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1.
Int J Mol Sci ; 24(3)2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36769290

RESUMO

We analyzed the expression of the serotonin receptors 5-HT1A, 5-HT2A, and 5-HT3A at four different stages of fetal lung development from 12 to 40 weeks of gestation, divided into four groups: the pseudoglandular stage (12-16th week of development; n = 8), the canalicular stage (16th-26th week of development; n = 7), the saccular stage (26th-36th week of development; n = 5), and the alveolar stage (36th-40th week of development; n = 5). The strongest expression of all three receptor types was found in the epithelium of the proximal airways during the pseudoglandular, canalicular, and saccular stages and in a vascular wall. 5-HT1A was also strongly expressed in the smooth muscle cells of the proximal airway. Vascular smooth muscle cells and endothelium occasionally showed a strong expression of 5-HT1A and 5-HT2A. In the alveolar stage, the expression of 5-HT1A, 5-HT2A, and 5-HT3A was detected in both type I (p1) and type II (p2) pneumocytes, with a stronger expression in p2. A significant decrease in percent the 5-HT2A area and in the integrated density was observed at the alveolar stage. On the other hand, a significant decrease in the percentage area but an increase in the integrated density was observed for 5-HT3A toward the alveolar stage, suggesting that a smaller number of cells expressed 5-HT3A but that they (p1 and p2) significantly increased their 5-HT3A expression at the alveolar stage. The results presented provided us with new data on the development and function of the serotonin system in the human fetal lung and gave us insight into their possible involvement in the pathogenesis of lung pathology, particularly that characteristic of the neonatal period.


Assuntos
Pulmão , Receptores de Serotonina , Recém-Nascido , Humanos , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Pulmão/metabolismo , Feto/metabolismo , Epitélio/metabolismo , Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/metabolismo
3.
Science ; 379(6633): 700-706, 2023 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-36795823

RESUMO

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.


Assuntos
Antidepressivos , Córtex Cerebral , Alucinógenos , Plasticidade Neuronal , Receptor 5-HT2A de Serotonina , Agonistas do Receptor 5-HT2 de Serotonina , Alucinógenos/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Serotonina/farmacologia , Transdução de Sinais , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Animais , Camundongos , Camundongos Knockout , Antidepressivos/farmacologia
4.
J Pharmacol Exp Ther ; 385(1): 62-75, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36669875

RESUMO

Novel psychoactive substances, including synthetic substituted tryptamines, represent a potential public health threat. Additionally, some substituted tryptamines are being studied under medical guidance as potential treatments of psychiatric disorders. Characterizing the basic pharmacology of substituted tryptamines will aid in understanding differences in potential for harm or therapeutic use. Using human embryonic kidney cells stably expressing 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT2C receptors (5-HT1AR, 5-HT2AR, and 5HT2CR, respectively) or the serotonin transporter (SERT), we measured affinities, potencies and efficacies of 21 substituted tryptamines. With the exception of two 4-acetoxy compounds, substituted tryptamines exhibited affinities and potencies less than one micromolar at the 5-HT2AR, the primary target for psychedelic effects. In comparison, half or more exhibited low affinities/potencies at 5-HT2CR, 5-HT1AR, and SERT. Sorting by the ratio of 5-HT2A to 5-HT2C, 5-HT1A, or SERT affinity revealed chemical determinants of selectivity. We found that although 4-substituted compounds exhibited affinities that ranged across a factor of 100, they largely exhibited high selectivity for 5-HT2ARs versus 5-HT1ARs and 5-HT2CRs. 5-substituted compounds exhibited high affinities for 5-HT1ARs, low affinities for 5-HT2CRs, and a range of affinities for 5-HT2ARs, resulting in selectivity for 5-HT2ARs versus 5-HT2CRs but not versus 5-HT1ARs. Additionally, a number of psychedelics bound to SERT, with non-ring-substituted tryptamines most consistently exhibiting binding. Interestingly, substituted tryptamines and known psychedelic standards exhibited a broad range of efficacies, which were lower as a class at 5-HT2ARs compared with 5-HT2CRs and 5-HT1ARs. Conversely, coupling efficiency/amplification ratio was highest at 5-HT2ARs in comparison with 5-HT2CRs and 5-HT1ARs. SIGNIFICANCE STATEMENT: Synthetic substituted tryptamines represent both potential public health threats and potential treatments of psychiatric disorders. The substituted tryptamines tested differed in affinities, potencies, and efficacies at 5-hydroxytryptamine (5-HT)2A, 5-HT2C, and 5HT1A receptors and the serotonin transporter (SERT). Several compounds were highly selective for and coupled very efficiently downstream of 5-HT2A versus 5-HT1A and 5-HT2C receptors, and some bound SERT. This basic pharmacology of substituted tryptamines helps us understand the pharmacologic basis of their potential for harm and as therapeutic agents.


Assuntos
Alucinógenos , Triptaminas , Humanos , Triptaminas/farmacologia , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo
5.
Molecules ; 28(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36615578

RESUMO

Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Here we report synthesis and detailed structural and behavioral studies of three indole derivatives: D2AAK5, D2AAK6, and D2AAK7 as serotonin 5-HT1A and 5-HT2A receptor ligands. X-ray studies revealed that the D2AAK5 compound crystallizes in centrosymmetric triclinic space group with one molecule in the asymmetric unit. The main interaction between the ligands and the receptors is the salt bridge between the protonatable nitrogen atom of the ligands and the conserved Asp (3.32) of the receptors. The complexes were stable in the molecular dynamic simulations. MD revealed that the studied ligands are relatively stable in their binding sites, with the exception of D2AAK7 in the serotonin 5-HT1A receptor. D2AAK7 exerts anxiolytic activity in the EPM test, while D2AAK5 has a beneficial effect on the memory processes in the PA test.


Assuntos
Antipsicóticos , Serotonina , Serotonina/metabolismo , Ligantes , Receptor 5-HT2A de Serotonina/metabolismo , Ligação Proteica , Receptores de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo
6.
Cell Signal ; 105: 110612, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36709823

RESUMO

Previously, we found that the 5-HT2A receptor plays a key role in cell injury. However, the mechanism by which the 5-HT2A receptor mediates intracellular processes remains unclear. In this study, we aimed to clarify this intracellular process in hepatocyte LO2 cells and evaluate its role in CCl4-induced hepatotoxicity in mice. In vitro, both the agonist and overexpression of 5-HT2A receptor could promote 5-HT degradation by upregulating the expression of 5-HT synthases and monoamine oxidase-A (MAO-A) to cause overproduction of ROS in mitochondria. We refer to this as the activation of the 5-HT degradation system (5DS) axis, which leads to the phosphorylation of JNK, p38 MAPK, STAT3, and NF-κB; upregulation of Bax, cleaved-caspase3, and cleaved-caspase9; and downregulation of Bcl-2, followed by apoptosis and oversecretion of TNF-α and IL-1ß in cells. This phenomenon could be markedly blocked by the 5-HT2A receptor antagonist, MAO-A inhibitor, or gene-silencing MAO-A. Through protein kinases C epsilon (PKCε) agonist treatment and gene silencing of the PKCε and 5-HT2A receptor, we demonstrated that the 5-HT2A receptor controls 5-HT synthases and MAO-A expression via the PKCε pathway in cells. Unexpectedly, we discovered that PKCε-mediated phosphorylation of the AKT/mTOR pathway is also a consequence of the activation of the 5DS axis. Furthermore, we confirmed that the inhibition of the 5DS axis using the 5-HT2A receptor antagonist could prevent hepatotoxicity induced by CCl4 both in vitro and in vivo, inhibiting the aforementioned signaling cascades, inflammation, and apoptosis, and that the 5DS activation area overlapped the necrotic area of mouse liver. Taken together, we revealed a 5DS axis in hepatocytes that controls the signaling cascades associated with inflammation and apoptosis and confirmed its role in CCl4-induced hepatotoxicity.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas , Animais , Camundongos , Apoptose , Tetracloreto de Carbono/toxicidade , Tetracloreto de Carbono/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/metabolismo , Inflamação/metabolismo , Monoaminoxidase/metabolismo , Monoaminoxidase/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Serotonina/farmacologia , Transdução de Sinais
7.
BMC Neurosci ; 24(1): 2, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631757

RESUMO

BACKGROUND: The head-twitch response (HTR) in mice is considered a behavioral model for hallucinogens and serotonin 5-HT2A receptor function, as well as Tourette syndrome in humans. It is mediated by 5-HT2A receptor agonists such as ( ±)- 2,5-dimethoxy-4-iodoamphetamine (DOI) in the prefrontal cortex (PFC). The 5-HT2A antagonist EMD 281014, can prevent both DOI-induced HTR during ageing and c-fos expression in different regions of PFC. Moreover, the nonselective monoamine releaser methamphetamine (MA) suppressed DOI-induced HTR through ageing via concomitant activation of inhibitory 5-HT1A receptors, but enhanced DOI-evoked c-fos expression. d-Fenfluramine is a selective 5-HT releaser and induces HTR in mice, whereas MA does not. Currently, we investigated whether EMD 281014 or MA would alter: (1) d-fenfluramine-induced HTR frequency in 20-, 30- and 60-day old mice, (2) d-fenfluramine-evoked c-fos expression in PFC, and (3) whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors would prevent suppressive effect of MA on d-fenfluramine-induced HTR. RESULTS: EMD 281014 (0.001-0.05 mg/kg) or MA (0.1-5 mg/kg) blocked d-fenfluramine-induced HTR dose-dependently during ageing. The 5-HT1A antagonist WAY 100635 countered the inhibitory effect of MA on d-fenfluramine-induced HTR in 30-day old mice, whereas the adrenergic ɑ2 antagonist RS 79948 reversed MA's inhibitory effect in both 20- and 30- day old mice. d-Fenfluramine significantly increased c-fos expressions in PFC regions. MA (1 mg/kg) pretreatment significantly increased d-fenfluramine-evoked c-fos expression in different regions of PFC. EMD 281014 (0.05 mg/kg) failed to prevent d-fenfluramine-induced c-fos expression, but significantly increased it in one PFC region (PrL at - 2.68 mm). CONCLUSION: EMD 281014 suppressed d-fenfluramine-induced HTR but failed to prevent d-fenfluramine-evoked c-fos expression which suggest involvement of additional serotonergic receptors in the mediation of evoked c-fos. The suppressive effect of MA on d-fenfluramine-evoked HTR is due to well-recognized functional interactions between stimulatory 5-HT2A- and the inhibitory 5-HT1A- and ɑ2-receptors. MA-evoked increases in c-fos expression in PFC regions are due to the activation of diverse monoaminergic receptors through increased synaptic concentrations of 5-HT, NE and/or DA, which may also account for the additive effect of MA on d-fenfluramine-evoked changes in c-fos expression. Our findings suggest potential drug receptor functional interaction during development when used in combination.


Assuntos
Fenfluramina , Metanfetamina , Córtex Pré-Frontal , Proteínas Proto-Oncogênicas c-fos , Animais , Humanos , Camundongos , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Envelhecimento/metabolismo , Fenfluramina/metabolismo , Fenfluramina/farmacologia , Metanfetamina/metabolismo , Metanfetamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo
8.
Life Sci ; 314: 121315, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36581095

RESUMO

Peripheral 5-hydroxytryptamine 2A receptor (5-HT2AR) could be a new pharmacological target for NASH, an evolution of NAFLD characterized by hepatic steatosis, cytoskeletal alterations, and hepatic inflammation that can arise with or without fibrosis. SJT4a is a synthetic ß-carboline antagonist for 5-HT2AR developed by SJT molecular research to treat NASH. We performed a combined in silico/in vivo study on this potential drug to elucidate its activity and possible mechanism of action. The in silico protocol compares SJT4a with four known 5-HT2AR ligands with different activities (LSD, methiothepin, zotepine, risperidone). We performed molecular docking calculations, evaluation of binding energy by AI-based methods and Molecular Dynamics simulations of the five ligand-target complexes. Moreover, we used a pseudo-semantic analysis to evaluate the potential mechanism of action of SJT4a. In silico predictions and pseudo-semantic analysis suggested antagonistic activity for SJT4a. The in silico prediction was confirmed by [3H]-5HT radioligand binding together with SJT4a competition analysis in CHO-K1 cell cultures expressing 5-HT2AR. SJT4a was then tested in vivo. We investigated the effect of 8 weeks of treatment with SJT4A on metabolic parameters, liver pathology, NAFLD activity score, and fibrosis stage in male DIO-NASH C57BL/6 J mice diet-induced obesity fed with an obesogenic diet compared with DIO-NASH and LEAN-CHOW vehicles. In our tests, SJT4a showed intense activity in diminishing the most relevant hallmarks of NASH in the DIO-NASH mice model. We proposed a possible mode of action for SJT4a based on its 5-HT2AR antagonist activity.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Simulação de Acoplamento Molecular , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Cirrose Hepática/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças
9.
Cells ; 11(19)2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36230998

RESUMO

The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [3H]D-aspartate ([3H]D-asp) release (which mimics glutamate exocytosis). The concomitant activation of the two receptors nulls their inhibitory activities, whereas blockade of the 5-HT2A heteroreceptors with MDL11,939 (1 µM) strengthens the inhibitory effect elicited by the mGlu2/3 receptor agonist LY329268 (1 µM). 5-HT2A receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. Clozapine (0.1-10 µM) mimics the 5-HT2A agonist (±) DOI and inhibits the KCl-evoked [3H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect. mGlu2 and 5-HT2A proteins do not co-immunoprecipitate from synaptosomal lysates, nor does the incubation of PFc synaptosomes with MDL11,939 (1 µM) or clozapine (10 µM) modify the insertion of mGlu2 subunits in synaptosomal plasma membranes. In conclusion, 5-HT2A and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT2A metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens.


Assuntos
Clozapina , Receptores de Glutamato Metabotrópico , Trazodona , Animais , Autorreceptores/metabolismo , Clozapina/farmacologia , Ácido D-Aspártico/farmacologia , Exocitose/fisiologia , Ácido Glutâmico/metabolismo , Ketanserina/farmacologia , Córtex Pré-Frontal/metabolismo , Ratos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Serotonina , Trazodona/farmacologia
10.
Nature ; 610(7932): 582-591, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36171289

RESUMO

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1-4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5-7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.


Assuntos
Antidepressivos , Pirrolidinas , Receptor 5-HT2A de Serotonina , Animais , Camundongos , Antidepressivos/farmacologia , Microscopia Crioeletrônica , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Alucinógenos/administração & dosagem , Alucinógenos/farmacologia , Ligantes , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Bibliotecas de Moléculas Pequenas
11.
Int J Mol Sci ; 23(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35955928

RESUMO

Serotonin (5-hydroxytriptamine or 5-HT) is known to be a weak platelet agonist, and is involved in thrombus formation. While 5-HT cannot induce platelet aggregation on its own, when secreted from the alpha granules, it binds to its G-protein Coupled Receptor (GPCR; i.e., 5HT2AR), thereby acting to amplify platelet functional responses (e.g., aggregation). Thus, 5HT2AR-mediated responses are more involved in the secondary amplification of platelet aggregation in the growing thrombus. Therefore, even though 5-HT can be seen as a weak inducer of platelet activation, it is an important amplifier of aggregation triggered by agonists such as ADP, collagen, and epinephrine, thereby enhancing thrombogenesis. The 5HT2AR/5HT2A signaling pathway is of clinical interest to the scientific and medical communities as it has been implicated in the genesis of several forms of cardiovascular disorders. However, efforts to develop antagonists for 5HT2AR as therapeutic agents in cardiovascular diseases have thus far failed due to these reagents having deleterious side-effects, and/or to lack of selectivity, amongst other reasons. In light of research efforts that identified that the 5HT2AR ligand binding domain resides in the second extracellular loop (EL2; amino acids P209-N233), we developed an antibody, i.e., referred to as 5HT2ARAb, against the EL2 region, and characterized its pharmacological activity in the context of platelets. Thus, we utilized platelets from healthy human donors, as well as C57BL/6J mice (10-12 weeks old) to analyze the inhibitory effects of the 5HT2ARAb on platelet activation in vitro, ex vivo, and on thrombogenesis in vivo as well as on 5HT2AR ligand binding. Our results indicate that the 5HT2ARAb inhibits 5-HT-enhanced platelet activation in vitro and ex vivo, but has no apparent effects on that which is agonist-induced. The 5HT2ARAb was also found to prolong the thrombus occlusion time, and it did so without modulating the tail bleeding time, in mice unlike the P2Y12 antagonist clopidogrel and the 5HT2AR antagonist ketanserin. Moreover, it was found that the 5HT2ARAb does so by directly antagonizing the platelet 5HT2AR. Our findings document that the custom-made 5HT2ARAb exhibits platelet function blocking activity and protects against thrombogenesis without impairing normal hemostasis.


Assuntos
Serotonina , Trombose , Animais , Anticorpos/metabolismo , Plaquetas/metabolismo , Hemostasia , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Agregação Plaquetária , Inibidores da Agregação Plaquetária/uso terapêutico , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Serotonina/farmacologia , Trombose/tratamento farmacológico , Trombose/metabolismo
12.
Neuroscience ; 502: 107-116, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-36038038

RESUMO

5-HT2A receptors (5-HT2ARs) are widely expressed in the central nervous system, including in the ventrolateral orbital cortex (VLO). The VLO is an important cortical component for pain processing. Brain 5-HT2ARs are implicated in both pro- and anti- nociceptive functions. However, the roles of 5-HT2ARs in the VLO in trigeminal neuralgia and neuronal synaptic function remain to be understood. We used chronic constriction injury of infraorbital nerve (IoN-CCI) model and shRNA mediated gene knockdown in mice to investigate the role of 5-HT2ARs in the VLO in trigeminal neuralgia. We found that knockdown of 5-HT2ARs in the VLO aggravated spontaneous pain and mechanical allodynia in mice after IoN-CCI. At the synaptic level, decreasing 5-HT2AR expression by shRNA or inhibition of 5-HT2AR activity by its antagonist ketanserin decreased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) of the neurons in the VLO, whereas 5-HT2AR partial agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI) enhanced sEPSCs of the neurons in the VLO. In summary, 5-HT2ARs in the VLO modulate the trigeminal pain by regulating neuronal glutamatergic activity.


Assuntos
Neuralgia do Trigêmeo , Ratos , Animais , Camundongos , Neuralgia do Trigêmeo/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Ratos Sprague-Dawley , Ketanserina/metabolismo , Serotonina/metabolismo , RNA Interferente Pequeno/metabolismo , Dor/metabolismo , Córtex Pré-Frontal/metabolismo
13.
Cells ; 11(15)2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35954229

RESUMO

Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation and biophysical and biochemical approaches. Heterodimerization decreased TrkB autophosphorylation, preventing its activation with agonist 7,8-DHF, even with low 5-HT2A receptor expression. A blockade of 5-HT2A receptor with the preferential antagonist ketanserin prevented the receptor-mediated downregulation of TrkB phosphorylation without restoring the TrkB response to its agonist 7,8-DHF in vitro. In adult mice, intraperitoneal ketanserin injection increased basal TrkB phosphorylation in the frontal cortex and hippocampus, which is in accordance with our findings demonstrating the prevalence of 5-HT2A-TrkB heteroreceptor complexes in these brain regions. An expression analysis revealed strong developmental regulation of 5-HT2A and TrkB expressions in the cortex, hippocampus, and especially the striatum, demonstrating that the balance between TrkB and 5-HT2A may shift in certain brain regions during postnatal development. Our data reveal the functional role of 5-HT2A-TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions during development and under pathophysiological conditions.


Assuntos
Receptor 5-HT2A de Serotonina/metabolismo , Receptor trkB/metabolismo , Serotonina , Animais , Ketanserina , Camundongos , Receptores de Serotonina , Serotonina/metabolismo , Serotonina/farmacologia , Tropomiosina
14.
Neuroscience ; 497: 196-205, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35597334

RESUMO

Previous experiences can drive adaptive behavior based on different characteristics, including contextual ones. Indeed, contextual information can be used as a criterion to guide the recall of the most relevant memory trace and the inhibition of others. The medial Prefontal Cortex (mPFC) has been proposed as an area that plays a pivotal role in regulating the retrieval of memory traces in downstream regions. Also, we have shown that mPFC Serotonin 2a Receptors (5-HT2aR) modulates the retrieval of a contextually guided recognition memory task and modulates the retrieval and reconsolidation of memories in the Perirhinal Cortex (PRH). However, how the mPFC output mediated by the 5-HT2aR activity is modulating memory retrieval in the PRH is a question that remains unclear. To tackle this question, we analyzed neuronal activity in the PRH and mPFC, by measuring expression of the immediate early gene c-Fos. We combined behavioral, pharmacological and immunohistochemical techniques to examine how mPFC 5-HT2aR controls mPFC and the PRH activity. We found that blockade of mPFC 5-HT2aR increase the level of c-Fos expression in the PHR and that this increase correlates with animals' performance in the task. We also found an increase in c-Fos expression in the mPFC after mPFC 5-HT2aR blockade that does not correlate with the animals' behavioral response. However, these changes showed a significant correlation with those observed in the PRH. These results suggest that mPFC 5-HT2aR signaling may modulate the behavioral response during memory recall by controlling the neuronal activation in the PRH.


Assuntos
Córtex Perirrinal , Animais , Rememoração Mental , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo
15.
Transl Psychiatry ; 12(1): 168, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459266

RESUMO

Blockade of N-methyl-D-aspartate receptors (NMDAR) is known to augment cortical serotonin 2A receptors (5-HT2ARs), which is implicated in psychosis. However, the pathways from NMDAR hypofunction to 5-HT2AR up-regulation are unclear. Here we addressed in mice whether genetic deletion of the indispensable NMDAR-subunit Grin1 principally in corticolimbic parvalbumin-positive fast-spiking interneurons, could up-regulate 5-HT2ARs leading to cortical hyper-excitability. First, in vivo local-field potential recording revealed that auditory cortex in Grin1 mutant mice became hyper-excitable upon exposure to acoustic click-train stimuli that release 5-HT in the cortex. This excitability increase was reproduced ex vivo where it consisted of an increased frequency of action potential (AP) firing in layer 2/3 pyramidal neurons of mutant auditory cortex. Application of the 5-HT2AR agonist TCB-2 produced similar results. The effect of click-trains was reversed by the 5-HT2AR antagonist M100907 both in vivo and ex vivo. Increase in AP frequency of pyramidal neurons was also reversed by application of Gαq protein inhibitor BIM-46187 and G protein-gated inwardly-rectifying K+ (GIRK) channel activator ML297. In fast-spiking interneurons, 5-HT2AR activation normally promotes GABA release, contributing to decreased excitability of postsynaptic pyramidal neurons, which was missing in the mutants. Moreover, unlike the controls, the GABAA receptor antagonist (+)-bicuculline had little effect on AP frequency of mutant pyramidal neurons, indicating a disinhibition state. These results suggest that the auditory-induced hyper-excitable state is conferred via GABA release deficits from Grin1-lacking interneurons leading to 5-HT2AR dysregulation and GIRK channel suppression in cortical pyramidal neurons, which could be involved in auditory psychosis.


Assuntos
Receptores de N-Metil-D-Aspartato , Esquizofrenia , Animais , Modelos Animais de Doenças , Camundongos , Células Piramidais/metabolismo , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Ácido gama-Aminobutírico/metabolismo
16.
Nat Rev Drug Discov ; 21(6): 463-473, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35301459

RESUMO

Psychedelic drugs including psilocybin, N,N'-dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) are undergoing a renaissance as potentially useful drugs for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. Notably, phase II trials have shown that psilocybin can produce statistically significant clinical effects following one or two administrations in depression and anxiety. These findings have inspired a 'gold rush' of commercial interest, with nearly 60 companies already formed to explore opportunities for psychedelics in treating diverse diseases. Additionally, these remarkable phenomenological and clinical observations are informing hypotheses about potential molecular mechanisms of action that need elucidation to realize the full potential of this investigative space. In particular, despite compelling evidence that the 5-HT2A receptor is a critical mediator of the behavioural effects of psychedelic drugs, uncertainty remains about which aspects of 5-HT2A receptor activity in the central nervous system are responsible for therapeutic effects and to what degree they can be isolated by developing novel chemical probes with differing specificity and selectivity profiles. Here, we discuss this emerging area of therapeutics, covering both controversies and areas of consensus related to the opportunities and perils of psychedelic and psychedelic-inspired therapeutics. We highlight how basic science breakthroughs can guide the discovery and development of psychedelic-inspired medications with the potential for improved efficacy without hallucinogenic or rewarding actions.


Assuntos
Alucinógenos , Transtornos Mentais , Psiquiatria , Alucinógenos/efeitos adversos , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Humanos , Dietilamida do Ácido Lisérgico/efeitos adversos , Dietilamida do Ácido Lisérgico/farmacologia , Dietilamida do Ácido Lisérgico/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Psilocibina/efeitos adversos , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Receptor 5-HT2A de Serotonina/metabolismo
17.
Mol Pain ; 18: 17448069221087583, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35240891

RESUMO

Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, and it is a typical disease which can develop chronic pain. Our previous study has proved that endocannabinoid (2-AG)-CB1R-GABA-5-HT pathway is involved in electroacupuncture (EA) mediated inhibition of chronic pain. However, it is still unclear which among the 5-HT receptor subtype is involved in EA evoked 5-HT mediated inhibition of chronic pain in the dorsal spinal cord. 5-HT2A is a G protein-coupled receptor and it is involved in 5-HT descending pain modulation system. We found that EA treatment at frequency of 2 Hz +1 mA significantly increased the expression of 5-HT2A receptor in the dorsal spinal cord and intrathecal injection of 5-HT2A receptor antagonist or agonist reversed or mimicked the analgesic effect of EA in each case respectively. Intrathecal injection of a selective GABAA receptor antagonist Bicuculline also reversed the EA effect on pain hypersensitivity. Additionally, EA treatment reversed the reduced expression of GABAA receptor and KCC2 in the dorsal spinal cord of KOA mice. Furthermore, we demonstrated that intrathecal 5-HT2A receptor antagonist/agonist reversed or mimicked the effect of EA up-regulate of KCC2 expression, respectively. Similarly, intrathecal injection of PLC and PKC inhibitors prevented both anti-allodynic effect and up-regulation of KCC2 expression by EA treatment. Our data suggest that EA treatment up-regulated KCC2 expression through activating 5-HT2A-Gq-PLC-PKC pathway and enhanced the inhibitory function of GABAA receptor, thereby inhibiting chronic pain in a mouse model of KOA.


Assuntos
Dor Crônica , Eletroacupuntura , Osteoartrite do Joelho , Simportadores , Animais , Dor Crônica/metabolismo , Dor Crônica/terapia , Camundongos , Osteoartrite do Joelho/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de GABA-A/metabolismo , Serotonina/metabolismo , Medula Espinal/metabolismo , Simportadores/metabolismo
18.
Biochemistry ; 61(3): 127-136, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35060714

RESUMO

In addition to producing profound subjective effects following acute administration, psychedelic compounds can induce beneficial behavioral changes relevant to the treatment of neuropsychiatric disorders that last long after the compounds have been cleared from the body. One hypothesis with the potential to explain the remarkable enduring effects of psychedelics is related to their abilities to promote structural and functional neuroplasticity in the prefrontal cortex (PFC). A hallmark of many stress-related neuropsychiatric diseases, including depression, post-traumatic stress disorder (PTSD), and addiction, is the atrophy of neurons in the PFC. Psychedelics appear to be particularly effective catalysts for the growth of these key neurons, ultimately leading to restoration of synaptic connectivity in this critical brain region. Furthermore, evidence suggests that the hallucinogenic effects of psychedelics are not directly linked to their ability to promote structural and functional neuroplasticity. If we are to develop improved alternatives to psychedelics for treating neuropsychiatric diseases, we must fully characterize the molecular mechanisms that give rise to psychedelic-induced neuroplasticity. Here, I review our current understanding of the biochemical signaling pathways activated by psychedelics and related neuroplasticity-promoting molecules, with an emphasis on key unanswered questions.


Assuntos
Alucinógenos/farmacologia , Transtornos Mentais/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Transtornos Mentais/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Science ; 375(6579): 403-411, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35084960

RESUMO

Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR ß-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.


Assuntos
Antidepressivos/farmacologia , Desenho de Fármacos , Alucinógenos/química , Alucinógenos/farmacologia , Receptor 5-HT2A de Serotonina/química , Animais , Antidepressivos/química , Antidepressivos/metabolismo , Arrestina/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Alucinações/induzido quimicamente , Alucinógenos/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Ligantes , Lisurida/química , Lisurida/metabolismo , Dietilamida do Ácido Lisérgico/química , Dietilamida do Ácido Lisérgico/metabolismo , Camundongos , Conformação Proteica , Psilocibina/análogos & derivados , Psilocibina/química , Psilocibina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/química , Serotonina/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade
20.
Br J Pharmacol ; 179(10): 2193-2207, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34766332

RESUMO

BACKGROUND AND PURPOSE: Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviours. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signalling pathway of GS, especially at the peripheral sensory neuronal levels. EXPERIMENTAL APPROACH: Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behaviour tests were also performed with wild-type and Trpv4 knockout mice. KEY RESULTS: GS activated DRG neurons in a manner involving both the 5-HT2A receptor and TRPV4. Furthermore, GS-induced responses were significantly suppressed by various inhibitors, including ketanserin (5-HT2A receptor antagonist), YM254890 (Gαq/11 inhibitor), gallein (Gßγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor) and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS-evoked scratching behaviours were greatly decreased by pretreatment with inhibitors of either 5-HT2A receptor or TRPV4. As expected, GS-evoked scratching behaviour was also significantly decreased in Trpv4 knockout mice. CONCLUSION AND IMPLICATIONS: Overall, the present study provides evidence for a novel molecular signalling pathway for GS-evoked pruritus, which utilizes both 5-HT2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.


Assuntos
Prurido , Psicosina , Receptor 5-HT2A de Serotonina , Células Receptoras Sensoriais , Canais de Cátion TRPV , Animais , Gânglios Espinais/metabolismo , Células HEK293 , Humanos , Camundongos , Prurido/induzido quimicamente , Prurido/metabolismo , Psicosina/análogos & derivados , Psicosina/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo
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