RESUMO
Serotonin (5-HT) plays a critical role in modulating synaptic plasticity in the marine mollusc Aplysia and in the mammalian nervous system. In Aplysia sensory neurons, 5-HT can activate several signal cascades, including PKA and PKC, presumably via distinct types of G protein-coupled receptors. However, the molecular identities of these receptors have not yet been identified. We here report the cloning and functional characterization of a 5-HT receptor that is positively coupled to adenylyl cyclase in Aplysia neurons. The cloned receptor, 5-HT(apAC1), stimulates the production of cAMP in HEK293T cells and in Xenopus oocytes. Moreover, the knockdown of 5-HT(apAC1) expression by RNA interference blocked 5-HT-induced cAMP production in Aplysia sensory neurons and blocked synaptic facilitation in nondepressed or partially depressed sensory-to-motor neuron synapses. These data implicate 5-HT(apAC1) as a major modulator of learning related synaptic facilitation in the direct sensory to motor neuron pathway of the gill withdrawal reflex.
Assuntos
Adenilil Ciclases/metabolismo , Aplysia/fisiologia , Pareamento Cromossômico/fisiologia , Aprendizagem/fisiologia , Receptores de Serotonina/fisiologia , Adenilil Ciclases/genética , Sequência de Aminoácidos , Animais , Aplysia/citologia , Aplysia/genética , Western Blotting , Linhagem Celular , Células Cultivadas , Clonagem Molecular , AMP Cíclico/metabolismo , Feminino , Humanos , Hibridização In Situ , Potenciais da Membrana , Dados de Sequência Molecular , Oócitos/metabolismo , Oócitos/fisiologia , Filogenia , Receptores de Serotonina/classificação , Receptores de Serotonina/genética , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/metabolismo , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Serotonina/farmacologia , Transfecção , Xenopus laevisRESUMO
In the central nervous system of the pond snail Lymnaea stagnalis, serotonergic transmission plays an important role in controlling feeding behavior. Recent electrophysiological studies have claimed that only metabotropic serotonin (5-HT(2)) receptors, and not ionotropic (5-HT(3)) receptors, are used in synapses between serotonergic neurons (the cerebral giant cells, CGCs) and the follower buccal motoneurons (the B1 cells). However, these data are inconsistent with previous results. In the present study, we therefore reexamined the serotonin receptors to identify the receptor subtypes functioning in the synapses between the CGCs and the B1 cells by recording the compound excitatory postsynaptic potential (EPSP) of the B1 cells evoked by a train of stimulation to the CGC in the presence of antagonists: cinanserin for 5-HT(2) and/or MDL72222 for 5-HT(3). The compound EPSP amplitude was partially suppressed by the application of these antagonists. The rise time of the compound EPSP was longer in the presence of MDL72222 than in that of cinanserin. These results suggest that these two subtypes of serotonin receptors are involved in the CGC-B1 synapses, and that these receptors contribute to compound EPSP. That is, the fast component of compound EPSP is mediated by 5-HT(3)-like receptors, and the slow component is generated via 5-HT(2)-like receptors.
Assuntos
Comportamento Alimentar/fisiologia , Neurônios/fisiologia , Receptores de Serotonina/classificação , Receptores de Serotonina/fisiologia , Caramujos/fisiologia , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiologia , Cinanserina/farmacologia , Neurônios/efeitos dos fármacos , Toxina Pertussis/farmacologia , Antagonistas da Serotonina/farmacologia , Tropanos/farmacologiaRESUMO
Serotonin is one of the most abundant molecules in the gastrointestinal tract and it plays a crucial role in the regulation of several physiological functions, such as motility, secretion and visceral sensitivity. Besides this well documented physiological role, increasing evidence supports the concept that 5-HT is directly involved in pathological mechanisms, as well as the modulation of immune/inflammatory responses within the gut. The wide range of pathophysiological actions exerted by 5-HT are mediated by several different serotonergic receptor types and subtypes. Depending on the receptor bound and its localization, 5-HT evokes different and, sometimes, opposite responses. Therapeutic interventions aiming at modulating 5-HT signaling are mainly focused on the development of receptor agonists/antagonists, characterized by high affinity and selectivity for serotonergic receptors in the gut, to avoid the presence of adverse effects in the brain, where 5-HT is important in control mood. This review summarizes the vast current knowledge on 5-HT as a physiological mediator and analyzes the increasing body of literature describing 5-HT signaling abnormalities in functional and inflammatory disorders both in animal models and in humans. Finally, an overview on the therapeutic agents used in clinical practice is provided.
Assuntos
Gastroenteropatias/fisiopatologia , Trato Gastrointestinal/fisiologia , Serotonina/fisiologia , Animais , Constipação Intestinal/fisiopatologia , Dispepsia/fisiopatologia , Sistema Nervoso Entérico/fisiologia , Gastroenterite/fisiopatologia , Gastroenteropatias/tratamento farmacológico , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Humanos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Síndrome do Intestino Irritável/fisiopatologia , Neurônios/fisiologia , Percepção da Dor/fisiologia , Receptores de Serotonina/classificação , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico , Nervo Vago/fisiologia , Dor Visceral/fisiopatologiaRESUMO
The present review summarizes the data concerning the influence of serotonin (5-HT) receptors on body temperature in warm-blooded animals and on processes associated with its maintenance. This review includes the most important part of investigations from the first studies to the latest ones. The established results on the pharmacological activation of 5-HT1A, 5-HT3, 5-HT7 and 5-HT2 receptor types are discussed. Such activation of the first 3 type of receptors causes a decrease in body temperature, whereas the 5-HT2 activation causes its increase. Physiological mechanisms leading to changes in body temperature as a result of 5-HT receptors' activation are discussed. In case of 5-HT1A receptor, they include an inhibition of shivering and non-shivering thermogenesis, as well simultaneous increase of peripheral blood flow, i.e., the processes of heat production and heat loss. The physiological processes mediated by 5-HT2 receptor are opposite to those of the 5-HT1A receptor. Mechanisms of 5-HT3 and 5-HT7 receptor participation in these processes are yet to be studied in more detail. Some facts indicating that in natural conditions, without pharmacological impact, these 5-HT receptors are important links in the system of temperature homeostasis, are also discussed.
Assuntos
Temperatura Corporal , Receptores de Serotonina/metabolismo , Animais , Circulação Sanguínea , Homeostase , Receptores de Serotonina/classificação , TermogêneseRESUMO
(Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for both 5-HT(2C) and 5-HT(6) receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amide (6b) exhibits the highest affinity towards both 5-HT(2C) (IC(50)=4 nM) and 5-HT(6) receptors (IC(50)=3 nM) with good selectivity over other serotonin (5-HT(1A), 5-HT(2A), and 5-HT(7)) and dopamine (D(2)-D(4)) receptor subtypes. In 5-HT(2C) and 5-HT(6) receptor functional assays, this compound showed considerable antagonistic activity for both receptors.
Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Antipsicóticos/síntese química , Piperazinas/química , Receptores de Serotonina/classificação , Receptores de Serotonina/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
This special issue of Trends in Pharmacological Sciences devoted to serotonin, or 5-hydroxytryptamine (5-HT), celebrates the 21st anniversary of the Serotonin Club, an event also marked by a major international meeting on serotonin held 17-20 July 2008, in Oxford (U.K.).
Assuntos
Serotonina/fisiologia , Sociedades Científicas/história , Austrália , História do Século XX , Receptores de Serotonina/classificação , Receptores de Serotonina/efeitos dos fármacos , Serotoninérgicos/farmacologia , Terminologia como AssuntoRESUMO
BACKGROUND: Dysfunctions in the serotonergic system have been implicated in several neurological disorders such as depression. Elderly individuals who have been diagnosed with clinical depression show elevated cases of neurodegenerative diseases. This has led to suggestions that modulating the serotonin (5-HT) system could provide an alternative method to current therapies for alleviating these pathologies. The neuroprotective effects of bilobalide in vitro have been documented. We aim to determine whether bilobalide affects the 5-HT system in the nematode C. elegans. The wild type worms, as well as well-characterized 5-HT mutants, were fed with bilobalide in a range of concentrations, and several 5-HT controlled behaviors were tested. RESULTS: We observed that bilobalide significantly inhibited 5-HT-controlled egg-laying behavior in a dose-dependent manner, which was blocked in the 5-HT receptor mutants (ser-4, mod-1), but not in the 5-HT transporter (mod-5) or synthesis (tph-1) mutants. Bilobalide also potentiated a 5-HT-controlled, experience-dependent locomotory behavior, termed the enhanced slowing response in the wild type animals. However, this effect was fully blocked in 5-HT receptor mod-1 and dopamine defective cat-2 mutants, but only partially blocked in ser-4 mutants. We also demonstrated that acetylcholine transmission was inhibited in a transgenic C. elegans strain that constitutively expresses Abeta, and bilobalide did not significantly affect this inhibition. CONCLUSION: These results suggest that bilobalide may modulate specific 5-HT receptor subtypes, which involves interplay with dopamine transmission. Additional studies for the function of bilobalide in neurotransmitter systems could aid in our understanding of its neuroprotective properties.
Assuntos
Comportamento Animal/efeitos dos fármacos , Ciclopentanos/farmacologia , Furanos/farmacologia , Ginkgolídeos/farmacologia , Serotonina/farmacologia , Fatores Etários , Aldicarb/farmacologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Comportamento Animal/fisiologia , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Canais de Cloreto/genética , Inibidores da Colinesterase/farmacologia , Dopamina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Locomoção/efeitos dos fármacos , Locomoção/genética , Mutação , Piperazinas/farmacologia , Piridinas/farmacologia , Receptores de Serotonina/classificação , Receptores de Serotonina/genética , Reprodução/efeitos dos fármacos , Reprodução/genética , Antagonistas da Serotonina/farmacologiaRESUMO
Serotonergic receptors take their physiologic effects by affecting adenylyl cyclase (AC) catalytic activity and cyclic adenosine monophosphate (cAMP) concentration. AC-cAMP second messenger pathway has been recently suggested to play an important role in depression. Therefore, the compound that regulates the signal pathway may have potential as antidepressant. Curcumin is the main component of Curcuma longa L, a well-known indigenous herb with comprehensive bioactivities. In the present study, we investigated the effects of chronic unpredictable mild stress (CUMS) and curcumin on behaviours and serotonergic receptor-coupled AC-cAMP signal pathway in rats. Curcumin produced beneficial effects on the stressed rats by effectively improving CUMS-induced low sucrose consumption and reducing serum corticosterone levels in rats. Moreover, curcumin enhanced AC activity and cAMP levels in platelet and various brain regions, and up-regulated mRNA expressions of AC subtypes AC 2, AC 8 and cAMP response element binding protein (CREB) in the hippocampus, cortex and hypothalamus of the CUMS rats. Curcumin also attenuated CUMS-induced reductions of 5-hydroxytryptamine (5-HT) levels and high expressions of central 5-HT(1A/1B/7) receptors in rats. These results suggested that the potent antidepressant property of curcumin might be attributed to its improvement of AC-cAMP pathway as well as CREB via suppressing central 5-HT(1A/1B/7) receptors in the CUMS rats. Our findings provided a basis for examining the interaction of serotonergic receptors and AC-cAMP pathway in depression and curcumin treatment.
Assuntos
Antidepressivos/uso terapêutico , Curcumina/uso terapêutico , Receptores de Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Adenilil Ciclases/classificação , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corticosterona/sangue , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Fluoxetina/uso terapêutico , Privação de Alimentos/fisiologia , Preferências Alimentares/efeitos dos fármacos , Preferências Alimentares/fisiologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Serotonina/classificação , Receptores de Serotonina/genética , Serotonina/metabolismo , Estresse Psicológico/etiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Regulação para Cima/efeitos dos fármacos , Privação de Água/fisiologiaRESUMO
The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.
Assuntos
Tonsila do Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Estresse Psicológico/metabolismo , Adaptação Psicológica/fisiologia , Animais , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Camundongos , Ratos , Receptores de Serotonina/classificação , Receptores de Serotonina/genética , Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologiaRESUMO
The present study examined the involvement of 5-HT in the ventrolateral orbital cortex (VLO) on descending antinociception and determined which subtypes of 5-HT receptors mediated this effect. This study focused on the effects of 5-HT microinjection in the VLO of lightly anesthetized male rats on the radiant heat-evoked tail flick (TF) reflex, as well as the influence of 5-HT(1A), 5-HT(2), 5-HT(3), and 5-HT(4) receptor subtype antagonists on the effect of 5-HT. Results showed that 5-HT microinjection (2, 5, 10 microg, in 0.5 microl) into the VLO depressed the TF reflex in a dose-dependent manner. Pretreatment with 5-HT receptor antagonists (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190), cyproheptadine hydrochloride (CPT) and 1-methyl-N-(8-methyl-8-azabicyclo[3.2.3]-oct-3-yl)-1H-indazole-3-carboxamide maleate salt (LY-278,584)), specific for 5-HT(1A), 5-HT(2) and 5-HT(3) receptors, respectively, partially reversed the 5-HT-evoked inhibition. In contrast, the 5-HT(4) receptor antagonist, 1-[2-[(methylsulfonyl)-amino]ethyl]-4-piperidinyl]methyl1-methyl-1H-indole-3-carboxylate (GR 113808), had no effect on the inhibition of 5-HT. Microinjections of NAN-190, CPT and LY-278,584 alone into the VLO had no effect on the TF reflex. These results suggest that 5-HT(1A), 5-HT(2) and 5-HT(3), but not 5-HT(4) receptors, are involved in mediating 5-HT-induced antinociception in the VLO. According to different properties and distribution patterns of the 5-HT receptor subtypes on neurons, the possible mechanism of 5-HT activation of the VLO-periaqueductal gray (PAG) descending antinociceptive pathway is discussed.
Assuntos
Lobo Frontal/efeitos dos fármacos , Nociceptores/fisiologia , Limiar da Dor/efeitos dos fármacos , Receptores de Serotonina/classificação , Receptores de Serotonina/fisiologia , Serotonina/farmacologia , Animais , Área Sob a Curva , Comportamento Animal , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Microinjeções/métodos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Antagonistas da Serotonina/administração & dosagem , Cauda/fisiologia , Fatores de TempoRESUMO
Chronic fatigue syndrome (CFS) is a debilitating disorder of unknown etiology with no known lesions, diagnostic markers or therapeutic intervention. The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined in 137 clinically evaluated subjects (40 CFS, 55 with insufficient fatigue, and 42 non-fatigued, NF, controls) derived from a population-based CFS surveillance study in Wichita, Kansas. Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS.
Assuntos
Cromossomos Humanos X/genética , Síndrome de Fadiga Crônica/genética , Fadiga/genética , Receptor 5-HT2A de Serotonina/genética , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Avaliação da Deficiência , Fadiga/diagnóstico , Síndrome de Fadiga Crônica/diagnóstico , Feminino , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Receptores de Serotonina/classificação , Receptores de Serotonina/genética , Valores de Referência , Proteínas da Membrana Plasmática de Transporte de Serotonina/genéticaRESUMO
This article addresses a question at the juncture of neurophysiology and neurogenetics--the role of the brain neurotransmitter serotonin in the genetic control of behavior. Published data are presented, along with results obtained from studies performed at the Behavioral Neurogenomics Laboratory. The role of protein elements of the brain serotonin system (key enzymes in serotonin metabolism and serotonin 5-HT(1A) receptors), which are subject to the direct influence of genes, in the genetic predisposition to aggressive behavior is discussed. Experimental results obtained in Norwegian rats selected over more than 50 generations for the absence of aggressivity and for high aggressivity to humans are presented, along with data from experiments on mouse lines and mice with genetic knockout of MAO A. These data provide evidence that 1) brain serotonin makes a significant contribution to the mechanisms underlying genetically determined individual differences in aggressivity, and 2) the genes encoding the main enzymes of serotonin metabolism in the brain (tryptophan hydroxylase-1 and MAO A) and the 5-HT(1A) receptor are members of a set of genes modulating aggressive behavior.
Assuntos
Agressão/fisiologia , Encéfalo/metabolismo , Regulação da Expressão Gênica , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Adaptação Fisiológica/genética , Adaptação Fisiológica/fisiologia , Adaptação Psicológica/fisiologia , Animais , Genética Comportamental , Camundongos , Camundongos Knockout , Monoaminoxidase/deficiência , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Ratos , Receptores de Serotonina/classificação , Receptores de Serotonina/genética , Serotonina/genética , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismoRESUMO
Conventional serotonin-enhancing antidepressants including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have shown effectiveness in the treatment of major depression, but their significant limitations such as slowness of action have led to intensive research efforts to develop new antidepressants. Increased synaptic neurotransmission of serotonin (5-hdroxytryptamine; 5-HT) through orchestration of stimulation and blockade of various subtypes of 5-HT receptors is involved in the mechanisms of action of SSRIs. Agonists at the 5-HT1A, 5-HT1B, 5-HT2C, 5-HT4, and 5-HT6 receptors and antagonists at the 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5- HT6, and 5-HT7 receptors have shown antidepressant properties in clinical and preclinical studies. However, paradoxical antidepressant-like effects of both agonists and antagonists at particular 5-HT receptors suggest the need to consider the neurochemical mechanisms of each 5-HT receptor subtype. Therefore, better knowledge of the involvement of individual 5-HT receptors in the mechanisms of action of currently used antidepressants as well as antidepressant effects of selective ligands of 5- HT receptor subtypes will provide opportunities for the development of future antidepressants with more rapid onset of action, fewer side effects, and better efficacy than SSRIs.
Assuntos
Antidepressivos/química , Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Receptores de Serotonina/classificação , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Descoberta de Drogas , Humanos , Receptores de Serotonina/genéticaRESUMO
The 5-ht5A receptor is enigmatic among 5-HT receptors since, although the human receptor was cloned in 1994, until recently, very little has been learnt about the function of the receptor in native tissues. Findings from 5-ht5A receptor mRNA localisation and immunolabelling studies have revealed widespread expression in the CNS, and have provided pointers to the potential functional role(s) of the receptor. The expression of the 5-ht5A receptor in raphe nuclei and in higher brain areas, such as the cerebral cortex and hippocampus, suggests a potential autoreceptor function whilst localisation in the suprachiasmatic nucleus (SCN) suggests a role in circadian rhythm control. Additionally, 5-ht5A receptor knockout mouse phenotyping studies support a role in the control of exploratory behaviour. The lack of understanding of the role of the receptor has been, in part, due to the lack of available selective 5-ht5A receptor ligands. However, a selective 5-ht5A receptor antagonist, 3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride (SB-699551-A), has recently been identified which appears to be a useful tool with which to elucidate the physiological function of the receptor. Brain localisation and functional studies to date potentially implicate the receptor in the control of circadian rhythms, mood and cognitive function, whilst gene association studies implicate the receptor in the aetiology of schizophrenia. Although much is still to be learnt about the function of the 5-ht5A receptor, on the basis of these findings, it can be speculated that 5-ht5A receptor-selective ligands might show utility in psychiatric disorders such as schizophrenia and unipolar depression in which cognitive or mood disturbances are a feature.
Assuntos
Receptores de Serotonina/fisiologia , Animais , Ritmo Circadiano , Humanos , Transtornos do Humor/tratamento farmacológico , RNA Mensageiro/análise , Receptores de Serotonina/classificação , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/genética , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/uso terapêuticoRESUMO
In order to determine whether short- (STM) and long-term memory (LTM) function in serial or parallel manner, serotonin (5-hydroxtryptamine, 5-HT) receptor agonists were tested in autoshaping task. Results show that control-vehicle animals were modestly but significantly mastering the autoshaping task as illustrated by memory scores between STM and LTM. Thus, post-training administration of 8-OHDPAT (agonist for 5-HT(1A/7) receptors) only at 0.250 and 0.500 mg/kg impaired both STM and LTM. CGS12066 (agonist for 5-HT(1B)) produced biphasic affects, at 5.0 mg/kg impaired STM but at 1.0 and 10.0 mg/kg, respectively, improved or impaired LTM. DOI (agonist for 5-HT(2A/2C) receptors) dose-dependently impaired STM and, at 10.0 mg/kg only impaired LTM. Both, STM and LTM were impaired by either mCPP (mainly agonist for 5-HT(2C) receptors) or mesulergine (mainly antagonist for 5-HT(2C) receptors) lower dose. The 5-HT(3) agonist mCPBG at 1.0 impaired STM and its higher dose impaired both STM and LTM. RS67333 (partial agonist for 5-HT(4) receptors), at 5.0 and 10.0 mg/kg facilitated both STM and LTM. The higher dose of fluoxetine (a 5-HT uptake inhibitor) improved both STM and LTM. Using as head-pokes during CS as an indirect measure of food-intake showed that of 30 memory changes, 21 of these were unrelated to the former. While some STM or LTM impairments can be attributed to decrements in food-intake, but not memory changes (either increase or decreases) produced by 8-OHDPAT, CGS12066, RS67333 or fluoxetine. Except for animals treated with DOI, mCPBG or fluoxetine, other groups treated with 5-HT agonists 6 h following autoshaping training showed similar LTM and unmodified CS-head-pokes scores.
Assuntos
Memória/fisiologia , Receptores de Serotonina/classificação , Receptores de Serotonina/fisiologia , Serotonina/metabolismo , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
The present study examined changes in spontaneous behavior of free-feeding pigeons in response to local injections of metergoline (MET, an antagonist of 5-HT(1/2) receptors; 5, 10 and 20 nmol), GR-46611 (GR, a 5-HT(1B/1D) agonist; 0.6 and 6 nmol) or vehicle into the paraventricular hypothalamic nucleus (PVN). When infused into the PVN, MET and GR promptly and reliably elicited feeding at their higher doses, without affecting drinking or non-ingestive behaviors (locomotion, exploration, preening, sleep) during the first hour after injection. Both GR- and MET-evoked ingestive responses were associated only with an increase in feeding duration, with no changes in latency to start feeding. In a second series of experiments, the effective doses of MET (20 nmol) and GR (6 nmol) were injected into other diencephalic areas. This exploratory study revealed that intense feeding responses to both MET and GR local injections are also observed in the n. medialis hypothalami posterioris and in the adjacent n. lateralis hypothalami posterioris (PMH/PLH complex, in the caudoventral hypothalamus) and in the n. magnocellularis preopticus (PPM, in the caudal preoptic region). The behavioral profiles associated with these hyperphagic responses were nucleus-specific: in the PMH/PLH, MET-induced feeding was accompanied by an increase in total feeding duration and by a reduction in the latency to start feeding, while ingestive responses evoked by MET in the PPM were associated only with an increase in feeding duration (similar to that observed in the PVN experiments). No ingestive effects were observed after intracerebroventricular (ICV, lateral ventricle) injections of MET (10, 30, 100 or 300 nmol), while ICV injections of GR (3, 15 or 30 nmol) increased feeding only at the higher dose [Da Silva RA, De Oliveira ST, Hackl LPN, Spilere CI, Faria MS, Marino-Neto J, Paschoalini MA. Ingestive behaviors and metabolic fuels after central injections of 5-HT1A and 5-HT1D/1B receptors agonists in the pigeon. Brain Res, 2004;1026:275-283]. These data indicate the presence of a tonic inhibitory influence on feeding behavior exerted by 5-HT afferents on these hypothalamic areas, and suggest that these inputs, possibly mediated by non-rodent-type 5-HT1D/1B receptors, can affect both satiety and satiation mechanisms.
Assuntos
Acrilamidas/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Indóis/farmacologia , Metergolina/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Acrilamidas/administração & dosagem , Análise de Variância , Animais , Columbidae , Relação Dose-Resposta a Droga , Comportamento Alimentar/fisiologia , Indóis/administração & dosagem , Masculino , Metergolina/administração & dosagem , Microinjeções , Núcleo Hipotalâmico Paraventricular/fisiologia , Receptores de Serotonina/classificação , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/administração & dosagemRESUMO
Ovariectomized rats with bilateral cannulae near the ventromedial nucleus of the hypothalamus were hormonally primed with 10 microg estradiol benzoate and 500 microg progesterone. Sexually receptive females were infused bilaterally with 200 ng of the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), or with a combination of 200 ng 8-OH-DPAT and 2000 ng of the 5-HT(2) receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCl (DOI). 8-OH-DPAT inhibited lordosis behavior and DOI reduced this inhibition. However, if females were preinfused with the PKC inhibitor, bisindolymaleimide I hydrochloride (BIM), DOI's effect was eliminated. BIM's attenuation of the effects of DOI was time-dependent. When BIM was infused 90 min, but not 30 min, before the 5-HT receptor agonists, BIM eliminated DOI's protection against the lordosis-inhibiting effects of 8-OH-DPAT. A concentration of BIM as low as 10(-5) nmol in a 0.5 microl infusion volume was effective and there was little evidence of dose responsivity between 10(-5) and 10(-1) nmol of BIM. In contrast, prior infusion with vehicle or with 10(-7) nmol BIM had no impact on the female's response to the 5-HT receptor agonists. These findings allow the suggestion that DOI's ability to increase PKC may be responsible for attenuation of the effects of 8-OH-DPAT on lordosis behavior.
Assuntos
Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Maleimidas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Anfetaminas/administração & dosagem , Anfetaminas/farmacologia , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/administração & dosagem , Feminino , Indóis/administração & dosagem , Maleimidas/administração & dosagem , Microinjeções , Postura , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Endogâmicos F344 , Receptores de Serotonina/classificação , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/administração & dosagem , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de TempoRESUMO
It was previously reported that brain areas containing serotonin (5-hydroxytryptamine, 5-HT) receptors mediate memory consolidation as well as short (STM)- and long-term memory (LTM). Here the effects of systemic and intrahippocampal administration of 5-HT agonists and antagonists on an autoshaping learning task were explored, which requires hippocampal translation and transduction as well as 5-HT receptors expression. As previously reported ketamine (glutamatergic antagonist) and two well-known amnesic drugs, scopolamine (cholinergic antagonist) and dizocilpine (NMDA antagonist) impaired STM but not LTM; dizocilpine even improved the latter. Since ketamine produces hallucinations and impairs memory in humans, we address the question if well-known antipsychotic haloperidol and clozapine might affect STM deficit. Indeed, systemic administration of clozapineAssuntos
Condicionamento Clássico/fisiologia
, Hipocampo/fisiologia
, Memória/fisiologia
, Receptores de Serotonina/fisiologia
, Análise de Variância
, Animais
, Antipsicóticos/farmacologia
, Condicionamento Clássico/efeitos dos fármacos
, Interações Medicamentosas
, Hipocampo/efeitos dos fármacos
, Masculino
, Memória/efeitos dos fármacos
, Neurotransmissores/farmacologia
, Ratos
, Ratos Wistar
, Receptores de Serotonina/classificação
, Receptores de Serotonina/efeitos dos fármacos
, Serotoninérgicos/farmacologia
RESUMO
The complexity of cardiovascular responses produced by 5-hydroxytryptamine (5-HT, serotonin), including bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction, has been explained by the capability of this monoamine to interact with different receptors in the central nervous system (CNS), on the autonomic ganglia and postganglionic nerve endings, on vascular smooth muscle and endothelium, and on the cardiac tissue. Depending, among other factors, on the species, the vascular bed under study, and the experimental conditions, these responses are mainly mediated by 5-HT(1), 5-HT(2), 5-HT(3), 5-HT(4), 5-ht(5A/5B), and 5-HT(7) receptors as well as by a tyramine-like action or unidentified mechanisms. It is noteworthy that 5-HT(6) receptors do not seem to be involved in the cardiovascular responses to 5-HT. Regarding heart rate, intravenous (i.v.) administration of 5-HT usually lowers this variable by eliciting a von Bezold-Jarisch-like reflex via 5-HT(3) receptors located on sensory vagal nerve endings in the heart. Other bradycardic mechanisms include cardiac sympatho-inhibition by prejunctional 5-HT(1B/1D) receptors and, in the case of the rat, an additional 5-ht(5A/5B) receptor component. Moreover, i.v. 5-HT can increase heart rate in different species (after vagotomy) by a variety of mechanisms/receptors including activation of: (1) myocardial 5-HT(2A) (rat), 5-HT(3) (dog), 5-HT(4) (pig, human), and 5-HT(7) (cat) receptors; (2) adrenomedullary 5-HT(2) (dog) and prejunctional sympatho-excitatory 5-HT(3) (rabbit) receptors associated with a release of catecholamines; (3) a tyramine-like action mechanism (guinea pig); and (4) unidentified mechanisms (certain lamellibranch and gastropod species). Furthermore, central administration of 5-HT can cause, in general, bradycardia and/or tachycardia mediated by activation of, respectively, 5-HT(1A) and 5-HT(2) receptors. On the other hand, the blood pressure response to i.v. administration of 5-HT is usually triphasic and consists of an initial short-lasting vasodepressor response due to a reflex bradycardia (mediated by 5-HT(3) receptors located on vagal afferents, via the von Bezold-Jarisch-like reflex), a middle vasopressor phase, and a late, longer-lasting, vasodepressor response. The vasopressor response is a consequence of vasoconstriction mainly mediated by 5-HT(2A) receptors; however, vasoconstriction in the canine saphenous vein and external carotid bed as well as in the porcine cephalic arteries and arteriovenous anastomoses is due to activation of 5-HT(1B) receptors. The late vasodepressor response may involve three different mechanisms: (1) direct vasorelaxation by activation of 5-HT(7) receptors located on vascular smooth muscle; (2) inhibition of the vasopressor sympathetic outflow by sympatho-inhibitory 5-HT(1A/1B/1D) receptors; and (3) release of endothelium-derived relaxing factor (nitric oxide) by 5-HT(2B) and/or 5-HT(1B/1D) receptors. Furthermore, central administration of 5-HT can cause both hypotension (mainly mediated by 5-HT(1A) receptors) and hypertension (mainly mediated by 5-HT(2) receptors). The increasing availability of new compounds with high affinity and selectivity for the different 5-HT receptor subtypes makes it possible to develop drugs with potential therapeutic usefulness in the treatment of some cardiovascular illnesses including hypertension, migraine, some peripheral vascular diseases, and heart failure.
Assuntos
Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Serotonina/farmacologia , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/fisiopatologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/inervação , Gânglios Simpáticos/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Ligantes , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Doenças Vasculares Periféricas/tratamento farmacológico , Doenças Vasculares Periféricas/fisiopatologia , Receptores de Serotonina/classificação , Serotonina/fisiologia , Serotoninérgicos/farmacologiaRESUMO
The receptors of amine subfamily are specifically major drug targets for therapy of nervous disorders and psychiatric diseases. The recognition of novel amine type of receptors and their cognate ligands is of paramount interest for pharmaceutical companies. In the past, Chou and co-workers have shown that different types of amine receptors are correlated with their amino acid composition and are predictable on its basis with considerable accuracy [Elrod and Chou (2002) Protein Eng., 15, 713-715]. This motivated us to develop a better method for the recognition of novel amine receptors and for their further classification. The method was developed on the basis of amino acid composition and dipeptide composition of proteins using support vector machine. The method was trained and tested on 167 proteins of amine subfamily of G-protein-coupled receptors (GPCRs). The method discriminated amine subfamily of GPCRs from globular proteins with Matthew's correlation coefficient of 0.98 and 0.99 using amino acid composition and dipeptide composition, respectively. In classifying different types of amine receptors using amino acid composition and dipeptide composition, the method achieved an accuracy of 89.8 and 96.4%, respectively. The performance of the method was evaluated using 5-fold cross-validation. The dipeptide composition based method predicted 67.6% of protein sequences with an accuracy of 100% with a reliability index > or =5. A web server GPCRsclass has been developed for predicting amine-binding receptors from its amino acid sequence [http://www.imtech.res.in/raghava/gpcrsclass/ and http://bioinformatics.uams.edu/raghava/gpersclass/ (mirror site)].