The association of T102C (rs6313) polymorphism in the 5-HT2A receptor gene with temporomandibular disorders and anxiety in a group of Turkish population.

OBJECTIVE: To investigate the relationship between T102C (rs6313) polymorphism in the 5-hydroxytryptamine receptor-2A (5HTR2A) gene and temporomandibular disorder (TMD) and anxiety. METHODS: This observational case-control study included 80 patients and 70 healthy controls. TMD was diagnosed using the criteria for TMD (DC/TMD). Anxiety was assessed with the Beck anxiety scale. A genotyping study of HTRR2A T102C (rs6313) gene polymorphism was performed from genomic DNA isolated from blood. RESULTS: The TMD group had higher anxiety scores than the control group (p < .05). The TMD group was similar to the control group regarding genotype and allele frequencies. However, the polymorphic CC genotype was more common in those with high anxiety (p < .05). CONCLUSION: There was no clear evidence of an association between TMD and the T102C polymorphism in HTR2A and TMD. However, anxiety is closely related to the T102C polymorphism in HTR2A.

Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

Association of serotonin receptor gene polymorphisms with anorexia nervosa: a systematic review and meta-analysis.

PURPOSE: Several studies have investigated the association between anorexia nervosa and polymorphisms of genes regulating serotonin neurotransmission, with a focus on the rs6311 polymorphism of 5-HTR2A. However, inconsistent results of these studies and conflicting conclusions of existing meta-analyses complicate the understanding of a possible association. We have updated these results and evaluated the involvement of other serotonin receptor gene polymorphisms in anorexia nervosa. METHODS: Adhering to PRISMA guidelines, we have searched studies on anorexia nervosa and serotonin-regulating genes published from 1997 to 2022, selected those concerning receptor genes and meta-analyzed the results from twenty candidate gene studies on the 5-HTR2A rs6311 polymorphism and the 5-HTR2C rs6318 polymorphism. RESULTS: Present analyses reveal an association for the 5-HTR2A rs6311 polymorphism, with G and A alleles, across eighteen studies (2049 patients, 2877 controls; A vs. G allele, Odds Ratio = 1.24; 95% Confidence Interval = 1.06-1.47; p = 0.009). However, after geographic subgrouping, an association emerged only in a Southern European area, involving five studies (722 patients, 773 controls; A vs. G allele, Odds Ratio = 1.82; 95% Confidence Interval = 1.41-2.37; p < 0.00001). No association was observed for the 5-HTR2C rs6318 polymorphism across three studies. CONCLUSIONS: To date, the involvement in the pathophysiology of anorexia nervosa of the 5-HTR2A rs6311 polymorphism appears limited to a specific genetic and/or environmental context, while that of the 5-HTR2C rs6318 polymorphism seems excluded. Genome-wide association studies and epigenetic studies will likely offer deeper insights of genetic and environmental factors possibly contributing to the disorder. LEVEL OF EVIDENCE: III Evidence obtained from well-designed cohort or case-control analytic studies. Clinical trial registration PROSPERO registration number: CRD42021246122.

Revealing receptor-ligand interactions of atypical antipsychotic drugs and screening anti-schizophrenia ingredients in Magnolia officinalis based on 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models.

Schizophrenia is a serious mental illness with unknown etiology, and shows increasing incidence and high lifetime prevalence rate. The main receptors related to the disease are DRD2 and 5-HTR2A. Thus, a comprehensive understanding of the interaction mode between antipsychotic drugs with relevant receptors is very important for developing more effective drugs. 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models constructed in this work provided a new method for studying the interaction between atypical antipsychotics and the two receptors. The results of comparative experiments showed that the new models not only met the high selectivity and specificity of the screening requirements but were also more stable and long-lasting than the traditional CMC model. Binding assays showed that the effects of three atypical antipsychotics (including clozapine, olanzapine, and quetiapine) on 5-HTR2A were stronger than their effects on DRD2. Additionally, two potentially active components, magnolol and honokiol, were screened in Magnolia officinalis methanol extract using the 5-HTR2A-SNAP-Tag/CMCHPLC-MS system. Nonlinear chromatographic analysis and molecular docking were conducted to study the interactions between screened compounds and the two receptors. The binding constants (KA) of magnolol and honokiol with 5-HTR2A were 17,854 ± 1,117 M-1 and 38,858 ± 4,964 M-1, respectively, and KA values with DRD2 were 4,872 ± 1,618 M-1 and 20,692 ± 10,267 M-1, respectively. We concluded that the established models are reliable for studying receptor-ligand interactions and screening antagonists of schizophrenia.

CX3CR1 mediates motor dysfunction in mice through 5-HTR2a.

CX3CR1 knockout could induce motor dysfunction in several neurological disease models mainly through regulating microglia's function. While CX3CR1 was expressed on neurons in a few reports, whether neuronal CX3CR1 could affect the function of neurons and mediate motor dysfunction under physiological conditions is unknown. To elucidate the roles of neuronal CX3CR1 on motor dysfunction, CX3CR1 knockout mice were created. Rotarod test and Open field test found that the CX3CR1-/- mice's motor capacity was reduced. Immunofluorescence staining detected the expression of CX3CR1 in neurons both in vivo and in vitro. Immunohistochemistry and West blot found that knockout of CX3CR1 did not affect the neurons' number in both spinal cord and brain of mice. While inhibiting the function of CX3CR1 by AZD8797 could decrease the expression of 5-Hydroxytryptamine receptor(5-HTR2a), which involved in the regulation of motor function. Further investigation revealed that CX3CR1 regulated the expression of HTR2a through the NF-κB pathway. For the first time, we reported that neuronal CXCR1 mediates motor dysfunction. Our results suggest that modulating CXCR1 activity offers a novel therapeutic strategy for motor dysfunction.

Association between the rs6313 polymorphism in the 5-HTR2A gene and the efficacy of antipsychotic drugs.

BACKGROUND: Prescribing the optimal antipsychotic treatment to schizophrenia is very important as it is well established that patients have different sensitivity to the available antipsychotic drugs. The genotype of the HTR2A T102C (rs6313) polymorphism has been suggested to affect the efficacy of antipsychotic drugs, but the results of different studies have been inconsistent METHODS: In this study, a meta-analysis was used to ascertain the association between allele and genotype polymorphism of rs6313 and the efficacy of antipsychotic drugs. Related studies publicated from January 1995 to December 2021 were retrieved from PubMed, Embase, ScienceDirect, and Web of Science databases. The correlations between allele and genotype polymorphism of rs6313 and the responder rate and scale score reduction rate of antipsychotics were analyzed. In addition, subgroup analyses were performed on time, drug, and ethnicity. RESULTS: A total of 18 studies were included. The meta-analysis showed that allele and genotype polymorphisms at the rs6313 locus overall were not associated with antipsychotic drug responder rate or scale score reduction rate. Ethnicity subgroup analysis showed that antipsychotic drugs were more effective in patients with allele T in the Caucasian population. Indian patients with the TT genotype had the lowest scale score reduction rate and poor drug treatment effect. East Asian patients with the TC genotype had better treatment effect, whereas in patients with the CC genotype, the treatment was less effective. Drug subgroup analysis showed that patients with the TC genotype treated with clozapine had the highest responder rate and score reduction rate. CONCLUSIONS: The association between rs6313 polymorphism and the efficacy of antipsychotic drugs is mainly influenced by drug and ethnicity. Caucasian patients with the T allele respond better to drug therapy, and Asian patients with TC genotype. The TC genotype was also a good predictor of the efficacy of clozapine treatment.

The discovery, structure, and function of 5-HTR1E serotonin receptor.

Serotonin (5-hydroxytryptamine, 5-HT) is a unique neurotransmitter which can regulate various biological processes by activating thirteen different receptors. These serotonin receptors are divided into seven different classes based on their structure and functions. Since these receptors co-express in various tissue and cell types and share the same ligand (5-HT), it has been a challenge for the researchers to define specific pathway and separate physiological role for each of these serotonin receptors. Though the evidence of operational diversity of these receptors is continuously emerging, much work remains to be done. 5-HTR1E is a member of 5-HT1 receptor family which belongs to G-protein coupled receptors (GPCRs). Even after three decades since its discovery, 5-HTR1E remains the least explored serotonin receptor. Very high similarity with another family member (5-HTR1F) and its non-existence in mice or rats makes 5-HTR1E a difficult target to study. Despite these challenges, recent findings on the role of 5-HTR1E in neuroprotection and diseases such as cancer, have excited many researchers to explore this receptor in detail. Here, we provide the first review of 5-HTR1E, since its discovery in 1989 to 2023. We highlight the structural and functional characteristics of this important serotonin receptor in detail and propose future directions in developing 5-HTR1E as a drug target. Video Abstract.

Activation of the 5-hydroxytryptamine 4 receptor ameliorates tight junction barrier dysfunction in the colon of type 1 diabetic mice.

Hyperglycemia drives dysfunction of the intestinal barrier. 5-Hydroxytryptaine 4 receptor (5-HT 4R) agonists have been considered therapeutics for constipation in clnic. However, the roles of 5-HT 4R activation in mucosa should be fully realized. Here, we investigate the effects of 5-HT 4R activation on diabetes-induced disruption of the tight junction (TJ) barrier in the colon. Not surprisingly, the TJ barrier in diabetic mice with or without 5-HT 4R is tremendously destroyed, as indicated by increased serum fluorescein isothiocyanate (FITC)-dextran and decreased transepithelial electrical resistance (TER). Simultaneously, decreased expressions of TJ proteins are shown in both wild-type (WT) and 5-HT 4R knockout (KO) mice with diabetes. Notably, chronic treatment with intraperitoneal injection of a 5-HT 4R agonist in WT mice with diabetes repairs the TJ barrier and promotes TJ protein expressions, including occludin, claudin-1 and ZO-1, in the colon, whereas a 5-HT 4R agonist does not improve TJ barrier function or TJ protein expressions in 5-HT 4R KO mice with diabetes. Furthermore, stimulation of 5-HT 4R inhibits diabetes-induced upregulation of myosin light chain kinase (MLCK), Rho-associated coiled coil protein kinase 1 (ROCK1), and phosphorylated myosin light chain (p-MLC), which are key molecules that regulate TJ integrity, in the colonic mucosa of WT mice. However, such action induced by a 5-HT 4R agonist is not observed in 5-HT 4R KO mice with diabetes. These findings indicate that 5-HT 4R activation may restore TJ integrity by inhibiting the expressions of MLCK, ROCK1 and p-MLC, improving epithelial barrier function in diabetes.

Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling.

The mTORC1 nutrient-sensing pathway integrates metabolic and endocrine signals into the brain to evoke physiological responses to food deprivation, such as autophagy. Nevertheless, the impact of neuronal mTORC1 activity on neuronal circuits and organismal metabolism remains obscure. Here, we show that mTORC1 inhibition acutely perturbs serotonergic neurotransmission via proteostatic alterations evoked by the autophagy inducer atg1. Neuronal ATG1 alters the intracellular localization of the serotonin transporter, which increases the extracellular serotonin and stimulates the 5HTR7 postsynaptic receptor. 5HTR7 enhances food-searching behaviour and ecdysone-induced catabolism in Drosophila. Along similar lines, the pharmacological inhibition of mTORC1 in zebrafish also stimulates food-searching behaviour via serotonergic activity. These effects occur in parallel with neuronal autophagy induction, irrespective of the autophagic activity and the protein synthesis reduction. In addition, ectopic neuronal atg1 expression enhances catabolism via insulin pathway downregulation, impedes peptidergic secretion, and activates non-cell autonomous cAMP/PKA. The above exert diverse systemic effects on organismal metabolism, development, melanisation, and longevity. We conclude that neuronal atg1 aligns neuronal autophagy induction with distinct physiological modulations, to orchestrate a coordinated physiological response against reduced mTORC1 activity.

Understanding the Molecular Regulation of Serotonin Receptor 5-HTR1B-ß-Arrestin1 Complex in Stress and Anxiety Disorders.

The serotonin receptor subtype 5-HTR1B is widely distributed in the brain with an important role in various behavioral implications including neurological conditions and psychiatric disorders. The neuromodulatory action of 5-HTR1B largely depends upon its arrestin mediated signaling pathway. In this study, we tried to investigate the role of unusually long intracellular loop 3 (ICL3) region of the serotonin receptor 5-HTR1B in interaction with ß-arrestin1 (Arr2) to compensate for the absence of the long cytoplasmic tail. Molecular modeling and docking tools were employed to obtain a suitable molecular conformation of the ICL3 region in complex with Arr2 which dictates the specific complex formation of 5-HTR1B with Arr2. This reveals the novel molecular mechanism of phosphorylated ICL3 mediated GPCR-arrestin interaction in the absence of the long cytoplasmic tail. The in-cell disulfide cross-linking experiments and molecular dynamics simulations of the complex further validate the model of 5-HTR1B-ICL3-Arr2 complex. Two serine residues (Ser281 and Ser295) within the 5-HTR1B-ICL3 region were found to be occupying the electropositive pocket of Arr2 in our model and might be crucial for phosphorylation and specific Arr2 binding. The alignment studies of these residues showed them to be conserved only across 5-HTR1B mammalian species. Thus, our studies were able to predict a molecular conformation of 5-HTR1B-Arr2 and identify the role of long ICL3 in the signaling process which might be crucial in designing targeted drugs (biased agonists) that promote GPCR-Arr2 signaling to deter the effects of stress and anxiety-like disorders.

On the construction of LIECE models for the serotonin receptor 5-HT[Formula: see text]R.

Computer-aided approaches to ligand design need to balance accuracy with speed. This is particularly true for one of the key parameters to be optimized during ligand development, the free energy of binding ([Formula: see text]G[Formula: see text]). Here, we developed simple models based on the Linear Interaction Energy approximation to free energy calculation for a G protein-coupled receptor, the serotonin receptor 2A, and critically evaluated their accuracy. Several lessons can be taken from our calculations, providing information on the influence of the docking software used, the conformational state of the receptor, the cocrystallized ligand, and its comparability to the training/test ligands.

The therapeutic mechanism of Curcumae Radix against primary dysmenorrea based on 5-HTR/Ca2+/MAPK and fatty acids metabolomics.

Background: Curcumae Radix (CW) is traditionally used to treat primary dysmenorrea (PD). However, the mechanisms of action of CW in the treatment of PD have not yet been comprehensively resolved. Objective: To investigate the therapeutic effects of CW on PD and its possible mechanisms of action. Methods: An isolated uterine spastic contraction model induced by oxytocin was constructed in an in vitro pharmacodynamic assay. An animal model of PD induced by combined estradiol benzoate and adrenaline hydrochloride-assisted stimulation was established. After oral administration of CW, a histopathological examination was performed and biochemical factor levels were measured to evaluate the therapeutic effect of CW on PD. The chemical compositions of the drug-containing serum and its metabolites were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Network pharmacology and serum untargeted metabolomics were used to predict the mechanism of CW treatment for PD, and the predicted results were validated by RT-qPCR, WB, and targeted fatty acid (FA) metabolism. Results: In vitro, CW can relax an isolated uterus by reducing uterine motility. In vivo, the results showed that CW attenuated histopathological damage in the uterus and regulated PGF2α, PGE2, ß-EP, 5-HT, and Ca2+ levels in PD rats. A total of 66 compounds and their metabolites were identified in the drug-containing serum, and the metabolic pathways of these components mainly included hydrogenation and oxidation. Mechanistic studies showed that CW downregulated the expression of key genes in the 5-HTR/Ca2+/MAPK pathway, such as 5-HTR2A, IP3R, PKC, cALM, and ERK. Similarly, CW downregulated the expression of key proteins in the 5-HTR/Ca2+/MAPK pathway, such as p-ERK/ERK. Indirectly, it ameliorates the abnormal FA metabolism downstream of this signaling pathway in PD rats, especially the metabolism of arachidonic acid (AA). Conclusion: The development of PD may be associated with the inhibition of the 5-HTR/Ca2+/MAPK signaling pathway and FA metabolic pathways, providing a basis for the subsequent exploitation of CW.

Identification and Characterization of 5-HT Receptor 1 from Scylla paramamosain: The Essential Roles of 5-HT and Its Receptor Gene during Aggressive Behavior in Crab Species.

Biogenic amines (BAs) play an important role in the aggressive behavior of crustaceans. In mammals and birds, 5-HT and its receptor genes (5-HTRs) are characterized as essential regulators involved in neural signaling pathways during aggressive behavior. However, only one 5-HTR transcript has been reported in crabs. In this study, the full-length cDNA of the 5-HTR1 gene, named Sp5-HTR1, was first isolated from the muscle of the mud crab Scylla paramamosain using the reverse-transcription polymerase chain reaction (RT-PCR) and rapid-amplification of cDNA ends (RACE) methods. The transcript encoded a peptide of 587 amino acid residues with a molecular mass of 63.36 kDa. Western blot results indicate that the 5-HTR1 protein was expressed at the highest level in the thoracic ganglion. Furthermore, the results of quantitative real-time PCR show that the expression levels of Sp5-HTR1 in the ganglion at 0.5, 1, 2, and 4 h after 5-HT injection were significantly upregulated compared with the control group (p < 0.05). Meanwhile, the behavioral changes in 5-HT-injected crabs were analyzed with EthoVision. After 0.5 h of injection, the speed and movement distance of the crab, the duration of aggressive behavior, and the intensity of aggressiveness in the low-5-HT-concentration injection group were significantly higher than those in the saline-injection and control groups (p < 0.05). In this study, we found that the Sp5-HTR1 gene plays a role in the regulation of aggressive behavior by BAs, including 5-HT in the mud crab. The results provide reference data for the analysis of the genetic mechanism of aggressive behaviors in crabs.

Nano Parthenolide Improves Intestinal Barrier Function of Sepsis by Inhibiting Apoptosis and ROS via 5-HTR2A.

Background: Intestinal barrier dysfunction is an important complication of sepsis, while the treatment is limited. Recently, parthenolide (PTL) has attracted much attention as a strategy of sepsis, but whether nano parthenolide (Nano PTL) is therapeutic in sepsis-induced intestinal barrier dysfunction is obscured. Methods: In this study, cecal ligation and puncture (CLP)-induced sepsis rats and lipopolysaccharide (LPS)-stimulated intestinal epithelial cells (IECs) were used to investigate the effect of PTL on intestinal barrier dysfunction. Meanwhile, we synthesized Nano PTL and compared the protective effect of Nano PTL with ordinary PTL on intestinal barrier function in septic rats and IECs. Network pharmacology and serotonin 2A (5-HTR2A) inhibitor were used to explore the mechanism of PTL on the intestinal barrier function of sepsis. Results: The encapsulation rate of Nano PTL was 95±1.5%, the drug loading rate was 11±0.5%, and the average uptake rate of intestinal epithelial cells was 94%. Ordinary PTL and Nano PTL improved the survival rate and survival time of septic rats, reduced the mean arterial pressure and the serum level of inflammatory cytokines, and protected the liver and kidney functions in vivo, and increased the value of transmembrane resistance (TEER) reduced the reactive oxygen species (ROS) and apoptosis in IECs in vitro through 5-HTR2A. Nano PTL had better effect than ordinary PTL. Conclusion: Ordinary PTL and Nano PTL can protect the intestinal barrier function of septic rats by inhibiting apoptosis and ROS through up-regulating 5-HTR2A, Nano PTL is better than ordinary PTL.

GABAA and serotonergic receptors participation in anxiolytic effect of chalcones in adult zebrafish.

The prevalence of anxiety is a significant public health problem, being the 24th leading cause of disability in individuals affected by this disorder. In this context, chalcones, a flavonoid subclass obtained from natural or synthetic sources, interact with central nervous system (CNS) receptors at the same binding site as benzodiazepines, the primary drugs used in the treatment of anxiety. Thus, our study investigates the anxiolytic effect of synthetic chalcones derived from the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone isolated from Croton anisodontus Müll.Arg. in modulating anxiolytic activity via GABAergic and serotoninergic neurotransmission in an adult zebrafish model. Chalcones 1 and 2 were non-toxic to adult zebrafish and showed anxiolytic activity via GABAA receptors. Chalcone 2 also had its anxiolytic action reversed by the antagonist granisetron, indicating the participation of serotonergic receptors 5HTR3A/3B in the anxiolytic effect. In addition, molecular docking results showed that chalcones have a higher affinity for the GABAA receptor than DZP and binding in the same region of the DZP binding site, indicating a similar effect to the drug. Furthermore, the interaction of chalcones with GABAA and 5-HT3A receptors demonstrates the anxiolytic effect potential of these molecules.Communicated by Ramaswamy H. Sarma.

The contribution of the 5-hydroxytryptamine receptor 2 A gene polymorphisms rs6311 and rs6313 to Schizophrenia in Iran.

OBJECTIVE: Schizophrenia is an acute mental disorder with an undefined etiology. Its high heritability suggests that several genetic variants and polymorphisms may contribute to the severity and emergence of its symptoms. Former molecular evidence has shed some light on the association of serotonergic pathway genetic polymorphisms with schizophrenia. This study aimed to investigate the association between schizophrenia and two SNPs from one haplotype block, which lies in the 5-hydroxytryptamine receptor 2 A (5-HTR2A) gene in the Iranian population. MATERIAL AND METHODS: Blood samples were collected from one-hundred and fifty-two patients diagnosed with schizophrenia and one-hundred and fifty-eight cases of the healthy control, who were matched in terms of age and gender. The participants were genotyped for rs6311 and rs6313 using PCR-RFLP. R programming language and Haploview software were respectively leveraged for statistical and haplotype inferencing. RESULTS: The results showed that there was no significant association between rs6313 and schizophrenia. However, the rs6311 T allele was independently associated with schizophrenia, and it was significantly associated with SCZ in an rs6311-rs6313 haplotype. Moreover, the general linear model confirmed the potential predictor role of rs6311 for schizophrenia and the C allele of rs6313 demonstrated a higher frequency among females compared to males. CONCLUSION: The findings of this study indicated the association of rs6311 and rs6311-rs6313 haplotype with schizophrenia in the Iranian population and also suggested a potential schizophrenia risk predictor role for rs6311.

Identification of potentially bioactive compounds from Blumea lacera essential oil by gas chromatography-mass spectroscopy and molecular docking studies for targeting inflammatory bowel disease.

Blumea lacera (Burm.f.) DC. (Asteraceae) is used in the traditional system of medicine for the treatment of inflammation or irritable bowel disease (IBD). In this study, B. lacera was collected from different geographical regions and oil was extracted by hydro-distillation and further chemo-profiled using GC-FID-MS. The major compounds identified were 2,5-dimethoxy-p-cymene (28.7-0.4%), ß-caryophyllene (25.5-0.5%), carvotanacetone (24.5-0.4%), chrysanthenone (21.9-9.8%) and 2,6-dimethyl phenol (11.4-1.8%). The constituents of B. lacera also showed marked qualitative and quantitative variations. The percent chemical similarity was observed to be in the range of 51.7% to 59.2% between the localities. Moreover, molecular modelling, membrane molecular dynamics simulations, target prediction were implemented to decipher the potential targets relevant to IBD. This inferred that all these major compounds could be potential drug moieties for treating IBD in terms of targeting h5HTR3A, thereby substantiating the traditional use of B. lacera for the treatment of IBD ailments.

Peer victimization, depression, and non-suicidal self-injury among Chinese adolescents: the moderating role of the 5-HTR2A gene rs6313 polymorphism.

BACKGROUND: Peer victimization is a crucial risk predictor for adolescent non-suicidal self-injury (NSSI). However, adolescent NSSI reactions to peer victimization exhibit large individual differences. This study explored whether depression mediated the association between peer victimization and adolescent NSSI, and whether this mediating path was moderated by the 5-HTR2A gene rs6313 polymorphism. METHODS: A total of 667 adolescents (Meanage = 12.81, SD = 0.48) completed questionnaires regarding peer victimization, depression, and NSSI. Genomic DNA was extracted from saliva and buccal cells from each participant. RESULTS: The results showed that the positive relation between peer victimization and adolescent NSSI was mediated by depression. Moreover, the triple interaction between peer victimization, rs6313 polymorphism, and gender on adolescent depression was significant. And the triple interaction between depression, rs6313 polymorphism, and gender on adolescent NSSI was also significant. Specifically, the risk effect of peer victimization on adolescent NSSI through increased depression was stronger for female adolescents with CC genotype than for female adolescents with CT or TT genotype, and male adolescents with CT or TT genotype. However, the indirect effect was nonsignificant for male adolescents with CC genotype. CONCLUSIONS: These findings promote the etiological understanding of adolescent NSSI, highlighting the mediating and moderating effect between peer victimization and NSSI, and adding evidence supporting the relationship between the 5-HTR2A gene rs6313 polymorphism, depression and adolescent NSSI.

Synergistic effect of serotonin 1A and serotonin 1B/D receptor agonists in the treatment of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.

BACKGROUND: The gold standard for symptomatic relief of Parkinson's disease (PD) is L-DOPA. However, long-term treatment often leads to motor complications such as L-DOPA-induced dyskinesia (LID). While amantadine (Gocovri™) is the only approved therapy for dyskinesia in PD patients on the American market, it is associated with neurological side effects and limited efficacy. Thus, there remains a high unmet need for addressing LID in PD patients worldwide. OBJECTIVE: The objective of this study was to evaluate the efficacy, safety and performance compared to approved treatments of the serotonin receptor 1A (5-HT1A) and 5-HT1B/D agonists buspirone and zolmitriptan in the 6-hydroxydopamine unilaterally lesioned rat model for PD. METHODS: The hemiparkinsonian 6-OHDA-lesioned rats underwent chronic treatment with L-DOPA to induce dyskinesia and were subsequently used for efficacy testing of buspirone, zolmitriptan and comparison with amantadine, measured as abnormal involuntary movement (AIM) scores after L-DOPA challenge. Safety testing was performed in model and naïve animals using forelimb adjusting, rotarod and open field tests. RESULTS: 5-HT1A and 5-HT1B/D agonism effectively reduced AIM scores in a synergistic manner. The drug combination of buspirone and zolmitriptan was safe and did not lead to tolerance development following sub-chronic administration. Head-to-head comparison with amantadine showed superior performance of buspirone and zolmitriptan in the model. CONCLUSIONS: The strong anti-dyskinetic effect found with combined 5-HT1A and 5-HT1B/D agonism renders buspirone and zolmitriptan together a meaningful treatment for LID in PD.

Phytochemical screening and effect of Viscum album L. on monoamine oxidase A and B activity and serotonin, dopamine and serotonin receptor 5-HTR1A levels in Galleria mellonealla (Lepidoptera).

ETHNOPHARMACOLOGICAL RELEVANCE: Viscum album L. (European mistletoe), a member of the Santalaceae, is a hemiparasitic, evergreen shrub growing on deciduous and coniferous trees. In traditional and folk medicine, mistletoe was used for the treatment of central nervous system disorders such as epilepsy, hysteria, insomnia, nervous excitability, neuralgia, headache, dizziness and fatigue. However, relatively little is known of its neuropharmacological activity. AIM OF THE STUDY: The aim of the present study was to evaluate the effect of treatment with aqueous and hydroethanolic extracts from Viscum album L. parasitizing birch, linden and pine, on MAO-A and MAO-B activity as well as serotonin, dopamine and serotonin receptor 5-HTR1A levels in Galleria mellonella (Lepidoptera) larvae. MATERIALS AND METHODS: The phytochemical composition of the extracts was characterised using UPLC-DAD-ESI-MS/MS. To investigate the neuropharmacological activity of Viscum album L. extracts, Galleria mellonella (Lepidoptera) larvae were used as a model organism. The inhibitory potential of the extracts against MAO-A and MAO-B was determined by fluorometry. The serotonin, dopamine and serotonin receptor 5-HTR1A levels in larvae hemolymph after treatment were quantified by ELISA. RESULTS: UPLC-DAD-ESI-MS/MS analysis allowed the identification of 88 compounds, either full or in part. Most of the characterised phytochemicals were flavonoids, hydroxycinnamic acids and lignans. Screening found that aqueous and hydroethanolic mistletoe extracts inhibited the enzymatic activity of either MAO-A or MAO-B or both. Additionally, mistletoe extract administration increased the levels of serotonin and serotonin receptor 5-HTR1A. None of the tested extracts had any significant effect on dopamine level. CONCLUSIONS: A key novel finding was that the aqueous and hydroethanolic extracts from Viscum album L. inhibited monoamine oxidase activity and increased the levels of serotonin and serotonin receptor 5-HTR1A in Galleria mellonella (Lepidoptera) larvae. These properties may be due to the presence of phenolic constituents, particularly flavonoids. Further research based on bioassay-guided fractionation of mistletoe is needed to identify CNS-active molecules.