RESUMO
Despite recent advances, current antidepressants have considerable limitations: late onset of action and the high profile of refractoriness. Biomedical research with natural products has gained growing interest in the last years, and had provide useful candidates for new antidepressants. Riparins are a group of natural alkamides obtained from Aniba riparia, which had marked neuroactive effects, mainly as antidepressant and antinociceptive agents. We made modifications of the basic structure of riparins, originating a synthetic alkamide, also known as riparin IV (RipIV). RipIV demonstrated a superior analgesic effect than its congeners and a marked antidepressant-like effect. However, the basic mechanism for the central effects of RipIV remains unknown. Here, we aimed to investigate the participation of monoaminergic neurotransmission targets in the antidepressant-like effects of RipIV. To do this, we applied a combined approach of experimental (classical pharmacology and neurochemistry) and computer-aided techniques. Our results demonstrated that RipIV presented antidepressant- and anxiolytic-like effects without modifying locomotion and motor coordination of mice. Also, RipIV increased brain monoamines and their metabolite levels. At the higher dose (100â¯mg/kg), RipIV increased serotonin concentrations in all studied brain areas, while at the lower one (50â¯mg/kg), it increased mainly dopamine and noradrenaline levels. When tested with selective receptor antagonists, RipIV antidepressant effect showed dependence of the activation of multiple targets, including D1 and D2 dopamine receptors, 5-HT2A/2, 5-HT3 receptors and α2 adrenergic receptors. Molecular docking demonstrated favorable binding conformation and affinity of RipIV to monoamine oxidase B (MAO-B), serotonin transporter (SERT), α1 receptor, D2 receptor, dopamine transporter (DAT) and at some extent GABA-A receptor. RipIV also presented a computationally predicted favorable pharmacokinetic profile. Therefore, this study demonstrated the involvement of monoaminergic targets in the mechanism of RipIV antidepressant-like action, and provide evidence of it as a promising new antidepressant.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Monoaminoxidase/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Tiramina/análogos & derivados , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bupropiona/farmacologia , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Fluoxetina/farmacologia , Imipramina/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Norepinefrina/metabolismo , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Receptores de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/efeitos dos fármacos , Receptores 5-HT2 de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/metabolismo , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tiramina/farmacologiaRESUMO
Epidemiologic studies describe a potential risk of depression and suicide in farm workers exposed to organophosphates (OPs). In a previous study we observed an increase in depressive-like behavior in adult mice exposed to the OP pesticide methamidophos. Considering the association between depression and the serotonergic (5HT) system, in the present study we investigated whether a subchronic exposure to methamidophos affects the serotonergic system of adult mice. From postnatal day 60 to 89 (PN60 to PN89), one of two concentrations of methamidophos (higher dose: 5.25 µg/ml; lower dose: 1.31 µg/ml) or vehicle was administered in the drinking water of male Swiss mice. We evaluated three serotonergic biomarkers during (PN89) and after (PN100) the exposure period: 5HT(1A) receptor binding with [(3)H]OH-DPAT, 5HT(2) receptor binding with [(3)H]ketanserin and 5HT transporter binding with [(3)H]paroxetine. Methamidophos elicited robust decreases in binding for all 5HT markers. These decreases were evident in brain regions containing 5HT cell bodies and dendritic arbors (midbrain, brainstem) as well as in the cerebral cortex, which contains 5HT projections. In the cerebral cortex, effects were identified in mice exposed to the higher dose of methamidophos while in the midbrain and brainstem, both doses elicited significant effects. Overall, effects were present both during and after exposure, even though there were some regional disparities regarding the persistence of effects. Our results indicate that exposure to methamidophos affects synaptic transmission promoting decreases of specific serotonergic biomarkers. These data suggest a mechanism of action of this pesticide that might explain the increased depressive-like behavior in adult mice.
Assuntos
Encéfalo/efeitos dos fármacos , Inseticidas/toxicidade , Compostos Organotiofosforados/toxicidade , Serotonina/metabolismo , Fatores Etários , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Regulação para Baixo , Masculino , Camundongos , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/efeitos dos fármacos , Receptores 5-HT2 de Serotonina/metabolismo , Medição de Risco , Fatores de Risco , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Fatores de TempoRESUMO
Sibutramine has been described as an anti-obesity drug with the ability to inhibit serotonin (5-HT), noradrenaline, and dopamine re-uptake, but without affinity to histamine and muscarinic receptors. On the other hand, cyproheptadine antagonizes serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C), histamine H1, and muscarinic (M) receptors. There are many reports concerning the influence of sibutramine on central serotoninergic pathways. In this study, we suggest that peripheral pathways may also be involved in the serotoninergic effects of sibutramine. In vivo experiments were undertaken to investigate the serotoninergic effects of sibutramine on body mass, the glycogen concentration in the diaphragm of rats, and locomotor behaviour. Rats were submitted to oral treatment with sibutramine, cyproheptadine, or sibutramine applied in combination with cyproheptadine, for a period of 2 months to investigate the 5-HT2 effects of sibutramine on these parameters. As the results demonstrated, the lower increase in body mass and the increased glycogen levels in the diaphragm muscle of rats treated with sibutramine seem to be modulated by 5-HT2 receptors, since these effects were completely antagonized by cyproheptadine in the group treated with the 2 drugs co-applied. Furthermore, the behavioural results also suggest that mechanisms modulated by 5-HT2 receptors are involved in the increase of locomotion in the rats treated with sibutramine, since the effect did not occur in the rats treated with sibutramine co-applied with the 5-HT2 receptor antagonist, cyproheptadine. The results suggest that sibutramine modifies energy-related parameters such as body mass, diaphragm glycogen, and locomotor behaviour in rats via 5-HT2 serotoninergic pathways.
Assuntos
Depressores do Apetite/farmacologia , Ciclobutanos/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores 5-HT2 de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Ciproeptadina/farmacologia , Diafragma/efeitos dos fármacos , Diafragma/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicogênio/metabolismo , Masculino , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Fatores de TempoRESUMO
The present study measured prolactin, cortisol, ACTH and growth hormone in healthy male volunteers following an acute oral administration of quetiapine, an atypical antipsychotic with high affinity for H1 and moderate affinity for sigma, alpha1, 5-HT2, alpha2 and D2 receptors. Fifteen male volunteers entered this randomized double-blind, cross-over, placebo-controlled study. Blood samples were drawn every 30 min from 09:00 hours to 13:00 hours. The first samples were drawn immediately before the administration of 150 mg quetiapine or placebo. Mean results for each hormone and ANOVA for repeated measures were performed. The area under the curve (AUC) hormonal values were calculated and compared by paired t test. The ANOVA showed an increase of prolactin after quetiapine administration from time 60 min up to the end of the observation period. Cortisol decreased after quetiapine administration from time 150 min to time 240 min. ACTH secretion showed no difference compared to placebo. There was a late increase in growth hormone secretion, significant in comparison with placebo only at time 210 min. The AUC values were statistically different for prolactin and cortisol compared to placebo. A single dose of quetiapine (150 mg) increased prolactin secretion probably due to a transiently high D2 receptor occupancy at the anterior pituitary. Cortisol secretion decreased as was expected from quetiapine's pharmacodynamic profile. The lack of response of ACTH might be, at least in part, explained by the low hormonal assay sensitivity. The late growth hormone increase might have been due to quetiapine's antagonism of H1 receptors.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Antipsicóticos/farmacologia , Dibenzotiazepinas/farmacologia , Hormônio do Crescimento Humano/sangue , Hidrocortisona/sangue , Prolactina/sangue , Adolescente , Adulto , Antipsicóticos/efeitos adversos , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Estudos Cross-Over , Dibenzotiazepinas/efeitos adversos , Método Duplo-Cego , Humanos , Masculino , Hipófise/efeitos dos fármacos , Hipófise/fisiologia , Fumarato de Quetiapina , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H1/fisiologia , Receptores 5-HT2 de Serotonina/efeitos dos fármacos , Receptores 5-HT2 de Serotonina/fisiologiaRESUMO
Due to the stimulatory action of serotonin (5HT) and nitric oxide (NO) on the secretion of gonadotropins and PRL, this work aimed at investigating the participation of serotoninergic receptors 5HT(1) and 5HT(2) of the medial preoptic area (MPOA) in the control of luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL) secretion and the possible modulation by ovarian steroids as well as the possible participation of NO as a mediator of the stimulatory effects of serotonin in the MPOA on LH secretion. Microinjections of three different doses (0.02, 0.2, and 2 ug) of methiothepin, a serotoninergic 5HT(1) antagonist or ketanserin, a seretoninergic 5HT(2) antagonist, were carried out into the MPOA in ovariectomized rats treated or not with estrogen or estrogen plus progesterone. Other groups of ovariectomized rats treated with estrogen, estrogen plus progesterone or vehicle were prepared to evaluate NOS activity in the MPOA. Plasma LH, FSH, and PRL in ovariectomized rats were not altered by the microinjection of methiothepin or ketanserin in the MPOA. Methiothepin microinjection in the MPOA reduced LH but did not change plasma FSH and PRL in ovariectomized rats treated with estrogen or estrogen plus progesterone. On the other hand, ketanserin microinjection in the MPOA reduced plasma LH and FSH but did not change plasma PRL in the animals submitted to the same steroidal treatment. NOS activity in the MPOA was significantly reduced by methiothepin or ketanserin in ovariectomized rats treated with estrogen or estrogen plus progesterone. In conclusion, this work showed that in the studied conditions, serotonin in the MPOA: (1) does not work in the control of PRL secretion through 5HT(1) and 5HT(2) receptors; (2) integrates the control of FSH secretion by 5HT(2) receptors, but not 5HT(1); (3) in the presence of estrogen, stimulates LH secretion by 5HT(1) and 5HT(2) receptors, which can be differentially modulated by progesterone; (4) at least partly, stimulates LH secretion by nitric oxide activity.