RESUMO
Neurons containing the neuropeptide orexin (hypocretin) are located exclusively in the lateral hypothalamus and send axons to numerous regions throughout the central nervous system, including the major nuclei implicated in sleep regulation. Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy. Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons. We propose that orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.
Assuntos
Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular , Narcolepsia/genética , Neuropeptídeos/deficiência , Neuropeptídeos/metabolismo , Precursores de Proteínas/deficiência , Idade de Início , Animais , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Doenças do Cão/genética , Cães , Eletroencefalografia , Eletromiografia , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modafinila , Narcolepsia/tratamento farmacológico , Narcolepsia/metabolismo , Narcolepsia/fisiopatologia , Narcolepsia/veterinária , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/fisiologia , Receptores de Orexina , Orexinas , Fenótipo , Postura , Precursores de Proteínas/genética , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos/deficiência , Receptores de Neuropeptídeos/genética , Sono/fisiologia , Sono REM/fisiologia , Especificidade da Espécie , Comportamento EstereotipadoRESUMO
Leptin (ob protein) is an adipose tissue derived circulating hormone that acts at specific receptors in the hypothalamus to reduce food intake. The protein is also critically involved in energy balance and metabolic status. Here the effect of leptin on sleep architecture in rats was evaluated because food consumption and metabolic status are known to influence sleep. Sprague-Dawley rats were chronically implanted with electrodes for EEG and EMG recording and diurnal sleep parameters were quantified over 9-h periods following leptin administration. Murine recombinant leptin (rMuLep) was administered systemically to rats that either had undergone 18 h of prior food deprivation or had received food ad libitum. In the normally fed rats, leptin significantly decreased the duration of rapid eye movement sleep (REMS) by about 30% and increased the duration of slow wave sleep (SWS) by about 13%, the latter effect reflecting enhanced power in the delta frequency band. These results are consistent with studies that have linked changes in metabolic rate with effects on sleep. Leptin administration has previously been shown to alter neuroendocrine parameters that could have mediated these changes in sleep architecture. Unexpectedly, prior food deprivation negated the effect of leptin on both REMS and SWS, a result that emphasizes the significance of the apparent coupling between sleep parameters and energy status.