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1.
J Nat Prod ; 85(9): 2149-2158, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36001775

RESUMO

Aporphine alkaloids have shown affinity for serotonin receptors (5-HTRs), and there has been a recent upsurge of interest in aporphines as 5-HT2CR ligands. 1,2,9,10-Tetraoxygenated aporphine alkaloids in particular have demonstrated good affinity for 5-HTRs. In continued efforts to understand the impacts of structural modification of the 1,2,9,10-tetraoxygenated aporphine template on affinity, selectivity, and activity at 5-HT2R subtypes, we used (+)-boldine (8) as a semisynthetic feedstock in the preparation of C-2-alkoxylated (+)-predicentrine analogues. Compound 10n, which contains a benzyloxy group at C-2, has been identified as a novel 5-HT2CR ligand with strong affinity (4 nM) and moderate selectivity versus 5-HT2BR and 5-HT2AR (12-fold and 6-fold, respectively). Compound 10n functions as an antagonist at 5-HT2A and 5-HT2C receptors. Computational experiments indicate that several hydrophobic interactions as well as strong H-bond and salt bridge interactions between the protonated amine moiety in 10n and Asp134 are responsible for the potent 5-HT2CR affinity of this compound. Furthermore, compound 10n displays favorable predicted drug-like characteristics, which is encouraging toward future optimization.


Assuntos
Aporfinas , Antagonistas do Receptor 5-HT2 de Serotonina , Aporfinas/química , Aporfinas/farmacologia , Células CACO-2 , Humanos , Ligantes , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia
2.
Neuropsychopharmacology ; 47(7): 1304-1314, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35449450

RESUMO

Psychedelic-assisted psychotherapy gained considerable interest as a novel treatment strategy for fear-related mental disorders but the underlying mechanism remains poorly understood. The serotonin 2A (5-HT2A) receptor is a key target underlying the effects of psychedelics on emotional arousal but its role in fear processing remains controversial. Using the psychedelic 5-HT2A/5-HT2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-HT2A receptor knockout (KO) mice we investigated the effect of 5-HT2A receptor activation on emotional processing. We show that DOI administration did not impair performance in a spontaneous alternation task but reduced anxiety-like avoidance behavior in the elevated plus maze and elevated zero maze tasks. Moreover, we found that DOI did not block memory recall but diminished fear expression in a passive avoidance task. Likewise, DOI administration reduced fear expression in an auditory fear conditioning paradigm, while it did not affect retention of fear extinction when administered prior to extinction learning. The effect of DOI on fear expression was abolished in 5-HT2A receptor KO mice. Administration of DOI induced a significant increase of c-Fos expression in specific amygdalar nuclei. Moreover, local infusion of the 5-HT2A receptor antagonist M100907 into the amygdala reversed the effect of systemic administration of DOI on fear expression while local administration of DOI into the amygdala was sufficient to suppress fear expression. Our data demonstrate that activation of 5-HT2A receptors in the amygdala suppresses fear expression but provide no evidence for an effect on retention of fear extinction.


Assuntos
Medo , Alucinógenos , Anfetaminas/farmacologia , Animais , Ansiedade/tratamento farmacológico , Extinção Psicológica , Medo/fisiologia , Alucinógenos/farmacologia , Humanos , Camundongos , Receptor 5-HT2A de Serotonina , Receptor 5-HT2C de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia
3.
Biomed Pharmacother ; 145: 112424, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34785417

RESUMO

Small drug-like molecules that can block the function of serotonin 5-HT2A receptors have garnered considerable attention due to their ability to inhibit platelet aggregation and the possible prevention of atherosclerotic lesions. Although clinical data provided compelling evidence for the efficacy of this approach in the prevention of various cardiovascular conditions, the chemical space of 5-HT2A receptor antagonists is limited to ketanserin and sarpogrelate. To expand the portfolio of novel chemical motifs with potential antiplatelet activity, we evaluated the antiplatelet activity of a series of 6-fluorobenzo[d]isoxazole derivatives that possess a high affinity for 5-HT2A receptor. Here we describe in vitro studies showing that 6-fluorobenzo[d]isoxazole derivatives exert promising antiplatelet activity in three various in vitro models of platelet aggregation, as well as limit serotonin-induced vasoconstriction. Compound AZ928 showed in vitro activity greater than the clinically approved drug sarpogrelate. In addition to promising antiplatelet activity, the novel series was characterized by a favorable safety profile. Our findings show that the novel series exerts promising antiplatelet efficacy while being deprived of potential side effects, such as hemolytic activity, which render these compounds as potential substances for further investigation in the field of cardiovascular research.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Isoxazóis/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Humanos , Isoxazóis/química , Isoxazóis/toxicidade , Masculino , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/toxicidade , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/toxicidade , Relação Estrutura-Atividade , Succinatos/farmacologia , Vasoconstrição/efeitos dos fármacos
4.
Lancet Psychiatry ; 9(1): 46-58, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34861170

RESUMO

BACKGROUND: Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but there are few effective treatments. We aimed to assess the effects of pimavanserin, a selective 5-HT2A inverse agonist and antagonist, on negative symptoms of schizophrenia. METHODS: The ADVANCE study was a phase 2, 26-week, randomised, double-blind, placebo-controlled study of pimavanserin in stable outpatients with schizophrenia aged 18-55 years with predominant negative symptoms. Patients were randomly assigned (1:1) across 83 sites (18 in North America and 65 in Europe) to receive pimavanserin or placebo daily, added to an ongoing antipsychotic medication, per a computer-generated schedule (stratification by geographical region). Eligible patients had a score of at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items (and scores of ≥4 on at least three or ≥5 on at least two of negative symptom items). The starting dosage of 20 mg of pimavanserin or placebo could be adjusted to 34 mg or 10 mg within the first 8 weeks of the study, after which dosage remained stable until the end of the study. Both pimavanserin and placebo were administered orally once daily as two individual tablets (pimavanserin tablets were either 10 mg or 17 mg). The primary endpoint was change in total score using the 16-item Negative Symptom Assessment (NSA-16) from baseline to week 26. Primary outcomes were analysed in patients who received at least one dose of the study drug and had NSA-16 assessments at baseline and at least once post-baseline (full analysis set). Safety outcomes were analysed in patients who had received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02970305, and is complete. FINDINGS: Between Nov 4, 2016, and April 16, 2019, we randomly assigned 403 patients to pimavanserin (n=201; 131 [65%] male; 187 [93%] White) or placebo (n=202; 137 [68%] male, 186 (92%) White), of whom 400 were included in the efficacy analysis (199 in the pimavanserin group, 201 in the placebo group). Mean age was 37·7 years (SD 9·4) in the pimavanserin group and 36·7 (9·2) years in the placebo group. The change in total NSA-16 score from baseline to week 26 was significantly improved with pimavanserin (least squares mean -10·4 [SE 0·67]) versus placebo (least squares mean -8·5 [0·67]; p=0·043; effect size: 0·211). The number of patients with treatment-emergent adverse events (TEAEs) was similar between groups: 80 (40%) patients experienced TEAEs in the pimavanserin group and 71 (35%) in the placebo group. Most TEAEs were headache (6% [n=13] vs 5% [n=10]) and somnolence (5% [n=11] vs 5% [n=10]). One patient from the placebo group reported severe headache (0·5%), rhinorrhoea (0·5%), cough (0·5%), and influenza (0·5%). In the pimavanserin group, one patient reported severe toothache (0·5%), and two patients had worsening of schizophrenia (1%). Mean change in QTcF interval was higher with pimavanerin (4·5 ms [SD 18·0]) than with placebo (0·0 ms [16·0]). INTERPRETATION: Stable patients with predominant negative symptoms of schizophrenia showed a reduction in negative symptoms after treatment with pimavanserin. However, given the small effect size, further investigation with optimised dosing is warranted to determine the clinical significance of this effect. FUNDING: Acadia Pharmaceuticals.


Assuntos
Piperidinas/farmacologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Ureia/análogos & derivados , Adolescente , Adulto , Método Duplo-Cego , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Avaliação de Resultados em Cuidados de Saúde , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/farmacologia , Adulto Jovem
5.
Neuropharmacology ; 206: 108926, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34921828

RESUMO

Perseveration is a characteristic of patients with obsessive-compulsive disorder (OCD). Clinically, neuronal activity in the lateral orbitofrontal cortex (OFC) is increased in OCD patients. Successful treatment with selective serotonin reuptake inhibitors (SSRIs) reduces activity in the lateral OFC of OCD patients, but the precise mechanisms underlying this effect are unclear. Previously, we reported that repeated injection of the dopamine D2 receptor agonist quinpirole (QNP) resulted in OCD-like deficits, including perseveration in a reversal learning task. QNP-treated mice showed hyperactivity in lateral OFC pyramidal neurons. The present study demonstrated that 4-week administration of an SSRI increased the rate of correct choice in a reversal learning task. Using the electrophysiological approach, we revealed that an SSRI decreased the activity of lateral OFC pyramidal neurons in QNP-treated mice by potentiating inhibitory inputs. The 4-week administration of an SSRI inhibited the potentiation of neuronal activity induced by a 5-HT2C receptor agonist. Additionally, both 4-week administration of SSRI and acute application of 5-HT2C receptor antagonist prevented the QNP-induced potentiation of inhibitory inputs to fast-spiking interneurons in the lateral OFC. Administration of a 5-HT2C receptor antagonist to mice for 4 days increased the rate of correct choice in a reversal learning task. Collectively, these results indicate that chronic SSRI ameliorated perseverative behavior in QNP-treated mice by modulating inhibitory inputs in the lateral OFC. Short-term 5-HT2C receptor blockade also ameliorated QNP-induced behavioral and neurological abnormalities by, at least in part, a common mechanism with chronic SSRI.


Assuntos
Comportamento Animal/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Animais , Modelos Animais de Doenças , Interneurônios/efeitos dos fármacos , Camundongos , Células Piramidais/efeitos dos fármacos , Reversão de Aprendizagem/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos
6.
J Neurophysiol ; 127(1): 150-160, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34936830

RESUMO

Serotonin (5-HT) is a neuromodulator that is critical for regulating the excitability of spinal motoneurons and the generation of muscle torque. However, the role of 5-HT in modulating human motor unit activity during rapid contractions has yet to be assessed. Nine healthy participants (23.7 ± 2.2 yr) ingested 8 mg of the competitive 5-HT2 antagonist cyproheptadine in a double-blinded, placebo-controlled, repeated-measures experiment. Rapid dorsiflexion contractions were performed at 30%, 50%, and 70% of maximal voluntary contraction (MVC), where motor unit activity was assessed by high-density surface electromyographic decomposition. A second protocol was performed where a sustained, fatigue-inducing dorsiflexion contraction was completed before undertaking the same 30%, 50%, and 70% MVC rapid contractions and motor unit analysis. Motor unit discharge rate (P < 0.001) and rate of torque development (RTD; P = 0.019) for the unfatigued muscle were both significantly lower for the cyproheptadine condition. Following the fatigue inducing contraction, cyproheptadine reduced motor unit discharge rate (P < 0.001) and RTD (P = 0.024), whereas the effects of cyproheptadine on motor unit discharge rate and RTD increased with increasing contraction intensity. Overall, these results support the viewpoint that serotonergic effects in the central nervous system occur fast enough to regulate motor unit discharge rate during rapid powerful contractions.NEW & NOTEWORTHY We have shown that serotonin activity in the central nervous system plays a role in regulating human motor unit discharge rate during rapid contractions. Our findings support the viewpoint that serotonergic effects in the central nervous system are fast and are most prominent during contractions that are characterized by high motor unit discharge rates and large amounts of torque development.


Assuntos
Sistema Nervoso Central/metabolismo , Neurônios Motores/fisiologia , Contração Muscular/fisiologia , Fadiga Muscular/fisiologia , Recrutamento Neurofisiológico/fisiologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Serotonina/metabolismo , Adulto , Sistema Nervoso Central/efeitos dos fármacos , Ciproeptadina/farmacologia , Método Duplo-Cego , Eletromiografia , Feminino , Humanos , Masculino , Neurônios Motores/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Fadiga Muscular/efeitos dos fármacos , Recrutamento Neurofisiológico/efeitos dos fármacos , Adulto Jovem
7.
Elife ; 102021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34919051

RESUMO

Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in 5 hr. The screen tested 1280 FDA-approved drugs and identified pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacological and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt signaling. In contrast, HTR2C induced epithelial-to-mesenchymal transition through activation of Wnt signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs.


Assuntos
Movimento Celular/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Transição Epitelial-Mesenquimal , Gastrulação/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Pizotilina/farmacologia , Receptor 5-HT2C de Serotonina/genética , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Descoberta de Drogas , Feminino , Humanos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Transplante Heterólogo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
8.
Sci Rep ; 11(1): 19714, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611182

RESUMO

Serotonin 5-HT2 receptors are expressed in many tissues and play important roles in biological processes. Although the 5-HT2A receptor is primarily known for its role in central nervous system, it is also expressed in peripheral tissues. We have found that 5-HT2A receptor antagonists inhibit human subcutaneous primary adipocyte differentiation. We also show that siRNA knockdown of the 5-HT2A receptor blocks differentiation. Using gene expression analysis in combination with receptor antagonists we found that activity of 5-HT2A receptors is necessary very early in the differentiation process to mediate expression of adipogenic genes, including peroxisome proliferator-activated receptor gamma (ppar-γ), adipocyte protein 2 (aP2), adiponectin, and serine/threonine-protein kinase 1 (sgk1). We show here for the first time that 5-HT2A receptor activity is necessary for differentiation of human primary subcutaneous preadipocytes to adipocytes, and that 5-HT2A receptor activity mediates key genes related to adipogenesis during this process. Importantly, this work contributes to a greater understanding of the adipocyte differentiation process, as well as to the role of 5-HT2A receptors in peripheral tissues, and may be relevant to the development of novel therapeutic strategies targeting this receptor for the treatment of obesity related diseases.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia , Diferenciação Celular , Regulação da Expressão Gênica , Receptor 5-HT2A de Serotonina/metabolismo , Adipócitos/efeitos dos fármacos , Adipogenia/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Relação Dose-Resposta a Droga , Humanos , Modelos Biológicos , RNA Mensageiro/genética , Receptor 5-HT2A de Serotonina/genética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia
9.
BMC Pharmacol Toxicol ; 22(1): 64, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702339

RESUMO

BACKGROUND: Dopamine D2 receptor agonists, bromocriptine and cabergoline, are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation was found between the initiation of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial activation of 5-hydroxytryptamine receptor 2 A (5-HT2A). The investigation aimed to examine the activity of sarpogrelate (a 5-HT2A receptor blocker) in reducing myocardial injury prompted by extended haul utilisation of D2 receptor agonists in rats with alloxan-induced diabetes. METHODS: Both bromocriptine and cabergoline were managed independently and combined with sarpogrelate for about a month in diabetic nephropathy rats. Both tail-cuff blood pressure and the BGL were recorded weekly. For all animals, the kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of lactate dehydrogenase-1 (LDH-1), cardiac troponin I, and tumor necrosis factor alpha 1 (TNF1). The triphenyltetrazolium chloride (TTC) staining method was used to determine the experimental myocardial infarction (MI) size. RESULTS: Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine and cabergoline, alone, or in combination with sarpogrelate fundamentally diminished the blood concentrations of alkaline phosphatase (ALP), Aspartate aminotransferase (AST), urea, and creatinine. Bromocriptine and cabergoline alone showed a noteworthy increase in the LDH-1, Troponin I, and TNF1 levels in the serum (p < 0.05). Paradoxically, utilising bromocriptine or cabergoline with sarpogrelate treatment altogether decreased the levels of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed through the TTC staining method. CONCLUSIONS: The examination demonstrated that the combined use of sarpogrelate with bromocriptine or cabergoline decreased the potential adverse effects of these two drugs on the myocardial tissues.


Assuntos
Bromocriptina/uso terapêutico , Cabergolina/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Succinatos/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Bromocriptina/farmacologia , Cabergolina/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Agonistas de Dopamina/farmacologia , Quimioterapia Combinada , Isoenzimas/sangue , Rim/efeitos dos fármacos , Rim/patologia , L-Lactato Desidrogenase/sangue , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Miocárdio/patologia , Ratos Wistar , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Succinatos/farmacologia , Troponina I/sangue , Fator de Necrose Tumoral alfa/sangue
10.
Neuropharmacology ; 201: 108838, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34666074

RESUMO

Prepulse inhibition (PPI) is disrupted in many neuropsychiatric diseases. Although the inverse agonist of the 5-hydroxytryptamine 2A (5-HT2A) receptors, pimavanserin, alleviates PPI deficits in rodents, the precise mechanisms and critical brain areas in the reversal effect of 5-HT2A receptor inverse agonists remain unclear. The present study aimed to investigate the critical brain areas responsible for the reversal effect of the 5-HT2A receptor inverse agonist on PPI deficits in male mice. The results showed that intraperitoneal administration of pimavanserin was found to improve normal PPI behavior and reverse PPI deficits elicited by the dopamine D1/D2 receptor nonselective agonist, pergolide. Further, local infusion of pimavanserin into the nucleus accumbens and ventral hippocampus reversed PPI deficits, whereas the same manipulation in the medial prefrontal cortex or ventral tegmental area did not reverse PPI deficits. Overall, the nucleus accumbens and ventral hippocampus are the critical brain areas responsible for the reversal effect of 5-HT2A inverse agonists on PPI deficits. Such findings contribute to the extensive exploration of the accurate molecular and neural mechanisms underlying the antipsychotic effects of 5-HT2A receptor inverse agonists, especially the neural circuits modulated by 5-HT2A receptor activity.


Assuntos
Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Piperidinas/farmacologia , Inibição Pré-Pulso/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina , Ureia/análogos & derivados , Animais , Masculino , Camundongos Endogâmicos C57BL , Ureia/farmacologia
11.
Naunyn Schmiedebergs Arch Pharmacol ; 394(12): 2381-2388, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34550406

RESUMO

PURPOSE: Antagonising serotonin (5-HT) type 2A receptors (5-HT2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR2), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT2AR antagonism with concurrent mGluR2 orthosteric stimulation and mGluR2 positive allosteric modulation. METHODS: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR2 orthosteric agonist (OA) LY-354,740, the mGluR2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. RESULTS: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed. CONCLUSION: Our results suggest that combining 5-HT2AR antagonism with mGluR2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR2 OA and a mGluR2 PAM are combined with a 5-HT2AR antagonist than when a mGluR2 OA or a mGluR2 PAM are added to a 5-HT2AR antagonist.


Assuntos
Antiparkinsonianos/farmacologia , Levodopa/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/toxicidade , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/farmacologia , Callithrix , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/prevenção & controle , Feminino , Indóis/administração & dosagem , Indóis/farmacologia , Levodopa/administração & dosagem , Levodopa/toxicidade , Masculino , Transtornos Parkinsonianos/psicologia , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Transtornos Psicóticos/etiologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia
12.
Pharmacol Biochem Behav ; 210: 173276, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34555392

RESUMO

Serotonin (5-HT) receptors have been implicated in responses to aversive stimuli in mammals and fish, but its precise role is still unknown. Moreover, since at least seven families of 5-HT receptors exist in vertebrates, the role of specific receptors is still debated. Aversive stimuli can be classified as indicators of proximal, distal, or potential threat, initiating responses that are appropriate for each of these threat levels. Responses to potential threat usually involve cautious exploration and increased alertness, while responses to distal and proximal threat involve a fight-flight-freeze reaction. We exposed adult zebrafish to a conspecific alarm substance (CAS) and observed behavior during (distal threat) and after (potential threat) exposure, and treated with the 5-HT2C receptor agonists MK-212 or WAY-161503 or with the antagonist RS-102221. The agonists blocked CAS-elicited defensive behavior (distal threat), but not post-exposure increases in defensive behavior (potential threat), suggesting inhibition of responses to distal threat. MK-212 blocked changes in freezing elicited by acute restraint stress, a model of proximal threat, while RS-102221 blocked changes in geotaxis elicited this stressor. We also found that RS-102221, a 5-HT2C receptor antagonist, produced small effect on behavior during and after exposure to CAS. Preprint: https://www.biorxiv.org/content/10.1101/2020.10.04.324202; Data and scripts: https://github.com/lanec-unifesspa/5-HT-CAS/tree/master/data/5HT2C.


Assuntos
Comportamento Animal/efeitos dos fármacos , Reação de Fuga/efeitos dos fármacos , Medo/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Peixe-Zebra
14.
Behav Brain Res ; 415: 113521, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34391796

RESUMO

Methamphetamine withdrawal can induce intense cravings leading to relapse. Contexts/cues paired with chronic methamphetamine use develop incentive motivational properties, promoting future drug-seeking and taking behavior. Research has shown that, in adult male rats, the selective 5-HT2A receptor antagonist M100907 attenuates the acquisition of methamphetamine-induced conditioned place preference (CPP), a measure that examines conditioned associations between the rewarding properties of drugs and contexts. However, these findings have not been extended to adult female rats. The present study investigated the effects of M100907 on the acquisition of methamphetamine-CPP in adult female rats. During conditioning, rats were administered M100907 (0, 0.025, 0.25 mg/kg, i.p.) 15 min before methamphetamine (1 mg/kg, i.p.) and then placed into their initially non-preferred chamber for 30 min, or administered saline and placed into their initially preferred chamber for 30 min. Conditioning sessions were separated by four hours. Following four days of conditioning, the effects of M100907 on the acquisition of methamphetamine-CPP were assessed during a 15 min drug-free test trial. Pretreatment with M100907 dose-dependently attenuated the acquisition of methamphetamine-induced CPP. Blocking 5-HT2A receptors with a low dose of the selective antagonist M100907 attenuated the rewarding effects of methamphetamine in adult female rats. These data provide further evidence that the 5-HT2A receptor subtype is involved in the behavioral effects of methamphetamine.


Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Metanfetamina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Feminino , Fluorbenzenos/farmacologia , Masculino , Metanfetamina/administração & dosagem , Piperidinas/farmacologia , Ratos , Ratos Long-Evans , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem
15.
Respir Physiol Neurobiol ; 294: 103768, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34343692

RESUMO

Acute intermittent hypoxia (AIH) modifies the functioning of the respiratory network, causing respiratory motor facilitation in anesthetized animals and a compensatory increase in pulmonary ventilation in freely behaving animals. However, it is still unclear whether the ventilatory facilitation induced by AIH in unanesthetized animals is associated with changes in the respiratory pattern. We found that Holtzman male rats (80-150 g) exposed to AIH (10 × 6% O2 for 30-40 s every 5 min, n = 9) exhibited a prolonged (30 min) increase in baseline minute ventilation (P < 0.05) compared to control animals (n = 13), combined with the occurrence of late expiratory peak flow events, suggesting the presence of active expiration. The increase in ventilation after AIH was also accompanied by reductions in arterial CO2 and body temperature (n = 5-6, P < 0.05). The systemic treatment with ketanserin (a 5-HT2 receptor antagonist) before AIH prevented the changes in ventilation and active expiration (n = 11) but potentiated the hypothermic response (n = 5, P < 0.05) when compared to appropriate control rats (n = 13). Our findings indicate that the ventilatory long-term facilitation elicited by AIH exposure in unanesthetized rats is linked to the generation of active expiration by mechanisms that may depend on the activation of serotonin receptors. In contrast, the decrease in body temperature induced by AIH may not require 5-HT2 receptor activation.


Assuntos
Hipóxia/fisiopatologia , Ketanserina/farmacologia , Ventilação Pulmonar/fisiologia , Mecânica Respiratória/fisiologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Ventilação Pulmonar/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Volume de Ventilação Pulmonar/fisiologia
16.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199392

RESUMO

Coordination of four-limb movements during quadrupedal locomotion is controlled by supraspinal monoaminergic descending pathways, among which serotoninergic ones play a crucial role. Here we investigated the locomotor pattern during recovery from blockade of 5-HT7 or 5-HT2A receptors after intrathecal application of SB269970 or cyproheptadine in adult rats with chronic intrathecal cannula implanted in the lumbar spinal cord. The interlimb coordination was investigated based on electromyographic activity recorded from selected fore- and hindlimb muscles during rat locomotion on a treadmill. In the time of recovery after hindlimb transient paralysis, we noticed a presence of an unusual pattern of quadrupedal locomotion characterized by a doubling of forelimb stepping in relation to unaffected hindlimb stepping (2FL-1HL) after blockade of 5-HT7 receptors but not after blockade of 5-HT2A receptors. The 2FL-1HL pattern, although transient, was observed as a stable form of fore-hindlimb coupling during quadrupedal locomotion. We suggest that modulation of the 5-HT7 receptors on interneurons located in lamina VII with ascending projections to the forelimb spinal network can be responsible for the 2FL-1HL locomotor pattern. In support, our immunohistochemical analysis of the lumbar spinal cord demonstrated the presence of the 5-HT7 immunoreactive cells in the lamina VII, which were rarely 5-HT2A immunoreactive.


Assuntos
Locomoção/genética , Receptor 5-HT2A de Serotonina/genética , Receptores de Serotonina/genética , Traumatismos da Medula Espinal/genética , Animais , Ciproeptadina/farmacologia , Estimulação Elétrica , Eletromiografia , Membro Anterior/efeitos dos fármacos , Membro Anterior/fisiopatologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Humanos , Locomoção/efeitos dos fármacos , Região Lombossacral/fisiopatologia , Ratos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Serotonina/genética , Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/fisiopatologia
17.
CNS Drugs ; 35(7): 727-741, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34224112

RESUMO

Psychosis occurs across a wide variety of dementias with differing etiologies, including Alzheimer's dementia, Parkinson's dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia. Pimavanserin, a selective serotonin 5-HT2A receptor (5-HT2AR) inverse agonist, has shown promising results in clinical trials by reducing the frequency and/or severity of hallucinations and delusions and the risk of relapse of these symptoms in patients with dementia-related psychosis. A literature review was conducted to identify mechanisms that explain the role of 5-HT2ARs in both the etiology and treatment of dementia-related psychosis. This review revealed that most pathological changes commonly associated with neurodegenerative diseases cause one or more of the following events to occur: reduced synaptic contact of gamma aminobutyric acid (GABA)-ergic interneurons with glutamatergic pyramidal cells, reduced cortical innervation from subcortical structures, and altered 5-HT2AR expression levels. Each of these events promotes increased pyramidal cell hyperexcitability and disruption of excitatory/inhibitory balance, facilitating emergence of psychotic behaviors. The brain regions affected by these pathological changes largely coincide with areas expressing high levels of 5-HT2ARs. At the cellular level, 5-HT2ARs are most highly expressed on cortical glutamatergic pyramidal cells, where they regulate pyramidal cell excitability. The common effects of different neurodegenerative diseases on pyramidal cell excitability together with the close anatomical and functional connection of 5-HT2ARs to pyramidal cell excitability may explain why suppressing 5-HT2AR activity could be an effective strategy to treat dementia-related psychosis.


Assuntos
Demência , Transtornos Psicóticos , Células Piramidais , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antipsicóticos/farmacologia , Excitabilidade Cortical/efeitos dos fármacos , Excitabilidade Cortical/fisiologia , Demência/complicações , Demência/patologia , Demência/fisiopatologia , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/etiologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Receptor 5-HT2A de Serotonina/metabolismo
18.
J Neurosci ; 41(34): 7246-7258, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34261701

RESUMO

Previously, studies using human neuroimaging and excitotoxic lesions in non-human primate have demonstrated an important role of ventrolateral prefrontal cortex (vlPFC) in higher order cognitive functions such as cognitive flexibility and the planning of behavioral sequences. In the present experiments, we tested effects on performance of temporary inactivation (using GABA receptor agonists) and dopamine (DA) D2 and 5-HT2A-receptor (R) blockade of vlPFC via local intracerebral infusions in the marmoset. We trained common marmosets to perform spatial self-ordered sequencing tasks in which one cohort of animals performed two and three response sequences on a continuously varying spatial array of response options on a touch-sensitive screen. Inactivation of vlPFC produced a marked disruption of accuracy of sequencing which also exhibited significant error perseveration. There were somewhat contrasting effects of D2 and 5-HT2A-R blockade, with the former producing error perseveration on incorrect trials, though not significantly impairing accuracy overall, and the latter significantly impairing accuracy but not error perseveration. A second cohort of marmosets were directly compared on performance of fixed versus variable spatial arrays. Inactivation of vlPFC again impaired self-ordered sequencing, but only with varying, and not fixed spatial arrays, the latter leading to the consistent use of fewer, preferred sequences. These findings add to evidence that vlPFC is implicated in goal-directed behavior that requires higher-order response heuristics that can be applied flexibly over different (variable), as compared with fixed stimulus exemplars. They also show that dopaminergic and serotonergic chemomodulation has distinctive effects on such performance.SIGNIFICANCE STATEMENT This investigation employing local intracerebral infusions to inactivate the lateral prefrontal cortex (PFC) of the New World marmoset reveals the important role of this region in self-ordered response sequencing in variable but not fixed spatial arrays. These novel findings emphasize the higher order functions of this region, contributing to cognitive flexibility and planning of goal directed behavior. The investigation also reports for the first time somewhat contrasting neuromodulatory deficits produced by infusions of dopamine (DA) D2 and 5-HT2A receptor (R) antagonists into the same region, of possible significance for understanding cognitive deficits produced by anti-psychotic drugs.


Assuntos
Dopamina/fisiologia , Córtex Pré-Frontal/fisiologia , Desempenho Psicomotor/fisiologia , Serotonina/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Antipsicóticos/efeitos adversos , Baclofeno/farmacologia , Callithrix , Transtornos Cognitivos/induzido quimicamente , Antagonistas dos Receptores de Dopamina D2/farmacologia , Fluorbenzenos/farmacologia , Agonistas GABAérgicos/farmacologia , Objetivos , Memória de Curto Prazo/fisiologia , Muscimol/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Comportamento Espacial , Sulpirida/farmacologia
19.
Int J Neuropsychopharmacol ; 24(9): 749-757, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34228806

RESUMO

BACKGROUND: Though drugs binding to serotonergic 5-HT2A receptors have long been claimed to influence human anxiety, it remains unclear if this receptor subtype is best described as anxiety promoting or anxiety dampening. Whereas conditioned fear expressed as freezing in rats is modified by application of 5-HT2A-acting drugs locally into different brain regions, reports on the effect of systemic administration of 5-HT2A receptor agonists and 5-HT2A antagonists or inverse agonists on this behavior remain sparse. METHODS: We assessed the possible impact of systemic administration of 5-HT2A receptor agonists, 5-HT2A receptor inverse agonists, and a selective serotonin reuptake inhibitor (SSRI)-per se or in combination-on the freezing displayed by male rats when re-exposed to a conditioning chamber in which they received foot shocks 7 days earlier. RESULTS: The 5-HT2A receptor agonists psilocybin and 25CN-NBOH induced a reduction in conditioned fear that was countered by pretreatment with 5-HT2A receptor inverse agonist MDL 100907. While both MDL 100907 and another 5-HT2A receptor inverse agonist, pimavanserin, failed to impact freezing per se, both compounds unmasked a robust fear-reducing effect of an SSRI, escitalopram, which by itself exerted no such effect. CONCLUSIONS: The results indicate that 5-HT2A receptor activation is not a prerequisite for normal conditioned freezing in rats but that this receptor subtype, when selectively over-activated prior to expression, exerts a marked fear-reducing influence. However, in the presence of an SSRI, the 5-HT2A receptor, on the contrary, appears to counter an anti-freezing effect of the enhanced extracellular serotonin levels following reuptake inhibition.


Assuntos
Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Medo/efeitos dos fármacos , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Animais , Compostos Bicíclicos com Pontes/farmacologia , Fluorbenzenos/farmacologia , Ligantes , Masculino , Metilaminas/farmacologia , Piperidinas/farmacologia , Psilocibina/farmacologia , Ratos , Ratos Sprague-Dawley , Ureia/análogos & derivados , Ureia/farmacologia
20.
Pharmacol Rep ; 73(5): 1361-1372, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34115343

RESUMO

BACKGROUND: Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT2A receptor antagonists could constitute alternative antiplatelet therapy. METHODS: Based on the structures of the conventional 5-HT2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure-activity relationships were studied following molecular docking to the 5-HT2A receptor model. RESULTS: Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC50 = 27.3 µM) being more active than sarpogrelate (IC50 = 66.8 µM) and comparable with ketanserin (IC50 = 32.1 µM). Moreover, compounds 2-5, 9-11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation. CONCLUSIONS: Our study confirmed that the 5-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.


Assuntos
Hidantoínas/síntese química , Hidantoínas/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Aorta , Células CHO , Cricetinae , Cricetulus , Humanos , Mianserina/farmacologia , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Ratos
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