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1.
Eur J Pharmacol ; 926: 175019, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35561752

RESUMO

Serotonin 5-HT1A receptor agonists increase locomotor activity of both preweanling and adult rodents. The part played by the 5-HT1B receptor in locomotion is less certain, with preliminary evidence suggesting that the actions of 5-HT1B receptor agonists are not uniform across ontogeny. To more fully examine the role of 5-HT1B receptors, locomotor activity and axillary temperatures of preweanling and adult male and female rats was assessed. In the first experiment, adult (PD 70) and preweanling (PD 10 and PD 15) male and female rats were injected with the 5-HT1B agonist CP 94253 (2.5-10 mg/kg) immediately before locomotor activity testing and 60 min before axillary temperatures were recorded. In the second experiment, specificity of drug action was determined in PD 10 rats by administering saline, WAY 100635 (a 5-HT1A antagonist), or GR 127935 (a 5-HT1B antagonist) 30 min before CP 94253 (10 mg/kg) treatment. CP 94253 significantly increased the locomotor activity of preweanling rats on PD 10, an effect that was fully attenuated by GR 127935. Conversely, CP 94253 significantly decreased the locomotor activity of male and female adult rats, while CP 94253 did not affect the locomotor activity of PD 15 rats. Regardless of age, CP 94253 (2.5-10 mg/kg) significantly reduced the axillary temperatures of preweanling and adult rats. When considered together, these results show that 5-HT1B receptor stimulation activates motor circuits in PD 10 rats; whereas, 5-HT1B receptor agonism reduces the overall locomotor activity of adult rats, perhaps by blunting exploratory tendencies.


Assuntos
Agonistas do Receptor de Serotonina , Serotonina , Animais , Temperatura Corporal , Feminino , Locomoção , Masculino , Atividade Motora , Piridinas , Ratos , Receptor 5-HT1B de Serotonina , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
2.
Respir Res ; 23(1): 42, 2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241072

RESUMO

BACKGROUND: Intermittent hypoxia induces increased ventilatory responses in a 5-HT-dependent manner. This study aimed to explore that effect of raphe magnus serotonin 1A receptor (5-HT1A) receptor on the increased ventilatory responses induced by intermittent hypoxia. METHODS: Stereotaxic surgery was performed in adult male rats, and acute and chronic intermittent hypoxia models were established after recovery from surgery. The experimental group received microinjections of 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the raphe magnus nucleus (RMg). Meanwhile, the control group received microinjections of artificial cerebrospinal fluid instead of 8-OH-DPAT. Ventilatory responses were compared among the different groups of oxygen status. 5-HT expressions in the RMg region were assessed by immunohistochemistry after chronic intermittent hypoxia. RESULTS: Compared with the normoxia group, the acute intermittent hypoxia group exhibited higher ventilatory responses (e.g., shorter inspiratory time and higher tidal volume, frequency of breathing, minute ventilation, and mean inspiratory flow) (P < 0.05). 8-OH-DPAT microinjection partly weakened these changes in the acute intermittent hypoxia group. Further, compared with the acute intermittent hypoxia group, rats in chronic intermittent hypoxia group exhibited higher measures of ventilatory responses after 1 day of intermittent hypoxia (P < 0.05). These effects peaked after 3 days of intermittent hypoxia treatment and then decreased gradually. Moreover, these changes were diminished in the experimental group. 5-HT expression in the RMg region increased after chronic intermittent hypoxia, which was consistent with the changing trend of ventilatory responses. While activation of the 5-HT1A receptor in the RMg region alleviated this phenomenon. CONCLUSIONS: The results indicate that RMg 5-HT1A receptor, via changing the expression level of 5-HT in the RMg region, is involved in the modulation of the increased ventilatory responses induced by intermittent hypoxia.


Assuntos
Hipóxia/metabolismo , Núcleo Magno da Rafe/metabolismo , Ventilação Pulmonar/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Volume de Ventilação Pulmonar/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hipóxia/tratamento farmacológico , Hipóxia/fisiopatologia , Masculino , Núcleo Magno da Rafe/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
3.
Curr Med Res Opin ; 38(5): 721-730, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35350937

RESUMO

OBJECTIVE: The robust enrollment in SPARTAN and SAMURAI provided the opportunity to present post-hoc descriptive details on migraine disease characteristics and treatment outcomes after treatment with lasmiditan, a selective serotonin (5-HT1F) receptor agonist, in racial and ethnic subgroups. METHODS: Descriptive data from racial (White [W](n = 3471) and Black or African American [AA](n = 792)) and ethnic (Hispanic or Latinx [HL](n = 775) and Non-Hispanic or Latinx [Non-HL](n = 3637)) populations are presented on pooled data from two double-blind, placebo-controlled, randomized Phase 3 studies (SAMURAI [NCT02439320] and SPARTAN [NCT2605174]). Patients were treated with lasmiditan (50 (SPARTAN only), 100, or 200 mg) or placebo for a single migraine attack of moderate-to-severe intensity. Efficacy data were recorded in an electronic diary at baseline, 30, 60, 90, and 120 min. Safety was evaluated and reported by occurrences of adverse events. RESULTS: Clinical characteristics were generally similar across populations. W participants had longer migraine history than AA participants, and Non-HL participants had more migraine disability than HL participants. In the lasmiditan single-attack studies, AA participants waited longer than W participants to take study drug. A higher proportion of HL participants rated baseline migraine severity as severe compared to Non-HL participants. Response to lasmiditan was similar across racial and ethnic groups, including pain response, freedom from most bothersome symptom and migraine-related disability, and safety and tolerability. Across multiple outcomes, AA and HL participants tended to report more positive outcomes. CONCLUSIONS: There were few differences in demographic and clinical characteristics across racial and ethnic groups. Similar lasmiditan efficacy and safety outcomes were observed in AA versus W participants, and in HL versus Non-HL participants. Small observed differences may be driven by a tendency toward a more positive response observed across all treatment groups by AA and HL participants.


Assuntos
Transtornos de Enxaqueca , Agonistas do Receptor de Serotonina , Benzamidas , Método Duplo-Cego , Humanos , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas , Agonistas do Receptor de Serotonina/efeitos adversos , Resultado do Tratamento
4.
Brain Res ; 1783: 147859, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35245487

RESUMO

The ability to adapt to stress is an essential defensive function of a living body, and disturbance of this ability in the brain may contribute to the development of affective illness. Previously, we reported that mice exposed to unadaptable restraint stress show emotional abnormality. Moreover, this emotional abnormality was alleviated by chronic treatment with flesinoxan, a serotonin (5-HT)1A receptor agonist. 5-HT1A receptor expression is regulated by several transcription factors such as nuclear deformed epidermal autoregulatory factor (NUDR/Deaf-1) and five prime repressors under dual repression binding protein 1 (Freud-1). The present study was designed to investigate the expression levels of 5-HT1A receptor and its transcription factors in the midbrain and hippocampus of stress-adaptive and -unadaptive mice. Mice were exposed to 14 days of repeated adaptable (1 h/day) or repeated unadaptable (4 h/day) restraint stress, or were left in their home cage (non-stressed groups). In a western blot analysis, a significant increase in the expression levels of 5HT1A receptor protein were observed in the hippocampal membrane fraction in stress-adaptive mice. In contrast, the expression levels of 5-HT1A receptor protein in stress-unadaptive mice were significantly increased in both cytoplasmic and membrane fraction of the midbrain. Furthermore, real-time PCR analysis revealed that, in the midbrain of stress-unadaptive mice, the expression levels of 5-HT1A receptor mRNA and Freud-1 or NUDR mRNA were significantly increased and decreased, respectively. These results suggest that increased expression of 5-HT1A receptor due to decrease in the expression of Freud-1 and NUDR in the midbrain may play a pivotal role in the emotional abnormality of stress-unadaptive mice.


Assuntos
Receptor 5-HT1A de Serotonina , Fatores de Transcrição , Animais , Regulação da Expressão Gênica , Mesencéfalo/metabolismo , Camundongos , RNA Mensageiro/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Serotonina , Agonistas do Receptor de Serotonina , Fatores de Transcrição/metabolismo
5.
ChemMedChem ; 17(10): e202100759, 2022 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-35286016

RESUMO

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1A (5-HT1A ) demonstrates a unique ability to inhibit ß-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT1A receptor. The compounds were prepared by conjugating the scaffold of the 5-HT1A receptor agonist 8-OH-DPAT with two fluorophores suitable for live-cell imaging. Compound 5a {5-(dimethylamino)-N-[5-[(8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino]pentyl]naphtalen-1-sulfonammide} showed high affinity for the 5-HT1A receptor (Ki =1.8 nM). Fluoroprobe 5a was able to label the 5-HT1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co-administration of the 5-HT1A receptor antagonist WAY-100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor's role.


Assuntos
Ilhotas Pancreáticas , Receptor 5-HT1A de Serotonina , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Humanos , Agonistas do Receptor de Serotonina/farmacologia
6.
Int J Mol Sci ; 23(4)2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35216076

RESUMO

The neurotransmitter serotonin (5-HT) plays an important role in mood disorders. It has been demonstrated that 5-HT signaling through 5-HT1A receptors (5-HT1A-R) is crucial for early postnatal hippocampal development and later-life behavior. Although this suggests that 5-HT1A-R signaling regulates early brain development, the mechanistic underpinnings of this process have remained unclear. Here we show that stimulation of the 5-HT1A-R at postnatal day 6 (P6) by intrahippocampal infusion of the agonist 8-OH-DPAT (D) causes signaling through protein kinase Cε (PKCε) and extracellular receptor activated kinase ½ (ERK1/2) to boost neuroblast proliferation in the dentate gyrus (DG), as displayed by an increase in bromodeoxy-uridine (BrdU), doublecortin (DCX) double-positive cells. This boost in neuroproliferation was eliminated in mice treated with D in the presence of a 5-HT1A-R antagonist (WAY100635), a selective PKCε inhibitor, or an ERK1/2-kinase (MEK) inhibitor (U0126). It is believed that hippocampal neuro-progenitors undergoing neonatal proliferation subsequently become postmitotic and enter the synaptogenesis phase. Double-staining with antibodies against bromodeoxyuridine (BrdU) and neuronal nuclear protein (NeuN) confirmed that 5-HT1A-R → PKCε → ERK1/2-mediated boosted neuroproliferation at P6 also leads to an increase in BrdU-labeled granular neurons at P36. This 5-HT1A-R-mediated increase in mature neurons was unlikely due to suppressed apoptosis, because terminal deoxynucleotidyl transferase dUTP nick-end labeling analysis showed no difference in DNA terminal labeling between vehicle and 8-OH-DPAT-infused mice. Therefore, 5-HT1A-R signaling through PKCε may play an important role in micro-neurogenesis in the DG at P6, following which many of these new-born neuroprogenitors develop into mature neurons.


Assuntos
Hipocampo/metabolismo , Neurogênese/fisiologia , Proteína Quinase C-épsilon/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Serotonina/metabolismo , Transdução de Sinais/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Bromodesoxiuridina/farmacologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos
7.
Neurosci Lett ; 771: 136459, 2022 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-35041907

RESUMO

Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the "TS + fentanyl" and "saline + fentanyl" group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.


Assuntos
Analgésicos Opioides/toxicidade , Fentanila/toxicidade , Isoindóis/uso terapêutico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Insuficiência Respiratória/tratamento farmacológico , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Feminino , Isoindóis/administração & dosagem , Masculino , Camundongos , Nociceptividade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/etiologia , Agonistas do Receptor de Serotonina/administração & dosagem
8.
Eur J Pharmacol ; 918: 174774, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35077674

RESUMO

Deficits in the translation between egocentric-allocentric strategies may become another diagnostic mark for neurodegenerative disorders, especially Alzheimer's disease. Regarding the specific regional distribution of serotonin-1A receptor in brain areas mediating allocentric (externally-centered) spatial navigation to the escape location, here we studied the effects of median raphe nucleus serotonin-1A autoreceptors stimulation, [8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT); 4 µg/0.5 µl saline], of a selective cholinergic denervation by intracerebroventricular administration of the 192IgG saporin (1µl/each ventricle), on male Wistar rats search strategies in a Morris maze during acquisition, and before probe sessions. Despite some evidence of spatial hippocampal dependent knowledge to those PBS/Saline animals, their performance dropped to chance levels on probe trial. Therefore, we considered two probabilities and first analyzed the ability of the rats to make better use of one or more strategies. We showed statistically significant increases in the distances associated with egocentric (body-centered) non-spatial strategies, random searching in particular, in 192IgG/8OH rats, which led to their improved performance. Second, considering to what extent a shift in search strategy use improves performance indicated that 8-OH-DPAT alone did not affect learning since it appeared the related performance was impaired over days. However, the strategy choices made by 192IgG/8OH rats increased performance by more than 12% compared to 192IgG/Saline rats, an effect reversed with pre-treatment by serotonin-1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635). The results strongly suggest the potential role of serotonergic system, via the serotonin-1A receptors, in spatial navigation. We argue that the receptors are of interest as therapeutic targets that can be used against age-related cognitive decline.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Anticorpos Monoclonais/farmacologia , Encéfalo , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Saporinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Navegação Espacial , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Colinérgicos/farmacologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Infusões Intraventriculares , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Navegação Espacial/efeitos dos fármacos , Navegação Espacial/fisiologia
9.
Exp Dermatol ; 31(4): 600-607, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34726306

RESUMO

Psoriasis pain is a common symptom underestimated and rarely evaluated in psoriasis clinical trials. This work aimed to investigate whether the development of secondary chronic allodynia and hyperalgesia in the imiquimod (IMQ)-induced psoriasis mice model could be modulated by anti-inflammatory agents and compound 48/80 (C48/80) and to determine whether the activation of 5-HT1A receptor modulates these nociceptive behaviours. C57BL/6 male mice were treated with 5% IMQ for 7 days. The paw withdrawal responses to von Frey filaments (10 and 250 mN) were used to assess the allodynia and hyperalgesia. Nociceptive behaviours were also evaluated using ketorolac 15 mg/kg s.c., adalimumab 10 mg/kg s.c. and C48/80 10 mg/kg i.p. Then, the serum serotonin and the impact of 8-OH-DPAT (1 mg/kg s.c), a 5-HT1A receptor agonist, on long-lasting pain were examined. Mice receiving IMQ showed enhanced nociception, which decreased with all tested compounds. The serum serotonin in the IMQ group showed a significant decrease (947.042 ng/ml) regarding the control group (1143.68 ng/ml). The pretreatment with 8-OH-DPAT alleviated pain-related behaviours. These results suggest that the long-lasting pain resulting from psoriasis inflammation is also associated with the serotonergic system. The 5-HT1A receptor should be further explored as a potential therapeutic target for psoriasis pain modulation.


Assuntos
Dor Crônica , Psoríase , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/uso terapêutico , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Imiquimode , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/induzido quimicamente , Psoríase/complicações , Psoríase/tratamento farmacológico , Receptor 5-HT1A de Serotonina , Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico
10.
Respir Physiol Neurobiol ; 296: 103810, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728431

RESUMO

Systemic 8-OH-DPAT (a 5-HT1A receptor agonist) challenge evokes hyperventilation independent of peripheral 5-HT1A receptors. Though the pre-Botzinger Complex (PBC) is critical in generating respiratory rhythm and activation of local 5-HT1A receptors induces tachypnea via disinhibition of local GABAA neurons, its role in the respiratory response to systemic 8-OH-DPAT challenge is still unclear. In anesthetized rats, 8-OH-DPAT (100 µg/kg, iv) was injected twice to confirm the reproducibility of the evoked responses. The same challenges were performed after bilateral microinjections of (S)-WAY-100135 (a 5-HT1A receptor antagonist) or gabazine (a GABAA receptor antagonist) into the PBC. Our results showed that: 1) 8-OH-DPAT caused reproducible hyperventilation associated with hypotension and bradycardia; 2) microinjections of (S)-WAY-100135 into the PBC attenuated the hyperventilation by ˜60 % without effect on the evoked hypotension and bradycardia; and 3) the same hyperventilatory attenuation was also observed after microinjections of gabazine into the PBC. Our data suggest that PBC 5-HT1A receptors play a key role in the respiratory response to systemic 8-OH-DPAT challenge likely via disinhibiting local GABAergic neurons.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Antagonistas GABAérgicos/farmacologia , Hiperventilação/induzido quimicamente , Hiperventilação/tratamento farmacológico , Bulbo/metabolismo , Receptor 5-HT1A de Serotonina/fisiologia , Centro Respiratório/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Modelos Animais de Doenças , Masculino , Bulbo/efeitos dos fármacos , Piperazinas/farmacologia , Piridazinas/farmacologia , Ratos , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Centro Respiratório/efeitos dos fármacos
11.
J Psychopharmacol ; 36(3): 273-294, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34666554

RESUMO

BACKGROUND: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring, short-acting psychedelic tryptamine, produced by a variety of plant and animal species. Plants containing 5-MeO-DMT have been used throughout history for ritual and spiritual purposes. The aim of this article is to review the available literature about 5-MeO-DMT and inform subsequent clinical development. METHODS: We searched PubMed database for articles about 5-MeO-DMT. Search results were cross-checked against earlier reviews and reference lists were hand searched. Findings were synthesised using a narrative synthesis approach. This review covers the pharmacology, chemistry and metabolism of 5-MeO-DMT, as well epidemiological studies, and reported adverse and beneficial effects. RESULTS: 5-MeO-DMT is serotonergic agonist, with highest affinity for 5-HT1A receptors. It was studied in a variety of animal models, but clinical studies with humans are lacking. Epidemiological studies indicate that, like other psychedelics, 5-MeO-DMT induces profound alterations in consciousness (including mystical experiences), with potential beneficial long-term effects on mental health and well-being. CONCLUSION: 5-MeO-DMT is a potentially useful addition to the psychedelic pharmacopoeia because of its short duration of action, relative lack of visual effects and putatively higher rates of ego-dissolution and mystical experiences. We conclude that further clinical exploration is warranted, using similar precautions as with other classic psychedelics.


Assuntos
Alucinógenos , Metoxidimetiltriptaminas , Animais , Alucinógenos/farmacologia , Agonistas do Receptor de Serotonina
12.
Pharmacol Ther ; 229: 107937, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34174274

RESUMO

Biased agonism (or "functional selectivity") at G-protein-coupled receptors has attracted rapidly increasing interest as a means to improve discovery of more efficacious and safer pharmacotherapeutics. However, most studies are limited to in vitro tests of cellular signaling and few biased agonists have progressed to in vivo testing. As concerns 5-HT1A receptors, which exert a major control of serotonergic signaling in diverse CNS regions, study of biased agonism has previously been limited by the poor target selectivity and/or partial agonism of classically available ligands. However, a new generation of highly selective, efficacious and druggable agonists has advanced the study of biased agonism at this receptor and created new therapeutic opportunities. These novel agonists show differential properties for G-protein signaling, cellular signaling (particularly pERK), electrophysiological effects, neurotransmitter release, neuroimaging by PET and pharmacoMRI, and behavioral tests of mood, motor activity and side effects. Overall, NLX-101 (a.k.a. F15599) exhibits preferential activation of cortical and brain stem 5-HT1A receptors, whereas NLX-112 (a.k.a. befiradol or F13640) shows prominent activation of 5-HT1A autoreceptors in Raphe nuclei and in regions associated with motor control. Accordingly, NLX-101 is potently active in rodent models of depression and respiratory control, whereas NLX-112 shows promising activity in models of Parkinson's disease across several species - rat, marmoset and macaque. Moreover, NLX-112 has also been labeled with 18F to produce the first agonist PET radiopharmaceutical (known as [18F]-F13640) for investigation of the active state of 5-HT1A receptors in rodent, primate and human. The structure-functional activity relationships of biased agonists have been investigated by receptor modeling and novel compounds have been identified which exhibit increased affinity at 5-HT1A receptors and new profiles of cellular signaling bias, notably for ß-arrestin recruitment versus pERK. Taken together, the data suggest that 5-HT1A receptor biased agonists constitute potentially superior pharmacological agents for treatment of CNS disorders involving serotonergic mechanisms.


Assuntos
Receptor 5-HT1A de Serotonina , Serotonina , Animais , Encéfalo , Humanos , Ratos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/farmacologia
13.
Biopharm Drug Dispos ; 43(1): 23-32, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34923646

RESUMO

Sumatriptan was introduced in 1983, as the first of the triptans, selective 5-hydroxytryptamine (5-HT1B/1D ) receptor agonists, to treat moderate to severe migraine. Migraine predominates in females. Although there have been reports of sex differences in migraine-associated features and pharmacokinetics (PKs) of some triptans, sex differences in the PKs of oral sumatriptan have never been evaluated in Korean. We conducted this study of oral sumatriptan to assess the sex differences in Korean population. Thirty-eight healthy Korean subjects who participated in two separate clinical studies receiving a single oral dose of 50 mg sumatriptan with the same protocols were included in this analysis. A total of 532 sumatriptan concentration observations were used for a population PK modeling. Validation of final population PK model of sumatriptan was performed using bootstrap and visual predictive check. The PK profile of oral sumatriptan was adequately described by a one-compartmental model with combined transit compartment model and a first-order absorption. The covariate analysis showed that the clearance of oral sumatriptan was significantly higher in males than in females (male: 444 L/h, female: 281 L/h). Our results showed that there were sex differences in the clearance of oral sumatriptan. These results encourage further studies to establish the sumatriptan pharmacokinetic-pharmacodynamic model considering sex-related PK differences, which may help to determine optimal dosing regimens for effective treatment of migraine in males and females. Clinical trial registration: CRIS Registration No. KCT0001784.


Assuntos
Transtornos de Enxaqueca , Sumatriptana , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/tratamento farmacológico , República da Coreia , Agonistas do Receptor de Serotonina , Caracteres Sexuais
14.
Lancet Psychiatry ; 9(2): 113-124, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34919834

RESUMO

BACKGROUND: Major depressive disorder is a severe illness that frequently manifests before the age of 18 years, often recurring later in life. Paediatric medical treatment options are scarce. The melatonin receptor agonist and 5-hydroxytryptamine2C receptor antagonist agomelatine is used to treat adults, and could offer a new therapeutic option for paediatric patients. Therefore, we aimed to investigate the short-term antidepressant efficacy and safety of agomelatine in children and adolescents with major depressive disorder. METHODS: We performed a 12 week, randomised, double-blind, parallel-group, multicentre, phase 3 trial in 46 specialist psychiatric units or centres in Bulgaria, Finland, Hungary, Poland, Romania, Russia, Serbia, South Africa, and Ukraine. Participants (aged 7-17 years) were eligible if they were unresponsive to psychosocial therapy during the 3-week run-in period (Children's Depression Rating Scale-revised [CDRS-R] score of ≥45). Ethnicity was not recorded. We investigated short-term antidepressant efficacy of agomelatine (10 mg or 25 mg per day) versus placebo with an active control (fluoxetine 10-20 mg depending on symptom severity) after 12 weeks of treatment in children (aged 7-11 years) and adolescents (12-17 years) with major depressive disorder. Patients were randomly assigned (1:1:1:1) to agomelatine 10 mg, agomelatine 25 mg, placebo, or fluoxetine via an interactive response system with permuted-block randomisation. Standardised manualised psychosocial counselling, developed for this trial, was initiated from selection and continued throughout the study, including the open-label extension. All people involved in the conduct of the clinical trial and patients were masked to treatment allocation. Study outcomes were measured using standardised interviews at each study visit. The primary endpoint was change in CDRS-R raw score from baseline to week 12. This study is registered with EudraCT, 2015-002181-23. FINDINGS: Between Feb 23, 2016, and Jan 14, 2020, 466 individuals were assessed for eligibility and of 400 included patients, 396 (247 [62%] girls, 149 [38%] boys; mean age 13·7 years [SD 2·7]) were analysed (full analysis set). The primary objective was met; 25 mg/day agomelatine (n=94, with n=102 receiving 10 mg/day) resulted in an improvement versus placebo (n=101) in CDRS-R raw score of 4·22 (95% CI 0·63-7·82; p=0·040) at 12 weeks, with a similar effect for fluoxetine (n=99), establishing assay sensitivity. The overall effect was confirmed in adolescents (n=317), but not in children (n=79). No unexpected safety signals were observed with agomelatine, with no significant weight gain or effect on suicidal behaviours. INTERPRETATION: This first study in a paediatric population supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals. This medication could provide another option in the limited psychopharmaceutical repertoire for management of major depressive disorder. FUNDING: Servier. VIDEO ABSTRACT.


Assuntos
Acetamidas/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Agonistas do Receptor de Serotonina/administração & dosagem , Acetamidas/efeitos adversos , Adolescente , Criança , Aconselhamento , Transtorno Depressivo Maior/terapia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Agonistas do Receptor de Serotonina/efeitos adversos
16.
Behav Brain Res ; 418: 113660, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34752844

RESUMO

Accumulating studies consistently show that methylphenidate (MPD), the first line drug for treating Attention-Deficit Hyperactivity Disorder (ADHD), is abused by patients to whom the drug is prescribed. Like other psychostimulants, only low doses of MPD improve cognitive performance while higher doses impair it. Preventing the use of high doses of MPD is important for retaining its therapeutic efficacy. Previously, it has been shown that performance in Morris water maze test is improved in rats treated, orally, with MPD in doses of 2.5 mg/kg; but higher doses (5 mg/kg) impair it. The present study is designed to monitor rewarding effects of 2.5 mg/kg MPD in conditioned place preference (CPP) paradigm and its potential inhibition in buspirone co-treated animals. Our results show that rewarding effects of MPD in CPP paradigm are prevented in rats co-treated with buspirone in doses of 0.1 and 0.3 mg/kg. Animals treated with MPD exhibit a downregulation of 5-HT1A receptor mRNA in the nucleus accumbens which is also prevented in rats co-treated with 0.1 and 0.3 mg/kg but not 1.0 and 2.0 mg/kg buspirone. Administration of buspirone in these doses is not rewarding in CPP test and upregulates 5-HT1A receptor mRNA in the nucleus accumbens. The findings suggest that co-use of low doses of buspirone can prevent rewarding effects of MPD to help retain its therapeutic efficacy.


Assuntos
Buspirona/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Metilfenidato/farmacologia , Núcleo Accumbens/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptor 5-HT1A de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Relação Dose-Resposta a Droga , Masculino , Ratos , Receptor 5-HT1A de Serotonina/metabolismo , Recompensa
17.
Aggress Behav ; 48(2): 197-204, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34904727

RESUMO

Severe aggressive behavior of juvenile pufferfish affects economic efficiency and fish welfare in aquaculture. 5-HT plays an important role in regulating the aggressive behavior of fish in aquaculture environment. This study examined the effects of different concentrations (0, 0.25, 0.5, 1 mg/kg) of 8-OH-DPAT, a selective 5-HT1A receptor agonist, on the aggressive behavior of juvenile pufferfish. Forty-five minutes after drug injection, the aggressive behavior of juvenile fish was recorded for 20 min, including the latency to the first attack and the frequency of aggressive behaviors. The results showed no significant differences in the latency to the first attack of juvenile fish among treatment groups. During the first 10 min of the observation period, there was no significant difference in the total aggressive acts and locomotor activity among treatment groups. Total aggressive acts and locomotor activity were the least in the 1 mg/kg 8-OH-DPAT-treated during the 20 min observation period. Both aggressive behavior and locomotor activity were negatively correlated with 8-OH-DPAT treatment overall, respectively. The above results suggested that the serotonergic system activation had suppressive effects on aggressive behavior and locomotor activity in juvenile pufferfish.


Assuntos
Receptor 5-HT1A de Serotonina , Takifugu , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Agressão/fisiologia , Animais , Humanos , Agonistas do Receptor de Serotonina/farmacologia
18.
Medicine (Baltimore) ; 100(51): e28003, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34941040

RESUMO

RATIONALE: Irritable bowel syndrome (IBS) is a chronic and debilitating functional disorder of the gastrointestinal tract manifested by abdominal pain and bowel habit dysregulation. The pathophysiology is complex and management targets symptom resolution. Therapeutic interventions range from dietary modification, psychological interventions, exercise, to the use of antispasmodics, antibiotics, and antidepressants. Anecdotal reports have suggested that buspirone may be beneficial in the treatment of functional dyspepsia and IBS and its physiological effect of reducing gastric tone provides a rational for its benefit. PATIENT CONCERNS: A 28-year-old man with unremarkable past medical and psychiatric history presented with worsening abdominal pain, bloating, and bowel movement dysregulation of over 6-year duration. DIAGNOSES: Physical examination revealed mild distension and discomfort on deep palpation. Thorough blood investigations, stool analysis and culture, and imaging were unremarkable except for the detection of mucus with stool. The patient was diagnosed with irritable bowel syndrome with mixed habits. INTERVENTIONS: Dietary adjustment and a range of medications (mebeverine, simethicone, loperamide, rifaximin, sertraline and amitriptyline) yielded unsatisfactory response of were not tolerated. Buspirone was eventually introduced. OUTCOMES: Buspirone was associated with a significant and sustained improvement in IBS symptoms and quality of life. LESSONS: This case suggests that buspirone was effective in treating refractory IBS. Further research is needed to assess the role of buspirone in IBS management.


Assuntos
Buspirona/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Agonistas do Receptor de Serotonina/uso terapêutico , Dor Abdominal/tratamento farmacológico , Dor Abdominal/etiologia , Adulto , Humanos , Masculino , Qualidade de Vida
19.
PLoS One ; 16(11): e0259104, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34762657

RESUMO

Cestodes are platyhelminth parasites with a wide range of hosts that cause neglected diseases. Neurotransmitter signaling is of critical importance for these parasites which lack circulatory, respiratory and digestive systems. For example, serotonin (5-HT) and serotonergic G-protein coupled receptors (5-HT GPCRs) play major roles in cestode motility, development and reproduction. In previous work, we deorphanized a group of 5-HT7 type GPCRs from cestodes. However, little is known about another type of 5-HT GPCR, the 5-HT1 clade, which has been studied in several invertebrate phyla but not in platyhelminthes. Three putative 5-HT GPCRs from Echinococcus canadensis, Mesocestoides vogae (syn. M. corti) and Hymenolepis microstoma were cloned, sequenced and bioinformatically analyzed. Evidence grouped these new sequences within the 5-HT1 clade of GPCRs but differences in highly conserved GPCR motifs were observed. Transcriptomic analysis, heterologous expression and immunolocalization studies were performed to characterize the E. canadensis receptor, called Eca-5-HT1a. Functional heterologous expression studies showed that Eca-5-HT1a is highly specific for serotonin. 5-Methoxytryptamine and α-methylserotonin, both known 5-HT GPCR agonists, give stimulatory responses whereas methysergide, a known 5-HT GPCR ligand, give an antagonist response in Eca-5-HT1a. Mutants obtained by the substitution of key predicted residues resulted in severe impairment of receptor activity, confirming that indeed, these residues have important roles in receptor function. Immunolocalization studies on the protoscolex stage from E. canadensis, showed that Eca-5-HT1a is localized in branched fibers which correspond to the nervous system of the parasite. The patterns of immunoreactive fibers for Eca-5-HT1a and for serotonin were intimately intertwined but not identical, suggesting that they are two separate groups of fibers. These data provide the first functional, pharmacological and localization report of a serotonergic receptor that putatively belongs to the 5-HT1 type of GPCRs in cestodes. The serotonergic GPCR characterized here may represent a new target for antiparasitic intervention.


Assuntos
Cestoides/metabolismo , Proteínas de Helminto/metabolismo , Sistema Nervoso/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Sequência de Aminoácidos , Animais , Echinococcus/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Helminto/química , Proteínas de Helminto/genética , Humanos , Hymenolepis/metabolismo , Receptores 5-HT1 de Serotonina/química , Receptores 5-HT1 de Serotonina/genética , Alinhamento de Sequência , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
20.
J Headache Pain ; 22(1): 132, 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34742230

RESUMO

BACKGROUND: Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). METHODS: Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. RESULTS: Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. CONCLUSION: In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. TRIAL REGISTRATION: NCT03670810.


Assuntos
Transtornos de Enxaqueca , Agonistas do Receptor de Serotonina , Adulto , Benzamidas , Método Duplo-Cego , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas , Piridinas , Resultado do Tratamento
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