RESUMO
RATIONALE: Histamine H3 receptors (H3Rs) are co-expressed with dopamine D1 receptors (D1Rs) by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D1R-mediated responses. OBJECTIVES AND METHODS: We examined whether the chronic administration of the H3R agonist immepip modifies dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), in rats lesioned with 6-hydroxydopamine in the substantia nigra pars compacta, and the effect of D1R and H3R co-activation on glutamate and GABA content in dialysates from the dorsal striatum of naïve rats. RESULTS: The systemic administration (i.p.) of L-Dopa for 14 days significantly increased axial, limb, and orolingual abnormal involuntary movements (AIMs) compared with the vehicle group. The chronic administration of the H3R agonist immepip alongside L-Dopa significantly decreased axial, limb, and orolingual AIMs compared with L-Dopa alone, but AIMs returned to previous values on immepip withdrawal. Chronic immepip was ineffective when administered prior to L-Dopa. The chronic administration of immepip significantly decreased GABA and glutamate content in striatal dialysates, whereas the administration of L-Dopa alone increased GABA and glutamate content. CONCLUSIONS: These results indicate that chronic H3R activation reduces LIDs, and the effects on striatal GABA and glutamate release provide evidence for a functional interaction between D1Rs and H3Rs.
Assuntos
Discinesia Induzida por Medicamentos/tratamento farmacológico , Agonistas dos Receptores Histamínicos/administração & dosagem , Imidazóis/administração & dosagem , Levodopa/toxicidade , Oxidopamina/toxicidade , Piperidinas/administração & dosagem , Receptores Histamínicos H3/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Masculino , Ratos , Ratos Wistar , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismoRESUMO
Histamine plays a significant role as a neuromodulator in the human central nervous system. Histamine-releasing neurons are exclusively located in the tuberomammillary nucleus of the hypothalamus, project to all major areas of the brain, and participate in functions such as the regulation of sleep/wakefulness, locomotor activity, feeding and drinking, analgesia, learning, and memory. The functional effects of histamine are exerted through the activation of four G protein-coupled receptors (H1, H2, H3 and H4), and in the central nervous system the first three receptors are widely expressed. The H3 receptor (H3R) is found exclusively in neuronal cells, where it functions as auto- and hetero-receptor. One remarkable characteristic of the H3R is the existence of isoforms, generated by alternative splicing of the messenger RNA. For the human H3R, 20 isoforms have been reported; although a significant number lack those regions required for agonist binding or receptor signaling, at least five isoforms appear functional upon heterologous expression. In this work we review the evidence for the generation of human H3R isoforms, their expression, and the available information regarding the functionality of such receptors.
Assuntos
Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiologia , Receptores Histamínicos H3/biossíntese , Receptores Histamínicos H3/fisiologia , Expressão Gênica , Humanos , Isoformas de Proteínas , Receptores Histamínicos H3/genéticaRESUMO
Histamine H3 receptors (H3Rs) co-localize with dopamine (DA) D1 receptors (D1Rs) on striatal medium spiny neurons and functionally antagonize D1R-mediated responses. The intra-striatal administration of D1R agonists reduces DA release whereas D1R antagonists have the opposite effect. In this work, a microdialysis method was used to study the effect of co-activating D1 and H3 receptors on the release of DA from the rat dorsal striatum. Infusion of the D1R agonist SKF-38393 (0.5 and 1 µM) significantly reduced DA release (26-58%), and this effect was prevented by co-administration of the H3R agonist immepip (10 µM). In turn, the effect of immepip was blocked by the H3R antagonist thioperamide (10 µM). Our results indicate that co-stimulation of post-synaptic D1 and H3 receptors may indirectly regulate basal DA release in the rat striatum and provide in vivo evidence for a functional interaction between D1 and H3 receptors in the basal ganglia.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacologia , Receptores de Dopamina D1/fisiologia , Receptores Histamínicos H3/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/antagonistas & inibidores , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Interações Medicamentosas , Agonistas dos Receptores Histamínicos/administração & dosagem , Agonistas dos Receptores Histamínicos/farmacologia , Imidazóis/administração & dosagem , Imidazóis/antagonistas & inibidores , Imidazóis/farmacologia , Masculino , Microdiálise , Microinjeções , Piperidinas/administração & dosagem , Piperidinas/antagonistas & inibidores , Piperidinas/farmacologia , Ratos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
Parkinson's disease is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic neurons in the substantia nigra pars compacta. However, other neurotransmitter systems (noradrenergic,cholinergic and serotoninergic) are also involved in the disease. On the other hand, there is increasing evidence for a role of histamine as a neuromodulator in the mammalian central nervous system. Histamine-releasing neurons are exclusively located in the tuberomammilary nucleus of the hypothalamus, project to all major areas of the brain and participate in functions such as the regulation of sleep/wakefulness, locomotor activity, autonomic and vestibular functions, feeding and drinking, analgesia, learning and memory. In this work we review the pathophysiological characteristics of Parkinson's disease and the emerging information about alterations in histaminergic transmission reported for parkinsonian patients and animal models of the disease. In particular, we focus on the role of histamine H3 receptors, expressed at high density in the basal ganglia, in the normal function of these nuclei and their possible participation in the pathophysiology of Parkinson's disease.
Assuntos
Gânglios da Base/fisiologia , Neurotransmissores/metabolismo , Doença de Parkinson/fisiopatologia , Receptores Histamínicos H3/fisiologia , HumanosRESUMO
Non-reinforced retrieval induces memory extinction, a phenomenon characterized by a decrease in the intensity of the learned response. This attribute has been used to develop extinction-based therapies to treat anxiety and post-traumatic stress disorders. Histamine modulates memory and anxiety but its role on fear extinction has not yet been evaluated. Therefore, using male Wistar rats, we determined the effect of the intra-hippocampal administration of different histaminergic agents on the extinction of step-down inhibitory avoidance (IA), a form of aversive learning. We found that intra-CA1 infusion of histamine immediately after non-reinforced retrieval facilitated consolidation of IA extinction in a dose-dependent manner. This facilitation was mimicked by the histamine N-methyltransferase inhibitor SKF91488 and the H2 receptor agonist dimaprit, reversed by the H2 receptor antagonist ranitidine, and unaffected by the H1 antagonist pyrilamine, the H3 antagonist thioperamide and the antagonist at the NMDA receptor (NMDAR) polyamine-binding site ifenprodil. Neither the H1 agonist 2-2-pyridylethylamine nor the NMDAR polyamine-binding site agonist spermidine affected the consolidation of extinction while the H3 receptor agonist imetit hampered it. Extinction induced the phosphorylation of ERK1 in dorsal CA1 while intra-CA1 infusion of the MEK inhibitor U0126 blocked extinction of the avoidance response. The extinction-induced phosphorylation of ERK1 was enhanced by histamine and dimaprit and blocked by ranitidine administered to dorsal CA1 after non-reinforced retrieval. Taken together, our data indicate that the hippocampal histaminergic system modulates the consolidation of fear extinction through a mechanism involving the H2-dependent activation of ERK signalling.
Assuntos
Medo , Histamina/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Inibição Neural , Neurônios/metabolismo , Receptores Histamínicos H2/fisiologia , Transdução de Sinais , Animais , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Medo/efeitos dos fármacos , Histamina/administração & dosagem , Agonistas dos Receptores Histamínicos/administração & dosagem , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/farmacologia , Histamina N-Metiltransferase/antagonistas & inibidores , Infusões Intraventriculares , Masculino , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Histamínicos H2/química , Receptores Histamínicos H3/química , Receptores Histamínicos H3/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
There is increasing evidence that describes a histamine role in normal and cancer cell proliferation. To better understand the importance of histamine in breast cancer development, the expression of histamine H3 (H3R) and H4 (H4R) receptors and their association with proliferating cell nuclear antigen (PCNA), histidine decarboxylase (HDC) and histamine content were explored in mammary biopsies. Additionally, we investigated whether H3R and H4R were implicated in the biological responses triggered by histamine in MDA-MB-231 breast cancer cells. The expression levels of H3R, H4R, PCNA, HDC and histamine content were determined by immunohistochemistry in 40 benign and malignant lesions. MDA-MB-231 cells proliferation (clonogenic assay and BrdU incorporation) and cell cycle distribution (flow cytometry) were evaluated upon treatment with histamine, H3R and H4R agonists and antagonists. Apoptosis was determined by Annexin staining and TUNEL assay. Cell migration was assessed by transwell system. Results indicate that H3R was detected in 67% (10/15) of benign lesions and in almost all carcinomas (24/25), being the level of its expression significantly higher in carcinomas (p = 0.0016). The non-tumoral breast tissue surrounding carcinomas revealed a lower H3R expression compared to the tumor cells. Only 13% (2/15) of the benign lesions expressed H4R compared to 44% (11/25) of the carcinomas. Interestingly, H3R expression was correlated in carcinomas with the expression of HDC and PCNA (p < 0.0001), and also histamine content (p = 0.0229). Accordingly, histamine increased MDA-MB-231 cells proliferation and also migration via H3R. In contrast, activation of H4R inhibited proliferation and this effect was associated with an arrest in the G(0)/G(1) phase of the cell cycle and an induction of apoptosis. Present findings demonstrate the presence of H3R and H4R in human mammary tissue and suggest that H3R may be involved in the regulation of breast cancer growth and progression representing a novel molecular target for new therapeutic approach.
Assuntos
Neoplasias da Mama/etiologia , Histamina/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Receptores Histamínicos H3/fisiologia , Receptores Histamínicos/fisiologia , Adulto , Idoso , Mama/química , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Histamina/análise , Histidina Descarboxilase/análise , Humanos , Imidazóis/farmacologia , Pessoa de Meia-Idade , Antígeno Nuclear de Célula em Proliferação/análise , Receptores Acoplados a Proteínas G/análise , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Histamínicos/análise , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos H3/análise , Receptores Histamínicos H3/efeitos dos fármacos , Receptores Histamínicos H4 , Tioureia/análogos & derivados , Tioureia/farmacologiaRESUMO
We have investigated the presence of histamine H(3) receptors (H(3)Rs) on rat thalamic isolated nerve terminals (synaptosomes) and the effect of their activation on glutamate and GABA release. N-alpha-[methyl-(3)H]histamine ([(3)H]-NMHA) bound specifically to synaptosomal membranes with dissociation constant (K(d)) 0.78+/-0.20 nM and maximum binding (B(max)) 141+/-12fmol/mg protein. Inhibition of [(3)H]-NMHA binding by histamine and the H(3)R agonist immepip fit better to a two-site model, whereas for the H(3)R antagonist clobenpropit the best fit was to the one-site model. GTPgammaS (30 microM) decreased [(3)H]-NMHA binding by 55+/-4% and made the histamine inhibition fit better to the one-site model. Immepip (30 nM) induced a modest, but significant increase (113+/-2% of basal) in [(35)S]-GTPgammaS binding to synaptosomal membranes, an effect prevented by clobenpropit (1 microM) and by pre-treatment with pertussis toxin. In thalamus synaptosomes depolarisation-induced, Ca(2+)-dependent glutamate release was inhibited by histamine (1 microM, 25+/-4% inhibition) and immepip (30 nM, 38+/-5% reduction). These effects were reversed by clobenpropit (1microM). Conversely, immepip (up to 1 microM) had no effect on depolarisation-evoked [(3)H]-GABA release. Extracellular synaptic responses were recorded in the thalamus ventrobasal complex by stimulating corticothalamic afferents. H(3)R activation reduced by 38+/-7% the glutamate receptor-mediated field potentials (FPs), but increased the FP2/FP1 ratio (from 0.86+/-0.03 to 1.38+/-0.05) in a paired-pulse paradigm. Taken together, our results confirm the presence of H(3)Rs on thalamic nerve terminals and show that their activation modulates pre-synaptically glutamatergic, but not GABAergic neurotransmission.
Assuntos
Ácido Glutâmico/metabolismo , Terminações Pré-Sinápticas/metabolismo , Receptores Histamínicos H3/fisiologia , Tálamo/metabolismo , Ácido gama-Aminobutírico/metabolismo , 4-Aminopiridina/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/efeitos da radiação , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Histamina/farmacologia , Antagonistas dos Receptores Histamínicos , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , Metilistaminas/farmacocinética , Toxina Pertussis/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Tálamo/ultraestrutura , Tioureia/análogos & derivados , Tioureia/farmacologia , Trítio/metabolismo , Trítio/farmacocinéticaRESUMO
The release of glutamate from striatal synaptosomes induced by depolarisation with 4-aminopyridine (4-AP) was studied by a method based on the fluorescent properties of the NAPDH formed by the metabolism of the neurotransmitter by glutamate dehydrogenase.Ca(2+)-dependent, depolarisation-induced glutamate release was inhibited in a concentration-dependent manner by the selective histamine H(3) agonist immepip. Best-fit estimates were: maximum inhibition 60+/-10% and IC(50) 68+/-10 nM. The effect of 300 nM immepip on depolarisation-evoked glutamate release was reversed by the selective H(3) antagonist thioperamide in a concentration-dependent manner (EC(50) 23 nM, K(i) 4 nM). In fura-2-loaded synaptosomes, the increase in the intracellular concentration of Ca(2+) ([Ca(2+)](i)) evoked by 4-AP-induced depolarisation (resting level 167+/-14 nM; Delta[Ca(2+)](i) 88+/-15 nM) was modestly, but significantly reduced (29+/-5% inhibition) by 300 nM immepip. The action of the H(3) agonist on depolarisation-induced changes in [Ca(2+)](i) was reversed by 100 nM thioperamide. Taken together, our results indicate that histamine modulates the release of glutamate from corticostriatal nerve terminals. Inhibition of depolarisation-induced Ca(2+) entry through voltage-dependent Ca(2+) channels appears to account for the effect of H(3) receptor activation on neurotransmitter release. Modulation of glutamatergic transmission in rat striatum may have important consequences for the function of basal ganglia and therefore for the control of motor behaviour.