1, POMC and diverse voltage-gated Ca2+ channels. Our findings support the hypothesis that disorders involving the mesocorticolimbic circuit may share key molecular pathology aspects and may be causally linked to NCDs, yielding novel targets for drug repurposing and personalized medicine.

Discovery of tetrahydro γ-carboline based novel glucose uptake agent for the treatment of diabetes and Alzheimer’s diseases

The emergence of diabetes mellitus (DM), one of the prevalent metabolic disorders, has increased at alarming rates around the globe in the past few decades. The early discovery of insulin paved the way for the broadened non-invasive anti-hyperglycemic drug therapies to manage and treat diabetes. Recently, insulin resistance in brain tissues has been considered a new hallmark of disease progression, leading to neurodegeneration. Tetrahydro γ-carbolines are privileged scaffolds with various activities against obesity, cancer, and central nervous system (CNS) diseases. The failure of Latrepirdine in clinical phase trials as anti-AD, prompted us to explore further the γ-Carboline derivatives with anti-diabetic activity. To address this, we have leveraged our expertise in drug design to develop tetrahydro γ-carboline derivatives and studied their effect on glucose uptake. All the compounds exhibited low cytotoxicity towards the mammalian cell line 3T3-L1. Next, we screened the 10 derivatives to identify the novel anti-diabetic activities using a fluorescent glucose analog 2-NBDG (2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)-2-deoxy-D-glucose) based on a glucose-uptake assay in differentiated 3T3-L1 adipocytes. Compound 11a has significantly increased glucose uptake at 100 µM compared to rH-Insulin. The dose optimization (1 nM-100 nM) of lead compounds for 2-NBDG-glucose uptake clearly indicated that 11a is superior compared to Insulin. The 11a is the close analog of Latrepirdine, an anti-histamine drug, reported for Alzheimer disease (AD). Further, to understand its anti-AD potential we carried out in silico docking studies with its probable targets, Acetylcholinesterase (AChE), 5-hydroxytryptamine (5HT6) receptor, Butyrylcholinesterase (BChE), and N-methyl-D-aspartate (NMDA) receptor. The docking studies revealed that 11a had stronger binding to these targets than Latrepirdine, correlating with the glucose uptake assay. Thus, 11a is a potential lead disease-modifying agent and could be considered for the management and treatment of type 2 DM and AD.

Fkbp5 gene deletion: Circadian rhythm profile and brain proteomics in aged mice.

FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub-anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel-running activity, but did offer protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal-cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51-focused therapeutics for stress-related disorders.

Morpho-physiological Diversity of Cholecystokinin-expressing Interneurons in the Dentate Gyrus.

The hippocampus plays a crucial role in learning, memory, and emotion, with the dentate gyrus (DG) serving as the primary gateway. The DG receives multimodal sensory inputs from outside the hippocampus and relays this integrated information to downstream regions for further processing. Within the DG, inhibitory GABAergic interneurons (INs) regulate information processing, thereby influencing the overall hippocampal function. Cholecystokinin (CCK)-expressing INs in the DG are particularly implicated in emotional behavior due to their expression of cannabinoid and serotonin receptors. However, studying the morpho-electrophysiological features and functions of these INs has been challenging due to the off-target labeling of granule cells (GCs), the primary excitatory neurons in the DG, when using the CCK recombinase driver line. To address this issue, we employed an intersectional strategy to selectively label CCK INs, allowing us to investigate their electrophysiological, morphological, and synaptic features, which were further confirmed by post hoc pro-CCK immunostaining. Our analysis identified nine distinct subtypes of CCK INs, each with unique projection patterns targeting specific domains along the axo-somato-dendritic axis of GCs. CCK INs also exhibited diverse passive intrinsic properties and firing patterns. In addition, we found that CCK INs generate action potentials before GCs in response to cortical input, suggesting that they play a role in modulating GC input-output transformation. In summary, our findings indicate that DG CCK INs are diverse subpopulations with distinct roles in network functions.

Concept article: Antidepressant-induced destabilization in bipolar illness mediated by serotonin 3 receptor (5HT3).

Antidepressants used by patients with bipolar disorder have been associated with destabilization with an increase in mania, depression, and cycling. The most commonly proposed mechanism, that antidepressants 'overshoot' their antidepressant effect to create a manic or mixed state, is unlikely since antidepressants have actually been found to be ineffective in treating bipolar depression. Beginning with known bipolar-specific pathophysiologic abnormalities provides the greatest likelihood of insight. PubMed was queried with 'bipolar', 'sodium', 'intracellular sodium', 'serotonin 3', '5HT3', '5-hydroxytryptamine type 3 receptors', and 'antidepressant' either individually or in combination. Pathologic mood states (both mania and depression) are associated with increased intracellular sodium (Na) concentrations that depolarize the resting membrane potential to increase cellular excitability (mania) or cause depolarization block (depression). Stimulation of the serotonin (5HT) receptors depolarizes the post-synaptic neuron. Stimulation of 5HT3 may be of particular importance since it is coupled to a cation channel that directly depolarizes the membrane. These effects directly impact the physiology of patients with bipolar disorder to alter neuronal excitability in a fashion that worsens both mania and depression. The most consistently observed biological abnormality in individuals going through mania or bipolar depression involves a decline in Na pump activity, with consequent elevation of intracellular Na levels. Antidepressant treatment potentiates this, particularly by activation of 5HT3. This hypothesis can be tested by coadministering a 5HT3 antagonist (e.g., vortioxetine or ondansetron) to achieve blockade of that receptor while treating bipolar depression with a serotoninergic antidepressant.

A nondestructive membrane engineering method using an amphiphilic polymer.

The cellular signaling process or ion transport is mediated by membrane proteins (MPs) located on the cell surface, and functional studies of MPs have mainly been conducted using cells endogenously or transiently expressing target proteins. Reconstitution of purified MPs in the surface of live cells would have advantages of short manipulation time and ability to target cells in which gene transfection is difficult. However, direct reconstitution of MPs in live cells has not been established. The traditional detergent-mediated reconstitution method of MPs into a lipid bilayer cannot be applied to live cells because this disrupts and reforms the lipid bilayer structure, which is detrimental to cell viability. In this study, we demonstrated that GPCRs (prostaglandin E2 receptor 4 [EP4] and glucagon-like peptide-1 receptor [GLP1R]) or serotonin receptor 3A (5HT3A), a ligand-gated ion channel, stabilized with amphiphilic poly-γ-glutamate (APG), can be reconstituted into mammalian cell plasma membranes without affecting cell viability. Furthermore, 5HT3A reconstituted in mammalian cells showed ligand-dependent Ca2+ ion transport activity. APG-mediated reconstitution of GPCR in synthetic liposomes showed that electrostatic interaction between APG and membrane surface charge contributed to the reconstitution process. This APG-mediated membrane engineering method could be applied to the functional modification of cell membranes with MPs in live cells.