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1.
Acta Physiol (Oxf) ; 230(4): e13562, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32969183
2.
CNS Neurosci Ther ; 26(3): 355-366, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31571389

RESUMO

AIMS: Histamine H3 receptor (H3R) antagonists/inverse agonists increase vigilance. We studied brain histaminergic pathways under hyperammonemia and the transcriptome of receptors and their signaling cascades to provide a rationale for wake-promoting therapies. METHODS: We analyzed histamine-induced long-lasting depression of corticostriatal synaptic transmission (LLDhist). As the expression of dopamine 1 receptors (D1R) is upregulated in LGS-KO striatum where D1R-H3R dimers may exist, we investigated actions of H3R and D1R agonists and antagonists. We analyzed transcription of selected genes in cortex and dorsal striatum in a mouse model of inborn hyperammonemia (liver-specific glutamine synthetase knockout: LGS-KO) and compared it with human hepatic encephalopathy. RESULTS: LGS-KO mice showed significant reduction of the direct depression (DD) but not the long-lasting depression (LLD) by histamine. Neither pharmacological activation nor inhibition of D1R significantly affected DDhist and LLDhist in WT striatum, while in LGS-KO mice D1R activation suppressed LLDhist. Histaminergic signaling was found unchanged at the transcriptional level except for the H2R. A study of cAMP-regulated genes indicated a significant reduction in the molecular signature of wakefulness in the diseased cortex. CONCLUSIONS: Our findings provide a rationale for the development of aminergic wake-promoting therapeutics in hyperammonemic disorders.

3.
Neuropharmacology ; 143: 327-338, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30219501

RESUMO

Histaminergic (HA) neurons located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus fire exclusively during waking and support many physiological functions. We investigated the role of the endovanilloid N-oleoyldopamine (OLDA) in TMN, where dopamine synthesis and its conjugation with oleic acid likely occur. We show that several known targets of OLDA including TRPV1 and cannabinoid receptors are expressed in HA neurons. In contrast to capsaicin, which failed to increase firing of HA neurons in TRPV1 knockout mice (TRPVI KO), OLDA was still able to induce excitation. This excitation was not sensitive to the blockade of cannabinoid receptors 1 and 2 and could result from OLDA interaction with GPR119, as the ligand of GPR119, oleoylethanolamide (OEA), also increased the firing of HA neurons. However, we ruled out this possibility as OEA- (but not OLDA-) excitation was abolished by the PPAR (peroxisome proliferator activated receptor) alpha antagonist MK886. The dopamine uptake blocker nomifensine blanked OLDA-excitation and dopamine receptor antagonists abolished the OLDA action in TRPV1 KO mice. Therefore OLDA excites HA neurons through multiple targets suggesting a central role of the histaminergic system in the behavioral stimulation seen after systemic OLDA application.


Assuntos
Dopamina/análogos & derivados , Histamina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Dopamina/farmacologia , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/crescimento & desenvolvimento , Região Hipotalâmica Lateral/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Técnicas de Cultura de Tecidos
4.
Neuropharmacology ; 119: 111-122, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28400256

RESUMO

N-oleoyl-dopamine (OLDA) is an amide of dopamine and oleic acid, synthesized in catecholaminergic neurons. The present study investigates OLDA targets in midbrain dopaminergic (DA) neurons. Substantia Nigra compacta (SNc) DA neurons recorded in brain slices were excited by OLDA in wild type mice. In transient receptor potential vanilloid 1 (TRPV1) knockout (KO) mice, however, SNc DA neurons displayed sustained inhibition of firing. In the presence of the dopamine type 2 receptor (D2R) antagonist sulpiride or the dopamine transporter blocker nomifensine no such inhibition was observed. Under sulpiride OLDA slightly excited SNc DA neurons, an action abolished upon combined application of the cannabinoid1 and 2 receptor antagonists AM251 and AM630. In ventral tegmental area (VTA) DA neurons from TRPV1 KO mice a transient inhibition of firing by OLDA was observed. Thus OLDA modulates the firing of nigrostriatal DA neurons through interactions with TRPV1, cannabinoid receptors and dopamine uptake. These findings suggest further development of OLDA-like tandem molecules for the treatment of movement disorders including Parkinson's disease.


Assuntos
Dopaminérgicos/farmacologia , Dopamina/análogos & derivados , Neurônios Dopaminérgicos/efeitos dos fármacos , Mesencéfalo/citologia , Canais de Cátion TRPV/metabolismo , Acrilamidas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Pirazóis/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Tirosina 3-Mono-Oxigenase/metabolismo
5.
Sci Rep ; 7: 40190, 2017 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-28067279

RESUMO

Genetic defects in ammonia metabolism can produce irreversible damage of the developing CNS causing an impairment of cognitive and motor functions. We investigated alterations in behavior, synaptic plasticity and gene expression in the hippocampus and dorsal striatum of transgenic mice with systemic hyperammonemia resulting from conditional knockout of hepatic glutamine synthetase (LGS-ko). These mice showed reduced exploratory activity and delayed habituation to a novel environment. Field potential recordings from LGS-ko brain slices revealed significantly reduced magnitude of electrically-induced long-term potentiation (LTP) in both CA3-CA1 hippocampal and corticostriatal synaptic transmission. Corticostriatal but not hippocampal slices from LGS-ko brains demonstrated also significant alterations in long-lasting effects evoked by pharmacological activation of glutamate receptors. Real-time RT-PCR revealed distinct patterns of dysregulated gene expression in the hippocampus and striatum of LGS-ko mice: LGS-ko hippocampus showed significantly modified expression of mRNAs for mGluR1, GluN2B subunit of NMDAR, and A1 adenosine receptors while altered expression of mRNAs for D1 dopamine receptors, the M1 cholinoreceptor and the acetylcholine-synthetizing enzyme choline-acetyltransferase was observed in LGS-ko striatum. Thus, inborn systemic hyperammonemia resulted in significant deficits in novelty acquisition and disturbed synaptic plasticity in corticostriatal and hippocampal pathways involved in learning and goal-directed behavior.


Assuntos
Encéfalo/fisiopatologia , Comportamento Exploratório , Glutamato-Amônia Ligase/deficiência , Hiperamonemia/genética , Hiperamonemia/psicologia , Plasticidade Neuronal , Animais , Encéfalo/metabolismo , Córtex Cerebral/fisiopatologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Glutamato-Amônia Ligase/genética , Habituação Psicofisiológica , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hiperamonemia/congênito , Fígado/metabolismo , Masculino , Camundongos Knockout , Receptores de Dopamina D2/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Transmissão Sináptica
6.
Neuropharmacology ; 106: 1-2, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27089982
7.
Neuropharmacology ; 106: 102-15, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26297536

RESUMO

Using a reporter mouse model with expression of the tomato fluorescent protein under the dopamine transporter promoter (Tmt-DAT) we discovered a new group of neurons in the histaminergic tuberomamillary nucleus (TMN), which, in contrast to tuberoinfundibular dopaminergic neurons of the dorsomedial arcuate nucleus, do not express tyrosine hydroxylase but can synthesize and store dopamine. Tmt-DAT neurons located within TMN share electrophysiological properties with histaminergic neurons: spontaneous firing at a membrane potential around -50 mV and presence of hyperpolarization-activated cyclic nucleotide-gated ion channels. Histamine (30 µM) depolarizes and excites Tmt-DAT neurons through H1R activation but inhibits histaminergic neurons through H3R activation thus allowing a pharmacological identification of the different neurons. Single-cell RT-PCR revealed that all histaminergic neurons expressing histidine decarboxylase (HDC) also express H3R. This includes neurons retrogradely traced from the striatum whose inhibition by a selective H3R agonist was indistinguishable from the whole population. Prolonged depolarization reduces the autoinhibition. The potency of histamine at H3R depends on membrane potential and on extracellular and intracellular calcium. Autoinhibition can be impaired by preincubation with capsaicin, a ligand of the calcium-permeable TRPV1 channel or by blockade of Ca(2+)-ATPase with thapsigargin. The pharmacology of autoinhibition is revisited and physiological conditions for its functionality are determined. Usage of reporter mouse models for the safe identification of aminergic neurons under pathophysiological conditions is recommended. This article is part of the Special Issue entitled 'Histamine Receptors'.


Assuntos
Histamina/metabolismo , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Receptores Histamínicos H3/metabolismo , Animais , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Histidina Descarboxilase/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Canais de Cátion TRPV/metabolismo , Técnicas de Cultura de Tecidos
8.
Pharmacol Rev ; 67(3): 601-55, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26084539

RESUMO

Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.


Assuntos
Desenho de Fármacos , Histamina/metabolismo , Receptores Histamínicos/efeitos dos fármacos , Animais , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Ligantes , Receptores Histamínicos/metabolismo
9.
Cell Mol Neurobiol ; 34(6): 777-89, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24798513

RESUMO

Breathing and vigilance are regulated by pH and CO2 levels in the central nervous system. The hypocretin/orexin (Hcrt/Orx)- and histamine (HA)-containing hypothalamic neurons synergistically control different aspects of the waking state. Acidification inhibits firing of most neurons but these two groups in the caudal hypothalamus are excited by hypercapnia and protons, similar to the chemosensory neurons in the brain stem. Activation of hypothalamic wake-on neurons in response to hypercapnia, seen with the c-Fos assay, is supported by patch-clamp recordings in rodent brain slices: Hcrt/Orx and HA neurons are excited by acidification in the physiological range (pH from 7.4 to 7.0). Multiple molecular mechanisms mediate wake-promoting effects of protons in HA neurons in the tuberomamillary nucleus (TMN): among them are acid-sensing ion channels, Na(+),K(+)-ATPase, group I metabotropic glutamate receptors (mGluRI). HA neurons are remarkably sensitive to the mGluRI agonist DHPG (threshold concentration 0.5 µM) and mGluRI antagonists abolish proton-induced excitation of HA neurons. Hcrt/Orx neurons are excited through block of a potassium conductance and release glutamate with their peptides in TMN. The two hypothalamic nuclei and the serotonergic dorsal raphe cooperate toward CO2/acid-induced arousal. Their interactions and molecular mechanisms of H(+)/CO2-induced activation are relevant for the understanding and treatment of respiratory and metabolic disorders related to sleep-waking such as obstructive sleep apnea and sudden infant death syndrome.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Potenciais de Ação/fisiologia , Hipotálamo/metabolismo , Neurônios/metabolismo , Animais , Ácido Glutâmico/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neuropeptídeos/metabolismo , Orexinas
10.
Arch Biochem Biophys ; 536(2): 176-82, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23416740

RESUMO

Hyperammonemia is a major pathophysiological factor in encephalopathies associated with acute and chronic liver failure. On mouse brain slice preparations we analyzed the effects of ammonium on the characteristics of corticostriatal long-term potentiation (LTP) induced by high-frequency electrical stimulation (HFS) of cortical input and the long-lasting effects of pharmacological NMDA receptor (NMDAR) activation. Ammonium chloride exposure enhanced the expression of HFS-induced LTP at the expense of LTD and promoted the generation of NMDA-induced LTD. This treatment did not affect two NMDAR-independent forms of plasticity: taurine-induced LTP and histamine-induced LTD. Alterations in NMDA-induced plasticity were prevented by treatment with green tea polyphenols suggesting the contribution of oxidative stress to the expression of abnormal corticostriatal plasticity.


Assuntos
Antioxidantes/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiologia , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Polifenóis/farmacologia , Compostos de Amônio Quaternário/metabolismo , Chá , Animais , Antioxidantes/química , Catequina/química , Catequina/farmacologia , Estimulação Elétrica , Histamina/metabolismo , Hiperamonemia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polifenóis/química , Receptores de N-Metil-D-Aspartato/metabolismo , Taurina/metabolismo , Chá/química
12.
PLoS One ; 7(8): e42512, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22880010

RESUMO

Since ancient times ursodeoxycholic acid (UDCA), a constituent of bile, is used against gallstone formation and cholestasis. A neuroprotective action of UDCA was demonstrated recently in models of Alzheimer's disease and retinal degeneration. The mechanisms of UDCA action in the nervous system are poorly understood. We show now that UDCA promotes wakefulness during the active period of the day, lacking this activity in histamine-deficient mice. In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine. In histaminergic neurons recorded in slices UDCA reduced amplitude and duration of spontaneous and evoked IPSCs. In acutely isolated histaminergic neurons UDCA inhibited GABA-evoked currents and sIPSCs starting at 10 µM (IC(50) = 70 µM) and did not affect NMDA- and AMPA-receptor mediated currents at 100 µM. Recombinant GABA(A) receptors composed of α1, ß1-3 and γ2L subunits expressed in HEK293 cells displayed a sensitivity to UDCA similar to that of native GABA(A) receptors. The mutation α1V256S, known to reduce the inhibitory action of pregnenolone sulphate, reduced the potency of UDCA. The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.


Assuntos
Antagonistas de Receptores de GABA-A/farmacologia , Histamina/metabolismo , Receptores de GABA-A/metabolismo , Ácido Ursodesoxicólico/farmacologia , Vigília/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Administração Oral , Animais , Histamina/deficiência , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Cinética , Camundongos , Proteínas Mutantes/metabolismo , Mutação/genética , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Picrotoxina/farmacologia , Receptores de GABA-A/genética , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Esteroides/farmacologia , Fatores de Tempo , Ácido Ursodesoxicólico/administração & dosagem
13.
J Neurochem ; 122(3): 545-56, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22639911

RESUMO

Hyperammonemia is a major pathophysiological factor in encephalopathies associated with acute and chronic liver failure. On mouse brain slice preparations, we analyzed the effects of ammonia on the characteristics of corticostriatal long-term depression (LTD) induced by electrical stimulation of cortical input or pharmacological activation of metabotropic glutamate receptors. Long exposure of neostriatal slices to ammonium chloride impaired the induction and/or expression of all studied forms of LTD. This impairment was reversed by the phosphodiesterase inhibitor zaprinast implying lowered cGMP signaling in LTD suppression. Polyphenols from green tea rescued short-term corticostriatal plasticity, but failed to prevent the ammonia-induced deficit of LTD. Zaprinast counteracts the ammonia-induced impairment of long-term corticostriatal plasticity and may thus improve fine motor skills and procedural learning in hepatic encephalopathy.


Assuntos
Amônia/farmacologia , Córtex Cerebral/citologia , Corpo Estriado/citologia , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Purinonas/farmacologia , Sinapses/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Biofísica , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiologia , Cicloeximida/farmacologia , Interações Medicamentosas , Estimulação Elétrica , Técnicas In Vitro , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Polifenóis/farmacologia , Inibidores da Síntese de Proteínas/farmacologia
14.
Front Syst Neurosci ; 6: 23, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22509157

RESUMO

The histaminergic neurons in the tuberomamillary nucleus (TMN) of the posterior hypothalamus are involved in the control of arousal. These neurons are sensitive to hypercapnia as has been shown in experiments examining c-Fos expression, a marker for increased neuronal activity. We investigated the mechanisms through which TMN neurons respond to changes in extracellular levels of acid/CO(2). Recordings in rat brain slices revealed that acidification within the physiological range (pH from 7.4 to 7.0), as well as ammonium chloride (5 mM), excite histaminergic neurons. This excitation is significantly reduced by antagonists of type I metabotropic glutamate receptors and abolished by benzamil, an antagonist of acid-sensing ion channels (ASICs) and Na(+)/Ca(2+) exchanger, or by ouabain which blocks Na(+)/K(+) ATPase. We detected variable combinations of 4 known types of ASICs in single TMN neurons, and observed activation of ASICs in single dissociated TMN neurons only at pH lower than 7.0. Thus, glutamate, which is known to be released by glial cells and orexinergic neurons, amplifies the acid/CO(2)-induced activation of TMN neurons. This amplification demands the coordinated function of metabotropic glutamate receptors, Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase. We also developed a novel HDC-Cre transgenic reporter mouse line in which histaminergic TMN neurons can be visualized. In contrast to the rat, the mouse histaminergic neurons lacked the pH 7.0-induced excitation and displayed only a minimal response to the mGluR I agonist DHPG (0.5 µM). On the other hand, ammonium-induced excitation was similar in mouse and rat. These results are relevant for the understanding of the neuronal mechanisms controlling acid/CO(2)-induced arousal in hepatic encephalopathy and obstructive sleep apnoea. Moreover, the new HDC-Cre mouse model will be a useful tool for studying the physiological and pathophysiological roles of the histaminergic system.

16.
Pflugers Arch ; 463(1): 31-42, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21796339

RESUMO

An essential component of the whole-body homoeostasis provided by the hypothalamus is the management of available energy. This includes the regulation of sleeping and waking, feeding and drinking, body temperature and activity, as well as the endocrinium. The waking brain, in particular the cerebral cortex, needs to be activated through neuronal pathways ascending from the brainstem reticular formation (ascending reticular activating system, ARAS) and reaching the cortical structures by a dorsal route through the thalamus and a ventral route, including the hypothalamus and the basal forebrain. This review concentrates on the more recently explored ventral route and the hypothalamus with its different regions involved in the control of the waking state.


Assuntos
Hipotálamo/fisiologia , Vigília/fisiologia , Animais , Ritmo Circadiano/fisiologia , Humanos , Neurônios/fisiologia , Sono/fisiologia
17.
Pflugers Arch ; 463(1): 187-99, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21735059

RESUMO

The histaminergic neurons of the posterior hypothalamus (tuberomamillary nucleus-TMN) control wakefulness, and their silencing through activation of GABA(A) receptors (GABA(A)R) induces sleep and is thought to mediate sedation under propofol anaesthesia. We have previously shown that the ß1 subunit preferring fragrant dioxane derivatives (FDD) are highly potent modulators of GABA(A)R in TMN neurons. In recombinant receptors containing the ß3N265M subunit, FDD action is abolished and GABA potency is reduced. Using rat, wild-type and ß3N265M mice, FDD and propofol, we explored the relative contributions of ß1- and ß3-containing GABA(A)R to synaptic transmission from the GABAergic sleep-on ventrolateral preoptic area neurons to TMN. In ß3N265M mice, GABA potency remained unchanged in TMN neurons, but it was decreased in cultured posterior hypothalamic neurons with impaired modulation of GABA(A)R by propofol. Spontaneous and evoked GABAergic synaptic currents (IPSC) showed ß1-type pharmacology, with the same effects achieved by 3 µM propofol and 10 µM PI24513. Propofol and the FDD PI24513 suppressed neuronal firing in the majority of neurons at 5 and 100 µM, and in all cells at 10 and 250 µM, respectively. FDD given systemically in mice induced sedation but not anaesthesia. Propofol-induced currents were abolished (1-6 µM) or significantly reduced (12 µM) in ß3N265M mice, whereas gating and modulation of GABA(A)R by PI24513 as well as modulation by propofol were unchanged. In conclusion, ß1-containing (FDD-sensitive) GABA(A)R represent the major receptor pool in TMN neurons responding to GABA, while ß3-containing (FDD-insensitive) receptors are gated by low micromolar doses of propofol. Thus, sleep and anaesthesia depend on different GABA(A)R types.


Assuntos
Anestesia , Subunidades Proteicas/fisiologia , Receptores de GABA-A/fisiologia , Sono/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fenômenos Eletrofisiológicos/fisiologia , Agonistas de Receptores de GABA-A/farmacologia , Expressão Gênica/genética , Histamina/metabolismo , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/metabolismo , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/fisiologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Mutação Puntual/fisiologia , Propofol/farmacologia , Ratos , Ratos Wistar , Receptores de GABA-A/genética , Ácido gama-Aminobutírico/farmacologia
18.
Cell Mol Neurobiol ; 32(1): 17-25, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21710252

RESUMO

Genetic ablation of the histamine producing enzyme histidine decarboxylase (HDC) leads to alteration in exploratory behaviour and hippocampus-dependent learning. We investigated how brain histamine deficiency in HDC knockout mice (HDC KO) affects hippocampal excitability, synaptic plasticity, and the expression of histamine receptors. No significant alterations in: basal synaptic transmission, long-term potentiation (LTP) in the Schaffer collateral synapses, histamine-induced transient changes in the CA1 pyramidal cell excitability, and the expression of H1 and H2 receptor mRNAs were found in hippocampal slices from HDC KO mice. However, when compared to WT mice, HDC KO mice demonstrated: 1. a stronger enhancement of LTP by histamine, 2. a stronger impairment of LTP by ammonia, 3. no long-lasting potentiation of population spikes by histamine, 4. a decreased expression of H3 receptor mRNA, and 5. less potentiation of population spikes by H3 receptor agonism. Parallel measurements in the hypothalamic tuberomamillary nucleus, the origin of neuronal histamine, demonstrated an increased expression of H3 receptors in HDC KO mice without any changes in the spontaneous firing of "histaminergic" neurons without histamine and their responses to the H3 receptor agonist (R)-α-methylhistamine. We conclude that the absence of neuronal histamine results in subtle changes in hippocampal synaptic transmission and plasticity associated with alteration in the expression of H3 receptors.


Assuntos
Amônia/metabolismo , Hipocampo/fisiologia , Histidina Descarboxilase/genética , Plasticidade Neuronal/genética , Receptores Histamínicos/genética , Amônia/sangue , Animais , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Masculino , Metilistaminas/farmacologia , Camundongos , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Receptores Histamínicos/metabolismo , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética
19.
Cell Mol Life Sci ; 68(15): 2499-512, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21318261

RESUMO

Wakefulness and consciousness depend on perturbation of the cortical soliloquy. Ascending activation of the cerebral cortex is characteristic for both waking and paradoxical (REM) sleep. These evolutionary conserved activating systems build a network in the brainstem, midbrain, and diencephalon that contains the neurotransmitters and neuromodulators glutamate, histamine, acetylcholine, the catecholamines, serotonin, and some neuropeptides orchestrating the different behavioral states. Inhibition of these waking systems by GABAergic neurons allows sleep. Over the past decades, a prominent role became evident for the histaminergic and the orexinergic neurons as a hypothalamic waking center.


Assuntos
Encéfalo/fisiologia , Vigília/fisiologia , Animais , Nível de Alerta/fisiologia , Monoaminas Biogênicas/metabolismo , Monoaminas Biogênicas/fisiologia , Histamina/metabolismo , Histamina/fisiologia , Humanos , Hipotálamo Posterior/fisiologia , Modelos Biológicos
20.
J Physiol ; 589(Pt 6): 1349-66, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21242252

RESUMO

L-Dopa is the most effective treatment of early and advanced stages of Parkinson's disease (PD), but its chronic use leads to loss of efficiency and dyskinesia. This is delayed by lower dosage at early stages, made possible by additional treatment with histamine antagonists. We present here evidence that histaminergic tuberomamillary nucleus (TMN) neurons, involved in the control of wakefulness, are excited under L-Dopa (EC50 15 µM), express Dopa decarboxylase and show dopamine immunoreactivity. Dopaergic excitation was investigated with patch-clamp recordings from brain slices combined with single-cell RT-PCR analysis of dopamine receptor expression. In addition to the excitatory dopamine 1 (D1)-like receptors, TMN neurons express D2-like receptors, which are coupled through phospholipase C (PLC) to transient receptor potential canonical (TRPC) channels and the Na+/Ca2+ exchanger. D2 receptor activation enhances firing frequency, histamine release in freely moving rats (microdialysis) and wakefulness (EEG recordings). In histamine deficient mice the wake-promoting action of the D2 receptor agonist quinpirole (1 mg kg⁻¹, I.P.) is missing. Thus the histamine neurons can, subsequent to L-Dopa uptake, co-release dopamine and histamine from their widely projecting axons. Taking into consideration the high density of histaminergic fibres and the histamine H3 receptor heteromerization either with D1 or with D2 receptors in the striatum, this study predicts new avenues for PD therapy.


Assuntos
Histamina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Levodopa/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Camundongos , Camundongos Knockout , Ratos , Ratos Wistar , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo
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