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1.
Proc Natl Acad Sci U S A ; 110(50): 20272-7, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24191004

RESUMO

Although the neural circuitry underlying homeostatic sleep regulation is little understood, cortical neurons immunoreactive for neuronal nitric oxide synthase (nNOS) and the neurokinin-1 receptor (NK1) have been proposed to be involved in this physiological process. By systematically manipulating the durations of sleep deprivation and subsequent recovery sleep, we show that activation of cortical nNOS/NK1 neurons is directly related to non-rapid eye movement (NREM) sleep time, NREM bout duration, and EEG δ power during NREM sleep, an index of preexisting homeostatic sleep drive. Conversely, nNOS knockout mice show reduced NREM sleep time, shorter NREM bouts, and decreased power in the low δ range during NREM sleep, despite constitutively elevated sleep drive. Cortical NK1 neurons are still activated in response to sleep deprivation in these mice but, in the absence of nNOS, they are unable to up-regulate NREM δ power appropriately. These findings support the hypothesis that cortical nNOS/NK1 neurons translate homeostatic sleep drive into up-regulation of NREM δ power through an NO-dependent mechanism.


Assuntos
Ondas Encefálicas/fisiologia , Córtex Cerebral/fisiologia , Interneurônios/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Sono/fisiologia , Animais , Contagem de Células , Eletroencefalografia , Eletromiografia , Imuno-Histoquímica , Camundongos , Ratos , Ratos Sprague-Dawley
2.
PLoS One ; 7(7): e39131, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22768296

RESUMO

The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4-6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking "drive".


Assuntos
Aminopiridinas/farmacologia , Benzoxazóis/farmacologia , Compostos de Fenilureia/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Sono/efeitos dos fármacos , Sulfonamidas/farmacologia , Ureia/análogos & derivados , Animais , Benzoxazóis/farmacocinética , Relação Dose-Resposta a Droga , Agonistas GABAérgicos/farmacocinética , Agonistas GABAérgicos/farmacologia , Masculino , Naftiridinas , Receptores de Orexina , Compostos de Fenilureia/farmacocinética , Ratos Sprague-Dawley , Ureia/farmacocinética , Ureia/farmacologia
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