RESUMO
G-protein-coupled receptors (GPCRs) play a major role in psychiatric disorders and are the targets of several current therapeutic approaches in this field. A number of studies have now shown that GPCRs can assemble as high molecular weight homo- and hetero-oligomers, which could affect ligand binding, intracellular signalling or trafficking. This information could be critical in design of new drugs to treat neurological and psychiatric disorders. This chapter describes a sequential co-immunoprecipitation and immunoblot protocol for determining oligomerisation of the 5-hydroxytryptamine (HT)1A receptor with other GPCRs in co-transfected HEK-293 cells.
Assuntos
Western Blotting/métodos , Cromatografia de Afinidade/métodos , Imunoprecipitação/métodos , Receptores Acoplados a Proteínas G/análise , Células HEK293 , Humanos , Oligopeptídeos , Multimerização Proteica , Proteínas Proto-Oncogênicas c-myc , Receptor 5-HT1A de Serotonina/análise , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT1B de Serotonina/análise , Receptor 5-HT1B de Serotonina/química , Receptor 5-HT1D de Serotonina/análise , Receptor 5-HT1D de Serotonina/química , Receptores Acoplados a Proteínas G/química , Proteínas Recombinantes de Fusão/análise , Proteínas Recombinantes de Fusão/química , TransfecçãoRESUMO
BACKGROUND: Migraine is a highly prevalent neurovascular disorder. OBJECTIVE: Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5-HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder. Indeed, the development of sumatriptan and second generation triptans in the 1990's led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors). Although the triptans represent the current mainstay of acute antimigraine treatment, a number of patients do not respond well to the triptans and are contraindicated in patients with cardiovascular pathologies. CONCLUSION: This mini-review outlines further developments in the design of novel (non-vasoconstrictor) antimigraine treatments acting via 5-HT receptors, including selective agonists at 5-HT1D and 5-HT1F receptors, agonists at 5-HT1B/1D receptors combined with other properties as well as antagonists at 5-HT2B/2C, 5-HT3 and 5-HT7 receptors. It also touches upon the recent development of antagonists and antibodies at calcitonin gene-related peptide (CGRP) and its receptors, which produce a direct blockade of the CGRPergic vasodilator mechanisms involved in migraine. These alternative pharmacological approaches will hopefully lead to less side-effects.
Assuntos
Desenho de Fármacos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Serotonina/metabolismo , Benzamidas/química , Benzamidas/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Piridinas/química , Piridinas/farmacologia , Receptor 5-HT1D de Serotonina/metabolismo , Serotonina/química , Agonistas do Receptor 5-HT1 de Serotonina/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêuticoRESUMO
Fluoxetine (FLX), a selective serotonin reuptake inhibitor is an antidepressant in the treatment of mood disorders. Its impact on reproductive processes is incompletely known. The present study analyzed the reproductive effects of FLX in prepubertal female rats. Two experiments were conducted. First (acute administration), 30-day-old female rats were injected intraperitoneally with 5mg/kg of fluoxetine-hydrochloride, and were terminated 24, 48 or 72h after the treatment. Second (subchronic administration), FLX was injected on days 30-33 of age, and the animals were terminated the day of first estrus. In acute treatment estradiol concentration increased to 72h. In subchronic treatment increased serotonin concentration in ovaries and decreased the number of ova shed. An increase in number of atretic follicles and oocyte fragmentation was observed in these animals. The results suggest that FLX acts on the ovary or hypothalamus-pituitary axis resulting in modifications of the follicular development and ovulation.
Assuntos
Fluoxetina/toxicidade , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Serotonina/metabolismo , Fatores Etários , Animais , Feminino , Hormônios Esteroides Gonadais/sangue , Hibridização Genética , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Oócitos/metabolismo , Oócitos/patologia , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Ovário/metabolismo , Ovário/patologia , Ovário/fisiopatologia , Ratos Long-Evans , Ratos Wistar , Receptor 5-HT1D de Serotonina/efeitos dos fármacos , Receptor 5-HT1D de Serotonina/genética , Receptor 5-HT1D de Serotonina/metabolismo , Maturidade Sexual , Fatores de TempoRESUMO
Serotonin (5-HT) participates in pain modulation by interacting with different 5-HT receptors. The role of 5-HT5A receptor in neuropathic pain has not previously studied. The purpose of this study was to investigate: A) the role of 5-HT5A receptors in rats subjected to spinal nerve injury; B) the expression of 5-HT5A receptors in dorsal spinal cord and dorsal root ganglia (DRG). Neuropathic pain was induced by L5/L6 spinal nerve ligation. Tactile allodynia in neuropathic rats was assessed with von Frey filaments. Western blot methodology was used to determine 5-HT5A receptor protein expression. Intrathecal administration (on day 14th) of 5-HT (10-100 nmol) or 5-carboxamidotryptamine (5-CT, 0.03-0.3 nmol) reversed nerve injury-induced tactile allodynia. Intrathecal non-selective (methiothepin, 0.1-0.8 nmol) and selective (SB-699551, 1-10 nmol) 5-HT5A receptor antagonists reduced, by ~60% and ~25%, respectively, the antiallodynic effect of 5-HT (100 nmol) or 5-CT (0.3 nmol). Moreover, both selective 5-HT1A and 5-HT1B/1D receptor antagonists, WAY-100635 (0.3-1 nmol) and GR-127935 (0.3-1 nmol), respectively, partially diminished the antiallodynic effect of 5-HT or 5-CT by about 30%. Injection of antagonists, by themselves, did not affect allodynia. 5-HT5A receptors were expressed in the ipsilateral dorsal lumbar spinal cord and DRG and L5/L6 spinal nerve ligation did not modify 5-HT5A receptor protein expression in those sites. Results suggest that 5-HT5A receptors reduce pain processing in the spinal cord and that 5-HT and 5-CT reduce neuropathic pain through activation of 5-HT5A and 5-HT1A/1B/1D receptors. These receptors could be an important part of the descending pain inhibitory system.
Assuntos
Neuralgia/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Medula Espinal/metabolismo , Nervos Espinhais/lesões , Analgésicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Vértebras Lombares , Metiotepina/farmacologia , Neuralgia/tratamento farmacológico , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Serotonina/análogos & derivados , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Medula Espinal/efeitos dos fármacos , TatoRESUMO
AIMS: The present study analyzed the potential antinociceptive effect of the antimigraine drugs sumatriptan, dihydroergotamine or methysergide in rats submitted to the formalin test. Moreover, by using selective antagonists, the role of 5-HT1B/1D serotonergic receptors was investigated in the antinociception induced by these antimigraine drugs. MAIN METHODS: The formalin test was used to assess the nociceptive activity. Overt pain-like behavior (flinching, 1h) and evoked nociception (long-lasting secondary mechanical allodynia and hyperalgesia, 6 days) were determined in the same rat. KEY FINDINGS: Ipsilateral, but not contralateral, pre-treatment (in µg/paw) with sumatriptan (10-300), methysergide (1-30) or dihydroergotamine (1-30) significantly prevented flinching behavior (at 1h) as well as secondary allodynia and hyperalgesia (at day 6) induced by formalin. Interestingly, the antinociceptive (flinching), antiallodynic and antihyperalgesic effects of sumatriptan were completely prevented by peripheral pre-treatment with selective antagonists at the 5-HT1B (SB 224289; 100) or 5-HT1D (BRL 15572; 100) receptors. In contrast, the acute antinociceptive effects of methysergide and dihydroergotamine were partially prevented by SB 224289 and BRL 15572. The antiallodynic and antihyperalgesic effects of both drugs were completely prevented by BRL 15572 and partially prevented by SB 224289. Given alone, SB 224289 or BRL 15572 did not modify per se the long-lasting secondary allodynia and hyperalgesia. SIGNIFICANCE: The above findings suggest that: (i) the antimigraine drugs sumatriptan, methysergide and dihydroergotamine reduce the acute and chronic nociception induced by formalin; and (ii) this antinociceptive effect results from activation of peripheral 5-HT1B/1D serotonergic receptors.
Assuntos
Hiperalgesia/metabolismo , Dor Nociceptiva/tratamento farmacológico , Receptor 5-HT1B de Serotonina/fisiologia , Receptor 5-HT1D de Serotonina/fisiologia , Antagonistas da Serotonina/uso terapêutico , Dor Aguda , Animais , Compostos de Bifenilo/uso terapêutico , Dor Crônica , Di-Hidroergotamina/uso terapêutico , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Formaldeído/toxicidade , Hiperalgesia/induzido quimicamente , Metisergida/uso terapêutico , Dor Nociceptiva/induzido quimicamente , Dor Nociceptiva/metabolismo , Piperazinas/uso terapêutico , Piperidonas/uso terapêutico , Ratos , Ratos Wistar , Compostos de Espiro/uso terapêutico , Sumatriptana/uso terapêuticoRESUMO
This study measured the effects of the preferential 5-HT1D/1B receptor agonist sumatriptan in healthy volunteers who performed the Simulated Public Speaking Test (SPST), which recruits the neural network involved in panic disorder and social anxiety disorder. In a double-blind, randomised experiment, 36 males received placebo (12), 50 mg (12) or 100 mg (12) of sumatriptan 2 h before the SPST. Subjective, physiological and hormonal measures were taken before, during and after the test. The dose of 100 mg of sumatriptan increased speech-induced fear more than either a 50mg dose of the drug or placebo. The largest dose of sumatriptan also enhanced vigilance more than placebo, without any change in blood pressure, heart rate or electrical skin conductance. Sumatriptan decreased plasma levels of prolactin. A significant but moderate increase in plasma cortisol after SPST occurred, independent of treatment. Because sumatriptan decreases 5-HT release into the extracellular space, the potentiation of SPST-induced fear caused by the drug supports the hypothesis that 5-HT attenuates this emotional state. As acute administration of antidepressants has also been shown to enhance speaking fear and increase plasma prolactin, in contrast to sumatriptan, the 5-HT regulation of stress-hormone release is likely to be different from that of emotion.
Assuntos
Medo/efeitos dos fármacos , Prolactina/sangue , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sumatriptana/farmacologia , Adulto , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Resposta Galvânica da Pele/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Masculino , Rede Nervosa/fisiologia , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/efeitos dos fármacos , Receptor 5-HT1D de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Fala/fisiologia , Sumatriptana/administração & dosagem , Adulto JovemRESUMO
We have previously shown that 5-HT(1B) receptors inhibit prejunctionally the rat vasodepressor CGRPergic sensory outflow. Since 5-HT(1) receptors comprise 5-HT(1A), 5-HT(1B), 5-HT(1D) and 5-HT(1F) functional subtypes, this study has further investigated the role of 5-HT(1A), 5-HT(1D) and 5-HT(1F) receptor subtypes in the inhibition of the above vasodepressor sensory outflow. Pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by 5-HT(1) receptor agonists. Then electrical spinal stimulation (T(9)-T(12)) or i.v. bolus injections of exogenous α-CGRP produced frequency-dependent or dose-dependent vasodepressor responses. The electrically-induced vasodepressor responses remained unchanged during infusions of the 5-HT(1A) receptor agonists 8-OH-DPAT and NN-DP-5-CT. In contrast, these responses were inhibited by the agonists sumatriptan (5-HT(1A/1B/1D/1F)), indorenate (5-HT(1A)), PNU-142633 (5-HT(1D)) or LY344864 (5-HT(1F)), which did not affect the vasodepressor responses to exogenous CGRP (implying a prejunctional sensory-inhibition). When analysing the effects of antagonists: (i) 310 µg/kg (but not 100 µg/kg) GR127935 (5-HT(1A/1B/1D/1F)) abolished the inhibition to sumatriptan, indorenate, PNU-142633 or LY344864; (ii) 310 µg/kg SB224289 (5-HT(1B)) or BRL15572 (5-HT(1D)) failed to block the inhibition to sumatriptan or PNU-142633, whereas SB224289+BRL15572 partly blocked the inhibition to sumatriptan; and (iii) 10 µg/kg WAY100635 (5-HT(1A)) failed to block the inhibition to indorenate. These results suggest that 5-HT(1F), but not 5-HT(1A) or 5-HT(1D), receptor subtypes inhibit the vasodepressor sensory CGRPergic outflow although, admittedly, no selective 5-HT(1F) receptor agonist is available yet. The pharmacological profile of these receptors resembles that shown in rat dorsal root ganglia by molecular biology techniques.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Estimulação Elétrica , Hemodinâmica/efeitos dos fármacos , Ligantes , Masculino , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Receptor 5-HT1F de SerotoninaRESUMO
This study assessed the possible antinociceptive role of peripheral 5-HT(1) receptor subtypes in the rat formalin test. Rats were injected into the dorsum of the hind paw with 50 microl of diluted formalin (1%). Nociceptive behavior was quantified as the number of flinches of the injected paw. Reduction of flinching was considered as antinociception. Ipsilateral, but not contralateral, peripheral administration of the 5-HT(1) receptor agonists R(+)-UH-301 (5-HT(1A); 0.1-3 microg/paw), CGS-12066A (5-HT(1B); 0.01-0.3 microg/paw), GR46611 (5-HT(1B/1D); 0.3-10 microg/paw), BRL54443 (5-HT(1E/1F); 3-300 microg/paw) or LY344864 (5-HT(1F); 3-300 microg/paw) significantly reduced formalin-induced flinching. The corresponding vehicle was devoid of any effect by itself. The local antinociceptive effect of R(+)-UH-301 (0.3 microg/paw) was significantly reduced by WAY-100635 (30-100 microg/paw; a 5-HT(1A) receptor antagonist). Moreover, the antagonists GR55562 (30-100 microg/paw; 5-HT(1B/D)) or SB224289 (30-100 microg/paw; 5-HT(1B)) dose-dependently reduced the antinociceptive effect of CGS-12066A (0.3 microg/paw) whereas GR55562 (30-100 microg/paw) or BRL15572 (30-100 microg/paw, 5-HT(1D)) reduced the antinociceptive effect of GR46611 (0.3 microg/paw). Interestingly, the effects of BRL54443 and LY344864 (300 microg/paw each) were partially reduced by methiothepin, but not by the highest doses of WAY-100635, SB224289 or BRL15572. The above antagonists did not produce any effect by themselves. These results suggest that peripheral activation of the 5-HT(1A,) 5-HT(1B), 5-HT(1D), 5-HT(1F) and, probably, 5-HT(1E) receptor subtypes leads to antinociception in the rat formalin test. Thus, the use of selective 5-HT(1) receptor agonists could be a therapeutic strategy to reduce inflammatory pain.
Assuntos
Dor/tratamento farmacológico , Dor/metabolismo , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Formaldeído , Lateralidade Funcional , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Dor/induzido quimicamente , Medição da Dor , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/administração & dosagem , Receptor 5-HT1F de SerotoninaRESUMO
This study examined the acute changes in feeding and drinking behaviours of free-feeding and free-drinking pigeons, in response to local injections of metergoline (MET, 5-HT(1/2) receptor antagonist; 7 and 20 nmol), GR46611 (GR, 5-HT(1B/1D) agonist; 2 and 6 nmol) or vehicle, into two components of the arcopallium: the nucleus taeniae of the amygdala (TnA) and the arcopallium intermedium (AI). In the TnA, the highest MET dose elicited a short-lived hyperphagy, without affecting drinking or non-ingestive behaviours during the first hour after injection. In contrast, all MET doses promptly increased drinking when injected in the AI, without affecting feeding; this effect was still evident 3 and 24 h after the treatment. When injected in the TnA, the highest GR dose promptly increased both food and water intake; these effects persisted 24 h after the treatments. GR injections in the AI evoked long-lasting increases in drinking, but not in feeding. Injections of these drugs into other arcopallial nuclei evoked no significant ingestive effects. These data indicate the presence of a tonic inhibitory influence of serotonergic inputs, partially mediated by 5-HT(1B/1D) receptors, on feeding- and drinking-related TnA circuits and on mechanisms controlling drinking in the AI. Compared to data from the rodent medial amygdala, our results suggest that a tonic inhibitory 5-HTergic control of feeding (but not drinking) behaviour, mediated by 5-HT(1/2) receptors and exerted in the medial amygdaloid area, may represent a broadly conserved functional attribute in the amniote brain, but probably involves many important taxa-specific neural mechanisms.
Assuntos
Tonsila do Cerebelo/fisiologia , Encéfalo/fisiologia , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/fisiologia , Receptores 5-HT1 de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Acrilamidas/administração & dosagem , Acrilamidas/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Cateterismo , Columbidae , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Indóis/administração & dosagem , Indóis/farmacologia , Masculino , Metergolina/administração & dosagem , Metergolina/farmacologia , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacologia , Fatores de TempoRESUMO
1 It has been hypothesized that craniovascular 5-HT receptors mediating dilatation of cranial vessels undergo sensitization on decreased serotonergic transmission in migraine. This study analysed the effect of chemical lesion of the 5-HT system in the brain with 5,7-dihydroxytryptamine (5,7-DHT) on 5-HT receptor-mediated dilator responses to 5-carboxamidotryptamine (5-CT) in the middle meningeal artery of anaesthetized rats. 5-CT has recently been shown to elicit dilator responses in this cranial vessel via 5-HT(7) receptors and, to a much lesser extent, 5-HT(1B/1D) receptors. 2 Pretreatment with 5,7-DHT produced a drastic and selective decrease of 5-HT levels in the brain (78 +/- 6% and 94 +/- 2% in dorsal raphe and hypothalamic paraventricular nuclei, respectively) compared with controls (1% ascorbic acid). 3 Topical application of 5-CT (1-1000 microm) to exposed dura mater encephali produced concentration-dependent decreases in diastolic blood pressure and dilator responses in the middle meningeal artery that were similar in vehicle- and 5,7-DHT-pretreaed animals. 4 Hypotensive and meningeal dilator responses to 5-CT were unaltered by the 5-HT(1B/1D) receptor antagonist, GR-127935 (1 mg kg(-1), i.v.), but were strongly inhibited by the 5-HT(7) receptor antagonist, SB-269970 (1 mg kg(-1), i.v.), with similar efficacy, in both groups of animals. Treatment with GR-127935 + SB-269970 (1 mg kg(-1), i.v. each), produced a stronger inhibitory effect than individual treatments on hypotensive but not on meningeal responses to 5-CT. Meningeal 5-HT(7) receptor-mediated responses (i.e. in GR-127935-pretreated animals) were unchanged by 5,7-DHT pretreatment. 5 Results suggest that the sensitivity of craniovascular 5-HT(7) receptors mediating dilatation is unaffected by a decrease of 5-HT levels in the brain. A neuronal involvement of 5-HT in migraine seems more likely, therefore.
Assuntos
Anestesia , Artérias Meníngeas/fisiologia , Receptores de Serotonina/fisiologia , Serotonina/deficiência , Vasodilatação/fisiologia , 5,7-Di-Hidroxitriptamina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Dopamina/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Masculino , Artérias Meníngeas/efeitos dos fármacos , Meninges/irrigação sanguínea , Meninges/efeitos dos fármacos , Norepinefrina/metabolismo , Oxidiazóis/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Fenóis/farmacologia , Piperazinas/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina/fisiologia , Receptor 5-HT1D de Serotonina/fisiologia , Serotonina/análogos & derivados , Serotonina/metabolismo , Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sulfonamidas/farmacologia , Vasodilatação/efeitos dos fármacosRESUMO
5-Carboxamidotryptamine (5-CT; 0.003-310 microg/kg, i.v.) produced dose-dependent hypotensive responses which were blocked in a complex manner by the 5-HT(7) receptor antagonist, (R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl) ethyl] pyrrolidine (SB-269970; 1 mg/kg, i.v.), in anesthetized vagosympathectomized rats. Interestingly, the 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride monohydrate GR-127935 (1 mg/kg, i.v.), also inhibited 5-CT-induced hypotension but the effect was clearly noncompetitive. Finally, the combination of GR-127935+SB-269970 (1 mg/kg, i.v., each) produced a further decreased of 5-CT-induced responses as compared to the effect of individual treatments. These data suggest that, in addition to 5-HT(7) receptors, 5-HT(1B/1D) receptors may also mediate hypotension in rats.
Assuntos
Hipotensão/fisiopatologia , Receptor 5-HT1B de Serotonina/fisiologia , Receptor 5-HT1D de Serotonina/fisiologia , Receptores de Serotonina/fisiologia , Anestesia , Animais , Pressão Sanguínea/efeitos dos fármacos , Masculino , Oxidiazóis/farmacologia , Fenóis/farmacologia , Piperazinas/farmacologia , Ratos , Ratos Wistar , Serotonina/análogos & derivados , Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sulfonamidas/farmacologiaRESUMO
L-694,247, a selective 5-HT1D receptor agonist, injected directly into the third ventricle (2.5, 5.0, and 10.0 micrograms/rat) of dehydrated rats induced a dose-dependent partial blockade of water intake. Injected in this way, the compound abolishes drinking behavior induced by third ventricle administration of carbachol (2 micrograms/rat), angiotensin II (5 ng/rat), and isoproterenol (40 micrograms/rat). In addition, intraventricular injections of L-694,247 did not modify water intake in normohydrated rats. The effects of L-694,247 are due to a specific interaction with 5-HT1D receptors, because its inhibitory effect on water intake in dehydrated rats is blocked by the previous administration of a 5-HT1D antagonist, GR 127935 (5 micrograms/rat), directly into the third ventricle. It is concluded that central 5-HT1D receptor activation disrupts the functional integrity of central pathways related to drinking behavior.
Assuntos
Ingestão de Líquidos/efeitos dos fármacos , Oxidiazóis/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Triptaminas/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Angiotensina II/farmacologia , Animais , Carbacol/farmacologia , Injeções Intraventriculares , Isoproterenol/farmacologia , Masculino , Microinjeções , Agonistas Muscarínicos/farmacologia , Oxidiazóis/administração & dosagem , Piperazinas/farmacologia , Ratos , Ratos Wistar , Receptor 5-HT1D de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagem , Triptaminas/administração & dosagem , Privação de ÁguaRESUMO
A series of tryptamine analogues has been prepared and tested for their 5-HT1 receptor agonist properties. The incorporation of an alkoxy group at the C-5 position of the indole nucleus resulted in a short-lived and dose-dependent immediate antihypertensive and bradycardic response in anaesthetized spontaneously hypertensive rats (SHR). In addition, a carbomethoxy function at the beta-position of the side-chain of the tryptamines significantly increased the mean resting arterial blood pressure (MAP) in pithed rats and also produced contraction of the canine basilar artery in a dose-dependent fashion. Structure-activity relationships (SAR) suggest that the 5-alkoxy group is an important pharmacophore in the production of the antihypertensive effect and that the introduction of a hydroxymethylene group on the side-chain, instead of the carbomethoxy group, changed the receptor affinity profile.