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3.
Neurosci Bull ; 34(6): 1029-1036, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30143981

RESUMO

The ventral pallidum (VP) is a crucial component of the limbic loop of the basal ganglia and participates in the regulation of reward, motivation, and emotion. Although the VP receives afferent inputs from the central histaminergic system, little is known about the effect of histamine on the VP and the underlying receptor mechanism. Here, we showed that histamine, a hypothalamic-derived neuromodulator, directly depolarized and excited the GABAergic VP neurons which comprise a major cell type in the VP and are responsible for encoding cues of incentive salience and reward hedonics. Both postsynaptic histamine H1 and H2 receptors were found to be expressed in the GABAergic VP neurons and co-mediate the excitatory effect of histamine. These results suggested that the central histaminergic system may actively participate in VP-mediated motivational and emotional behaviors via direct modulation of the GABAergic VP neurons. Our findings also have implications for the role of histamine and the central histaminergic system in psychiatric disorders.


Assuntos
Prosencéfalo Basal/citologia , Neurônios GABAérgicos/efeitos dos fármacos , Histamina/farmacologia , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Dimaprit/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Feminino , Agonistas dos Receptores Histamínicos/farmacologia , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Técnicas de Patch-Clamp , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Ácido gama-Aminobutírico/metabolismo
4.
Biochem Biophys Res Commun ; 490(4): 1314-1318, 2017 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-28688766

RESUMO

Recently we found that synthetic compounds containing amino group linked to hydrophobic or aromatic moiety are potent modulators of the proton-gated channels (ASICs). These structures have clear similarity with ligands of histamine receptors. We have also demonstrated that histamine potentiates homomeric ASIC1a by shifting its activation dependence to less acidic conditions. In the present work the action of a series of histamine receptors ligands on recombinant ASIC1a and ASIC2a was characterized. Two types of action were found for ASIC1a. 1-methylhistamine, N-alpha-methylhistamine, dimaprit and thioperamide caused significant potentiation, which was pH-dependent and voltage-independent. The H4R antagonist A943931 caused inhibition, which is likely due to voltage-dependent pore block. ASIC2a were virtually insensitive to the drugs tested. We conclude that ligands of histamine receptors should also be considered as ASIC modulators.


Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histamina/farmacologia , Receptores Histamínicos/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Células CHO , Cricetulus , Dimaprit/farmacologia , Regulação da Expressão Gênica , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Metilistaminas/farmacologia , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Receptores Histamínicos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais
5.
J Occup Health ; 58(5): 470-476, 2016 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-27488042

RESUMO

OBJECTIVE: Hairdressers have an increased risk for airway symptoms especially when using hair-bleaching powder containing persulfate. To minimize exposure, dust-free bleaching powder (DFP) has been made available. We studied the effects of regular powder (RP) or DFP on the airway symptoms of hairdressers with hair-bleaching associated rhinitis. METHODS: Twelve hairdressers each performed three hair-bleachings on a wig in an exposure chamber. Half of the subjects used RP and half used DFP. Exposure to persulfate and ammonia was measured. Before and after each bleaching, the participants stated their degree of airway symptoms on a visual analogue scale. Nasal lavage and blood were sampled before exposure, after the last bleaching, and in the morning after exposure to measure inflammatory markers. RESULTS: Exposure to persulfate was higher when using RP compared to DFP, 22 (11-55) vs. 12 (8-13) µg/m3; median (min-max). Exposure to ammonia did not differ between the groups. Both groups reported an increase in asthma-like symptoms and this increase was significant. Neutrophils, lymphocytes, and monocytes increased after exposure in both groups; monocytes decreased the day after. In nasal lavage, IL-8 was increased the morning after for both types of powder, and the increase was significant in the total group. IL-6 increased immediately after exposure and the day after only in the group using RP. CONCLUSIONS: Although DFP powder emits lower levels of persulfate, effects are still elicited in symptomatic hairdressers.


Assuntos
Amônia/efeitos adversos , Asma/induzido quimicamente , Dimaprit/análogos & derivados , Descolorantes de Cabelo/efeitos adversos , Exposição Ocupacional/efeitos adversos , Rinite/induzido quimicamente , Indústria da Beleza , Biomarcadores/sangue , Dimaprit/efeitos adversos , Poeira , Humanos , Mucosa Nasal/imunologia , Doenças Profissionais/induzido quimicamente , Espirometria , Escala Visual Analógica
6.
Behav Brain Res ; 278: 83-9, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25257105

RESUMO

Recent findings suggest a role of brain histamine in the regulation of memory consolidation, particularly in one-trial inhibitory avoidance (IA) learning and that disruption in the mother infant relationship i.e. maternal deprivation induces cognitive deficits. We investigate whether histamine itself, and histaminergic compounds given into the basolateral amygdala (BLA) immediately post-training can affect retention (24 h after training) of one-trial (IA) in rats submitted to early postnatal maternal deprivation. In all cases, deprived (Dep) animals had lower retention scores than non-deprived controls (N-dep). Histamine induced memory enhancement on its own in N-dep animals and was able to overcome the deleterious effect of Dep. The effects by SKF-91488 is similar to histamine. The H3 agonist, imetit mimetized the enhancing effects of histamine; neither agonist H1 pyridylethylamine nor the H2 dimaprit had any effect. Ranitidine and thioperamide (50 nmol) co-infused with histamine (10 nmol) fully blocked the restorative effect of histamine on retention in Dep animals. Thioperamide, in addition, blocked the enhancing effect of histamine on memory of the N-dep animals as well. None of the drugs used given into BLA had any effect on open-field or elevated plus-maze behavior in N-dep or Dep rats. Our results are limited to experimental design in rats. Extrapolation i.e. in humans requires further experimentations. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may at least in part be due to an impairment of histamine H3 receptor-mediated mediated mechanisms in the BLA.


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Histamina/farmacologia , Privação Materna , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/patologia , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Dimaprit/análogos & derivados , Dimaprit/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Histamina/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Inibição Psicológica , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar
7.
Neurosci Lett ; 587: 57-61, 2015 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-25524412

RESUMO

Histaminergic fibers are present in the molecular and granular layers of the cerebellum and have a high density in the vermis and flocullus. Evidence supports that the cerebellar histaminergic system is involved in memory consolidation. Our recent study showed that histamine injections facilitate the retention of an inhibitory avoidance task, which was abolished by pretreatment with an H2 receptor antagonist. In the present study, we investigated the effects of intracerebellar post training injections of H1 and H2 receptor antagonists as well as the selective H2 receptor agonist on fear memory consolidation. The cerebellar vermi of male mice were implanted with guide cannulae, and after three days of recovery, the inhibitory avoidance test was performed. Immediately after a training session, animals received a microinjection of the following histaminergic drugs: experiment 1, saline or chlorpheniramine (0.016, 0.052 or 0.16 nmol); experiment 2, saline or ranitidine (0.57, 2.85 or 5.07 nmol); and experiment 3, saline or dimaprit (1, 2 or 4 nmol). Twenty-four hours later, a retention test was performed. The data were analyzed using one-way analysis of variance (ANOVA) and Duncan's tests. Animals microinjected with chlorpheniramine did not show any behavioral effects at the doses that we used. Intra-cerebellar injection of the H2 receptor antagonist ranitidine inhibited, while the selective H2 receptor agonist dimaprit facilitated, memory consolidation, suggesting that H2 receptors mediate memory consolidation in the inhibitory avoidance task in mice.


Assuntos
Vermis Cerebelar/metabolismo , Medo , Memória , Receptores Histamínicos H2/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Vermis Cerebelar/efeitos dos fármacos , Clorfeniramina/farmacologia , Dimaprit/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H2/farmacologia , Masculino , Camundongos , Microinjeções , Ranitidina/farmacologia
8.
Life Sci ; 100(1): 67-72, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24530738

RESUMO

AIMS: The diverse physiological functions of histamine are mediated through distinct histamine receptors. In this study we investigated the role of H2R and H4R in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood. MAIN METHODS: Changes in reactive oxygen species (ROS) production by whole blood phagocytes after treatment with histamine, H4R agonists (4-methylhistamine, VUF8430), H2R agonist (dimaprit) and their combinations with H4R antagonist (JNJ10191584) and H2R antagonist (ranitidine) were determined using the chemiluminescence (CL) assay. To exclude the direct scavenging effects of the studied compounds on the CL response, the antioxidant properties of all compounds were measured using several methods (TRAP, ORAC, and luminol-HRP-H2O2 based CL). KEY FINDINGS: Histamine, 4-methylhistamine, VUF8430 and dimaprit inhibited the spontaneous and OZP-activated whole blood CL in a dose-dependent manner. On the other hand, only VUF8430 was able to inhibit PMA-activated whole blood CL. Ranitidine, but not JNJ10191584, completely reduced the effects of histamine, 4-methylhistamine and dimaprit. The direct scavenging ability of tested compounds was negligible. SIGNIFICANCE: Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by H2R. Our results also suggest that H4R agonists in concentrations higher than 10(-6)M may also influence ROS production via binding to H2R.


Assuntos
Histamina/fisiologia , Fagócitos/metabolismo , Espécies Reativas de Oxigênio/sangue , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos/metabolismo , Benzimidazóis/farmacologia , Dimaprit/farmacologia , Guanidinas/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Masculino , Metilistaminas/farmacologia , Fagócitos/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/agonistas , Receptores Histamínicos H4 , Tioureia/análogos & derivados , Tioureia/farmacologia
10.
Int J Neuropsychopharmacol ; 16(7): 1539-45, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23308396

RESUMO

The role of the basolateral amygdala (BLA) in the consolidation of aversive memory is well established. Here we investigate the involvement of the histaminergic system in BLA on this variable. Rats were chronically implanted with bilateral cannulae in the BLA and after recovery were trained in a one-trial step-down inhibitory avoidance task. Immediately after training histaminergic compounds either alone or in combination were infused through the cannulae. Memory was assessed in test sessions carried out 24 h after the training session. Post-training histamine (1-10 nmol; 0.5 µl/side) enhanced consolidation and the histamine H3 receptor antagonist thioperamide (50 nmol; 0.5 µl/side) impaired memory consolidation. The effect was shared by the histamine N-methyltransferase inhibitor SKF-91844 (50 nmol; 0.5 µl/side) as well as by the H3 receptor agonist imetit (10 nmol; 0.5 µl/side). The promnesic action of histamine was unaffected by the H1 receptor antagonist pyrilamine (50 nmol; 0.5 µl/side). The H1 receptor agonist pyridylethylamine (10 nmol; 0.5 µl/side), the H2 agonist dimaprit (10 nmol; 0.5 µl/side) and the H2 antagonist ranitidine (50 nmol; 0.5 µl/side) were ineffective. Histaminergic compounds infused into the BLA had no effect on open-field or elevated plus-maze behaviour. The data show that histamine induces a dose-dependent mnemonic effect in rats and indicate that this reflects a role of endogenous histamine in the BLA mediated by H3 receptors.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/farmacologia , Memória/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Análise de Variância , Animais , Dimaprit/análogos & derivados , Dimaprit/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Estatísticas não Paramétricas
11.
Neurosignals ; 21(3-4): 174-83, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23006827

RESUMO

The superior vestibular nucleus (SVN), which holds a key position in vestibulo-ocular reflexes and nystagmus, receives direct hypothalamic histaminergic innervations. By using rat brainstem slice preparations and extracellular unitary recordings, we investigated the effect of histamine on SVN neurons and the underlying receptor mechanisms. Bath application of histamine evoked an excitatory response of the SVN neurons, which was not blocked by the low-Ca(2+)/high-Mg(2+) medium, indicating a direct postsynaptic effect of the amine. Selective histamine H1 receptor agonist 2-pyridylethylamine and H2 receptor agonist dimaprit, rather than VUF8430, a selective H4 receptor agonist, mimicked the excitation of histamine on SVN neurons. In addition, selective H1 receptor antagonist mepyramine and H2 receptor antagonist ranitidine, but not JNJ7777120, a selective H4 receptor antagonist, partially blocked the excitatory response of SVN neurons to histamine. Moreover, mepyramine together with ranitidine nearly totally blocked the histamine-induced excitation. Immunostainings further showed that histamine H1 and H2 instead of H4 receptors existed in the SVN. These results demonstrate that histamine excites the SVN neurons via postsynaptic histamine H1 and H2 receptors, and suggest that the central histaminergic innervation from the hypothalamus may actively bias the SVN neuronal activity and subsequently modulate the SVN-mediated vestibular functions and gaze control.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Histamina/farmacologia , Neurônios/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Núcleos Vestibulares/efeitos dos fármacos , Animais , Dimaprit/farmacologia , Feminino , Agonistas dos Receptores Histamínicos/farmacologia , Masculino , Neurônios/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Núcleos Vestibulares/metabolismo
12.
Neuroscience ; 217: 84-95, 2012 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-22579982

RESUMO

Histamine acts centrally to increase energy expenditure and reduce body weight by mechanisms not fully understood. It has been suggested that in the obese state hypothalamic histamine signaling is altered. Previous studies have also shown that histamine acting in the preoptic area controls thermoregulation. We aimed to study the influence of preoptic histamine on body temperature and energy homeostasis in control and obese mice. Activating histamine receptors in the preoptic area by increasing the concentration of endogenous histamine or by local injection of specific agonists induced an elevation of core body temperature and decreased respiratory exchange ratio (RER). In addition, the food intake was significantly decreased. The hyperthermic effect was associated with a rapid increase in mRNA expression of uncoupling proteins in thermogenic tissues, the most pronounced being that of uncoupling protein (UCP) 1 in brown adipose tissue and of UCP2 in white adipose tissue. In diet-induced obese mice histamine had much diminished hyperthermic effects as well as reduced effect on RER. Similarly, the ability of preoptic histamine signaling to increase the expression of uncoupling proteins was abolished. We also found that the expression of mRNA encoding the H1 receptor subtype in the preoptic area was significantly lower in obese animals. These results indicate that histamine signaling in the preoptic area modulates energy homeostasis by regulating body temperature, metabolic parameters and food intake and that the obese state is associated with a decrease in neurotransmitter's influence.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Histamina/metabolismo , Homeostase/fisiologia , Obesidade/metabolismo , Receptores Histamínicos/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Dimaprit/análogos & derivados , Dimaprit/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Agonistas dos Receptores Histamínicos/farmacologia , Homeostase/efeitos dos fármacos , Camundongos , Camundongos Obesos , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo
13.
J Neurosci Res ; 90(1): 132-42, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21922515

RESUMO

The central histaminergic nervous system, originating from the tuberomammillary nucleus of the hypothalamus, widely innervates almost the whole brain as well as the spinal cord. However, the effect of histamine on spinal motoneurons, the final common path for motor control, is still unknown. By using 8-14-day-old rat spinal slice preparations and intracellular recordings, the effect of histamine on motoneurons in lumbar spinal cord and the underlying mechanisms were studied. Bath application of histamine (30-300 µM) induced a membrane depolarization in the majority of recorded spinal motoneurons (78/90, 86%). Perfusing slices with tetrodotoxin or low-Ca(2+) /high-Mg(2+) medium did not block the histamine-induced excitation, indicating a direct postsynaptic action of histamine on motoneurons. Separate application of the selective histamine H(1) receptor antagonist mepyramine or the selective histamine H(2) receptor antagonist ranitidine partially suppressed the histamine-induced excitation, whereas a combination of ranitidine and mepyramine totally blocked the excitatory effect of histamine on motoneurons. On the other hand, both the selective histamine H(1) receptor agonist 2-pyridylethylamine and the selective histamine H(2) receptor agonist dimaprit mimicked the excitation of histamine on spinal motoneurons. These agonist-induced excitations were also blocked by mepyramine or ranitidine. Furthermore, histamine affected membrane input resistance and potentiated repetitive firing behavior of spinal motoneurons. These results demonstrate that histamine excites rat spinal motoneurons via the histamine H(1) and H(2) receptors and increases their excitability, suggesting that the hypothalamospinal histaminergic fibers may directly modulate final motor outputs and actively regulate ongoing motor execution andspinal motor reflexes.


Assuntos
Histamina/farmacologia , Neurônios Motores/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Medula Espinal/citologia , Potenciais de Ação/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Biofísica , Bloqueadores dos Canais de Cálcio/farmacologia , Dimaprit/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H2/farmacologia , Técnicas In Vitro , Técnicas de Patch-Clamp , Piridinas/farmacologia , Ranitidina/farmacologia , Ratos , Tetrodotoxina/farmacologia
14.
Neurosci Lett ; 502(3): 133-7, 2011 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-21683759

RESUMO

Previous studies have shown an excitatory effect of histamine on neurons in two cerebellar nuclei, the fastigial nucleus and the interposed nucleus. Here we investigated action of histamine on the dentate nucleus (DN), another nucleus of the cerebellum, and provided more evidence for motor control by histamine via the cerebellum. Spontaneous unitary discharge of neurons in the DN was extracellularly recorded by use of cerebellar slice preparations. In total 79-recorded neurons, which were from 53 cerebellar slices, 67 neurons (84.8%) had an excitatory response to histamine stimulation, and the rest (15.2%) were not reactive. The histamine-induced excitation of the DN neurons was not blocked by low-Ca(2+)/high-Mg(2+) medium, demonstrating that this effect of histamine was postsynaptic. Triprolidine, an antagonist of histamine H(1) receptors, did not block the excitatory effect of histamine, but ranitidine, an antagonist for H(2) receptors, blocked the excitatory response to histamine in a concentration-dependent manner. Further, histamine H(1) receptor agonist 2-pyridylethylamine did not elicit any response of DN neurons, but H(2) receptor agonist dimaprit had an excitatory action on the DN cells and this action was blocked by ranitidine. These results indicate that histamine excites cerebellar DN neurons via histamine H(2) receptors. Since the DN receives hypothalamocerebellar histaminergic projections and plays a role in initiation and planning of somatic movement, the postsynaptic excitation of the DN neurons by histamine suggests the possibility that the initiation and planning of movement may be modulated by the histaminergic projections.


Assuntos
Movimento Celular/fisiologia , Núcleos Cerebelares/citologia , Núcleos Cerebelares/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Histamina/fisiologia , Neurônios/fisiologia , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos H2/fisiologia , Animais , Movimento Celular/efeitos dos fármacos , Núcleos Cerebelares/efeitos dos fármacos , Dimaprit/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/metabolismo , Vias Neurais/citologia , Vias Neurais/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley
15.
J Neurochem ; 118(5): 749-59, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21682723

RESUMO

Exploring the mechanisms of serotonin [5-hydroxytryptamine (5-HT)] in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized fast-scan cyclic voltammetry for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely because of increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR.


Assuntos
Eletroquímica/métodos , Histamina/metabolismo , Feixe Prosencefálico Mediano/fisiologia , Serotonina/metabolismo , Substância Negra/metabolismo , Animais , Dimaprit/análogos & derivados , Dimaprit/farmacologia , Estimulação Elétrica/métodos , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Modelos Lineares , Masculino , Vias Neurais/fisiologia , Piperidinas/farmacologia , Núcleos da Rafe/fisiologia , Ratos , Ratos Sprague-Dawley , Serotonina/farmacologia
16.
Neuroreport ; 22(11): 520-4, 2011 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-21697749

RESUMO

We investigated the interaction between ambient histamine and acetylcholine by studying γ oscillations in rat hippocampus, induced by bath application of acetylcholine (10 µM combined with 2 µM physostigmine). The power of γ was significantly increased by the H1 antagonist, fexofenadine, and H2 receptor agonist, dimaprit, and reduced by the H2 receptor antagonist, cimetidine. These effects suggest an interference with ambient histamine. Depletion of histamine from their fibers by hypoxia and blockade of histamine uptake resulted in loss of the fexofenadine-mediated and cimetidine-mediated effects on acetylcholine-induced γ. We conclude that acetylcholine can cause histamine release from histaminergic fibers and thereby can influence attentional states by augmenting γ. This effect is likely due to activation of H2 receptors by histamine and thereby might contribute to the previously described enhancement of working memory.


Assuntos
Acetilcolina/farmacologia , Eletroencefalografia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Histamina/fisiologia , Animais , Atenção/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Cimetidina/farmacologia , Dimaprit/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H2/farmacologia , Liberação de Histamina/efeitos dos fármacos , Hipóxia Encefálica/fisiopatologia , Técnicas In Vitro , Masculino , Microeletrodos , Fisostigmina/farmacologia , Tratos Piramidais/efeitos dos fármacos , Tratos Piramidais/fisiologia , Ratos , Ratos Wistar , Terfenadina/análogos & derivados , Terfenadina/farmacologia
17.
J Psychopharmacol ; 25(2): 281-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19825905

RESUMO

Cholestasis is associated with analgesia. The histamine H(2) receptors control pain perception. The involvement of histamine H(2) receptors on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using zolantidine and cimetidine as two H(2) receptor antagonists and dimaprit as a selective H(2) receptor agonist. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct at the midpoint between them. A significant increase in tail-flick latencies was observed in cholestatic rats compared to non-cholestatic rats. Administration of zolantidine (10, 20 and 40 mg/kg) and cimetidine (25, 50 and 100 mg/kg) in the cholestatic group significantly increased tail-flick latencies while dimaprit (10 and 20 mg/kg) injection in the cholestatic group decreased tail-flick latencies compared to the saline treated cholestatic group. Antinociception produced by injection of zolantidine and cimetidine in cholestatic rats was attenuated by co-administration of naloxone. Drug injection in non-cholestatic rats did not alter tail-flick latencies compared to the saline treated rats at any of the doses. At the doses used here, none of the drugs impaired motor coordination as revealed by the rota rod test. These data show that the histamine H(2) receptor system may be involved in the regulation of nociception during cholestasis. According to the hypothesis that increasing the nociception threshold in cholestasis may lead to a decrease in the perception of pruritus, the provision of the drugs that increase the threshold to nociception may be a novel approach to the treatment of cholestatic pruritus.


Assuntos
Benzotiazóis/farmacologia , Cimetidina/farmacologia , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos H2/farmacologia , Percepção da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Analgesia/psicologia , Animais , Benzotiazóis/antagonistas & inibidores , Colestase/complicações , Colestase/tratamento farmacológico , Cimetidina/antagonistas & inibidores , Dimaprit/farmacologia , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/complicações , Dor/fisiopatologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Percepção da Dor/fisiologia , Fenoxipropanolaminas/antagonistas & inibidores , Piperidinas/antagonistas & inibidores , Ratos , Ratos Wistar , Receptores Histamínicos H2/fisiologia , Teste de Desempenho do Rota-Rod
18.
Biophys J ; 99(6): 1906-15, 2010 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-20858436

RESUMO

The flow properties of DNA are important for understanding cell division and, indirectly, cancer therapy. DNA topology controlling enzymes such as topoisomerase II are thought to play an essential role. We report experiments showing how double-strand passage facilitated by topoisomerase II controls DNA rheology. For this purpose, we have measured the elastic storage and viscous loss moduli of a model system comprising bacteriophage λ-DNA and human topoisomerase IIα using video tracking of the Brownian motion of colloidal probe particles. We found that the rheology is critically dependent on the formation of temporal entanglements among the DNA molecules with a relaxation time of ∼1 s. We observed that topoisomerase II effectively removes these entanglements and transforms the solution from an elastic physical gel to a viscous fluid depending on the consumption of ATP. A second aspect of this study is the effect of the generic topoisomerase II inhibitor adenylyl-imidodiphosphate (AMP-PNP). In mixtures of AMP-PNP and ATP, the double-strand passage reaction gets blocked and progressively fewer entanglements are relaxed. A total replacement of ATP by AMP-PNP results in a temporal increase in elasticity at higher frequencies, but no transition to an elastic gel with fixed cross-links.


Assuntos
DNA Topoisomerases Tipo II/metabolismo , DNA Viral/metabolismo , Movimento/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Monofosfato de Adenosina/metabolismo , Adenilil Imidodifosfato/metabolismo , Adenilil Imidodifosfato/farmacologia , Bacteriófago lambda , DNA Viral/química , Dimaprit/análogos & derivados , Dimaprit/metabolismo , Módulo de Elasticidade/efeitos dos fármacos , Humanos , Reologia , Inibidores da Topoisomerase II/metabolismo , Viscosidade/efeitos dos fármacos
19.
Neurosci Lett ; 479(2): 118-22, 2010 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-20493926

RESUMO

Astrocytes are thought to play a role in the maintenance of homeostasis and the provision of metabolic substrates for neurons as well as the coupling of cerebral blood flow to neuronal activity. Accordingly, astrocytic death due to various types of injury can critically influence neuronal survival. The exact pathway of cell death after brain ischemia is under debate. In the present study, we used astrocytes from rat primary culture treated with persistent oxygen-glucose-deprivation (OGD) as a model of ischemia to examine the pathway of cell death and the relevant mechanisms. We observed changes in the cellular morphology, the energy metabolism of astrocytes, and the percentage of apoptosis or oncosis of the astrocytes induced by OGD. Electron microscopy revealed the co-existence of ultrastructural features in both apoptosis and oncosis in individual cells. The cellular ATP content was gradually decreased and the percentages of apoptotic and oncotic cells were increased during OGD. After 4h of OGD, ATP depletion to less than 35% of the control was observed, and oncosis became the primary pathway for astrocytic death. Increased plasma membrane permeability due to oncosis was associated with increased calpain-mediated degradation of several cytoskeletal proteins, including paxillin, vinculin, vimentin and GFAP. Pre-treatment with the calpain inhibitor 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid (PD150606) could delay the OGD-induced astrocytic oncosis. These results suggest that there is a narrow range of ATP that determines astrocytic oncotic death induced by persistent OGD and that calpain-mediated hydrolysis of the cytoskeletal-associated proteins may contribute to astrocytes oncosis.


Assuntos
Astrócitos/citologia , Calpaína/fisiologia , Proteínas do Citoesqueleto/metabolismo , Glucose/deficiência , Oxigênio/metabolismo , Acrilatos/farmacologia , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Astrócitos/ultraestrutura , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Calpaína/antagonistas & inibidores , Morte Celular , Permeabilidade da Membrana Celular , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Dimaprit/análogos & derivados , Dimaprit/metabolismo , Metabolismo Energético , Hidrólise , Ratos
20.
Am J Physiol Gastrointest Liver Physiol ; 297(6): G1147-62, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19808660

RESUMO

We tested the novel hypothesis that endogenous adenosine (eADO) activates low-affinity A3 receptors in a model of neurogenic diarrhea in the guinea pig colon. Dimaprit activation of H2 receptors was used to trigger a cyclic coordinated response of contraction and Cl(-) secretion. Contraction-relaxation was monitored by sonomicrometry (via intracrystal distance) simultaneously with short-circuit current (I(sc), Cl(-) secretion). The short interplexus reflex coordinated response was attenuated or abolished by antagonists at H2 (cimetidine), 5-hydroxytryptamine 4 receptor (RS39604), neurokinin-1 receptor (GR82334), or nicotinic (mecamylamine) receptors. The A1 agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) abolished coordinated responses, and A1 antagonists could restore normal responses. A1-selective antagonists alone [8-cyclopentyltheophylline (CPT), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), or 8-cyclopentyl-N(3)-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-xanthine (FSCPX)] caused a concentration-dependent augmentation of crypt cell secretion or contraction and acted at nanomolar concentrations. The A3 agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) abolished coordinated responses and the A3 antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191) could restore and further augment responses. The IB-MECA effect was resistant to knockdown of adenosine A1 receptor with the irreversible antagonist FSCPX; the IC(50) for IB-MECA was 0.8 microM. MRS1191 alone could augment or unmask coordinated responses to dimaprit, and IB-MECA suppressed them. MRS1191 augmented distension-evoked reflex I(sc) responses. Adenosine deaminase mimicked actions of adenosine receptor antagonists. A3 receptor immunoreactivity was differentially expressed in enteric neurons of different parts of colon. After tetrodotoxin, IB-MECA caused circular muscle relaxation. The data support the novel concept that eADO acts at low-affinity A3 receptors in addition to high-affinity A1 receptors to suppress coordinated responses triggered by immune-histamine H2 receptor activation. The short interplexus circuit activated by histamine involves adenosine, acetylcholine, substance P, and serotonin. We postulate that A3 receptor modulation may occur in gut inflammatory diseases or allergic responses involving mast cell and histamine release.


Assuntos
Adenosina/metabolismo , Colo/metabolismo , Sistema Nervoso Entérico/metabolismo , Motilidade Gastrointestinal , Histamina/metabolismo , Músculo Liso/metabolismo , Inibição Neural , Intestino Neurogênico/metabolismo , Receptor A3 de Adenosina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Cloretos/metabolismo , Cimetidina/farmacologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/inervação , Di-Hidropiridinas/farmacologia , Dimaprit/farmacologia , Relação Dose-Resposta a Droga , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/fisiopatologia , Motilidade Gastrointestinal/efeitos dos fármacos , Cobaias , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H2/farmacologia , Técnicas In Vitro , Secreções Intestinais/metabolismo , Masculino , Mecamilamina/farmacologia , Contração Muscular , Relaxamento Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/imunologia , Músculo Liso/inervação , Inibição Neural/efeitos dos fármacos , Intestino Neurogênico/imunologia , Intestino Neurogênico/fisiopatologia , Antagonistas do Receptor de Neuroquinina-1 , Antagonistas Nicotínicos/farmacologia , Piperidinas/farmacologia , Propano/análogos & derivados , Propano/farmacologia , Receptor A1 de Adenosina/efeitos dos fármacos , Receptor A1 de Adenosina/metabolismo , Receptor A3 de Adenosina/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacos , Receptores Histamínicos H2/metabolismo , Receptores da Neurocinina-1/metabolismo , Reflexo , Teofilina/análogos & derivados , Teofilina/farmacologia , Xantinas/farmacologia
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