RESUMO
Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.
Assuntos
Locus Cerúleo , Ratos Sprague-Dawley , Receptor MT1 de Melatonina , Sono REM , Animais , Masculino , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Locus Cerúleo/fisiologia , Ratos , Receptor MT1 de Melatonina/agonistas , Receptor MT1 de Melatonina/metabolismo , Sono REM/fisiologia , Sono REM/efeitos dos fármacos , Norepinefrina/metabolismo , Neurônios Adrenérgicos/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Neurônios Adrenérgicos/fisiologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologiaRESUMO
Post-operative sleep disorders induce adverse effects on patients, especially the elderly, which may be associated with surgery and inhalational anaesthetics. Melatonin is a neuroendocrine regulator of the sleep-wake cycle. In this study, we analysed the alterations of post-operative sleep in aged melatonin-deficient (C57BL/6J) mice, and investigated if exogenous melatonin could facilitate entrainment of circadian rhythm after laparotomy under sevoflurane anaesthesia. The results showed that laparotomy under sevoflurane anaesthesia had a greater influence on post-operative sleep than sevoflurane alone. Laparotomy under anaesthesia led to circadian rhythm shifting forward, altered EEG power density and delta power of NREM sleep, and lengthened REM and NREM sleep latencies. In the light phase, the number of waking episodes tended to decline, and wake episode duration elevated. However, these indicators presented the opposite tendency during the dark phase. Melatonin showed significant efficacy for ameliorating the sleep disorder and restoring physiological sleep, and most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.
Assuntos
Anestésicos Inalatórios/toxicidade , Ritmo Circadiano/efeitos dos fármacos , Laparotomia/efeitos adversos , Melatonina/farmacologia , Complicações Pós-Operatórias/prevenção & controle , Sevoflurano/toxicidade , Medicamentos Indutores do Sono/farmacologia , Fases do Sono/efeitos dos fármacos , Transtornos do Sono-Vigília/prevenção & controle , Ciclos de Atividade/efeitos dos fármacos , Fatores Etários , Animais , Eletroencefalografia , Eletromiografia , Feminino , Melatonina/deficiência , Camundongos Endogâmicos C57BL , Fotoperíodo , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/fisiopatologia , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/fisiopatologia , Sono REM/efeitos dos fármacos , Fatores de TempoAssuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Bupropiona/efeitos adversos , Clonidina/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores da Captação de Dopamina/efeitos adversos , Sonhos/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Clonidina/administração & dosagem , Feminino , HumanosRESUMO
Hypocretin 1 and hypocretin 2 (orexin A and B) regulate sleep, wakefulness and emotion. Tumour necrosis factor alpha (TNF-α) is an important neuroinflammation mediator. Here, we examined the effects of TNF-α treatment on hypocretin expression in vivo and behaviour in mice. TNF-α decreased hypocretin 1 and hypocretin 2 expression in a dose-dependent manner in cultured hypothalamic neurons. TNF-α decreased mRNA stability of prepro-hypocretin, the single precursor of hypocretin 1 and hypocretin 2. Mice challenged with TNF-α demonstrated decreased expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in hypothalamus. In response to TNF-α, prepro-hypocretin mRNA decay was increased in hypothalamus. TNF-α neutralizing antibody restored the expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in vivo in TNF-α challenged mice, supporting hypocretin system can be impaired by increased TNF-α through decreasing hypocretin expression. Repeated TNF-α challenge induced muscle activity during rapid eye movement sleep and sleep fragmentation, but decreased learning, cognition and memory in mice. TNF-α neutralizing antibody blocked the effects of TNF-α; in contrast, hypocretin receptor antagonist enhanced the effects of TNF-α. The data support that TNF-α is involved in the regulation of hypocretin expression, sleep and cognition. The findings shed some lights on the role of neuroinflammation in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
Assuntos
Comportamento Animal , Orexinas/metabolismo , Sono , Fator de Necrose Tumoral alfa/farmacologia , Animais , Anticorpos Neutralizantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Cognição/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/metabolismo , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Músculos/efeitos dos fármacos , Músculos/fisiologia , Neurônios/metabolismo , Orexinas/genética , Estabilidade de RNA/efeitos dos fármacos , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sono/efeitos dos fármacos , Privação do Sono , Sono REM/efeitos dos fármacosRESUMO
BACKGROUND: Sleep disturbances are common in smoking cessation attempts and are predictive of relapse. Despite this knowledge, there is no established animal model to study the effect of nicotine abstinence on sleep and EEG parameters. OBJECTIVES: The present study was conducted to characterize sleep and wakefulness in male C57BL/6J mice during periods of oral nicotine administration and abstinence. METHODS: Male C57BL/6J mice were implanted with EEG/EMG recording devices. EEG/EMG data were recorded continuously for a period of 4 weeks. At the beginning of week 2, 200 µg/ml of nicotine was added to the 0.2% saccharin vehicle drinking solution. Following a 2-week period of oral nicotine administration, abstinence was initiated by excluding the nicotine from the 0.2% saccharin vehicle drinking solution. EEG/EMG were analyzed at pre-nicotine baseline, during nicotine administration, and on days 1, 2, and 5 of abstinence from nicotine. RESULTS: Oral nicotine administration decreased total sleep time during the active phase, consistent with the stimulant actions of nicotine. In contrast, NREM sleep quantity was increased during the active phase on nicotine abstinence day 1 and REM sleep was decreased during days 2 and 5 of abstinence. Further, sleep fragmentation was increased during the inactive phase on all days of abstinence. Oral nicotine administration and abstinence from nicotine also altered EEG relative power frequencies during the inactive and active phase. CONCLUSIONS: Both oral nicotine administration and abstinence lead to sleep disturbances in mice. Similarities between this model and human reports on the effect of nicotine/nicotine withdrawal on sleep support its utility in examining the molecular mechanisms that modulate the relationship between sleep, nicotine, and nicotine abstinence/withdrawal.
Assuntos
Nicotina/administração & dosagem , Transtornos do Sono-Vigília/induzido quimicamente , Transtornos do Sono-Vigília/fisiopatologia , Sono/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia , Vigília/efeitos dos fármacos , Administração Oral , Animais , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Sono/fisiologia , Sono REM/efeitos dos fármacos , Sono REM/fisiologia , Síndrome de Abstinência a Substâncias/etiologia , Vigília/fisiologiaRESUMO
Sleep disorders increase pain sensitivity and the risk of developing painful conditions; however, the underlying mechanisms are poorly understood. It has been suggested that nucleus accumbens (NAc) influences sleep-wake cycle by means of a balance between adenosine activity at A2A receptors and dopamine activity at D2 receptors. Because the NAc also plays an important role in pain modulation, we hypothesized that the NAc and its A2A and D2 receptors mediate the pronociceptive effect of rapid eye movement (REM) sleep deprivation (SD). We found that 24 hours of REM-SD induced an intense pronociceptive effect in Wistar rats, which decreases progressively over a sleep rebound period. Although the level of fecal glucocorticoid metabolites increased with SD within group, it did not differ between sleep-deprived group and control group, indicating a stress response with similar magnitude between groups. The pronociceptive effect of REM-SD was prevented by excitotoxic lesion (N-Methyl-D-aspartate, 5.5 µg) of NAc and reverted by its acute blockade (Qx-314, 2%). The administration of an A2A receptor antagonist (SCH-58261, 7 ng) or a D2 receptor agonist (piribedil, 6 µg) into the NAc increased home cage activity and blocked the pronociceptive effect of REM-SD. Complementarily, an A2A receptor agonist (CGS-21680, 24 ng) impaired the reversal of the pronociceptive effect and decreased home cage activity, as it did a D2 receptor antagonist (raclopride, 5 µg). Rapid eye movement SD did not affect the expression of c-Fos protein in NAc. These data suggest that SD increases pain by increasing NAc adenosinergic A2A activity and by decreasing NAc dopaminergic D2 activity.
Assuntos
Nociceptividade/fisiologia , Núcleo Accumbens/fisiopatologia , Dor/fisiopatologia , Privação do Sono/fisiopatologia , Sono REM/efeitos dos fármacos , Adenosina/análogos & derivados , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Animais , Masculino , Atividade Motora , Nociceptividade/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Fenetilaminas/farmacologia , Piribedil/farmacologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Receptor A2A de Adenosina/fisiologia , Receptores de Dopamina D2/fisiologia , Triazóis/farmacologiaRESUMO
Ethanol has extensive effects on sleep and daytime alertness, causing premature disability and death. Adenosine, as a potent sleep-promoting substance, is involved in many cellular and behavioral responses to ethanol. However, the mechanisms of hypnotic effects of ethanol remain unclear. In this study, we investigated the role of adenosine in ethanol-induced sleep using C57BL/6Slac mice, adenosine A2A receptor (A2AR) knockout mice, and their wild-type littermates. The results showed that intraperitoneal injection of ethanol (3.0 g/kg) at 21:00 decreased the latency to non-rapid eye movement (NREM) sleep and increased the duration of NREM sleep for 5 h. Ethanol dose-dependently increased NREM sleep, which was consistent with decreases in wakefulness in C57BL/6Slac mice compared with their own control. Caffeine (5, 10, or 15 mg/kg), a nonspecific adenosine receptor antagonist, dose-dependently and at high doses completely blocked ethanol-induced NREM sleep when administered 30 min prior to (but not after) ethanol injection. Moreover, ethanol-induced NREM sleep was completely abolished in A2AR knockout mice compared with wild-type mice. These findings strongly indicate that A2AR is a key receptor for the hypnotic effects of ethanol, and pretreatment of caffeine might be a strategy to counter the hypnotic effects of ethanol.
Assuntos
Etanol/farmacologia , Hipnóticos e Sedativos/farmacologia , Receptor A2A de Adenosina/metabolismo , Animais , Cafeína/farmacologia , Eletroencefalografia , Etanol/administração & dosagem , Camundongos Endogâmicos C57BL , Latência do Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Vigília/efeitos dos fármacosRESUMO
Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases, and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminobutiratos/farmacologia , Calpaína/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Pirazóis/farmacologia , Aminobutiratos/síntese química , Aminobutiratos/farmacocinética , Animais , Catepsinas , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacocinética , Cães , Hipocampo/metabolismo , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Niacinamida/síntese química , Niacinamida/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Wistar , Sono REM/efeitos dos fármacos , Espectrina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We are at least as dream deprived as we are sleep deprived. Many of the health concerns attributed to sleep loss result from a silent epidemic of REM sleep deprivation. REM/dream loss is an unrecognized public health hazard that silently wreaks havoc with our lives, contributing to illness, depression, and an erosion of consciousness. This paper compiles data about the causes and extent of REM/dream loss associated with commonly used medications, endemic substance use disorders, rampant sleep disorders, and behavioral and lifestyle factors. It examines the consequences of REM/dream loss and concludes with recommendations for restoring healthy REM/dreaming.
Assuntos
Sonhos/fisiologia , Sonhos/psicologia , Estilo de Vida , Privação do Sono/diagnóstico , Privação do Sono/epidemiologia , Sono REM/fisiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Sonhos/efeitos dos fármacos , Humanos , Fumar Maconha/efeitos adversos , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Psicotrópicos/efeitos adversos , Privação do Sono/induzido quimicamente , Sono REM/efeitos dos fármacosRESUMO
INTRODUCTION: REM sleep deprivation is associated with impairment in learning and memory, and nicotine treatment has been shown to attenuate this effect. Recent studies have demonstrated the importance of DREAM protein in learning and memory processes. This study investigates the association of DREAM protein in REM sleep-deprived rats hippocampus upon nicotine treatment. METHODS: Male Sprague Dawley rats were subjected to normal condition, REM sleep deprivation and control wide platform condition for 72 hr. During this procedure, saline or nicotine (1 mg/kg) was given subcutaneously twice a day. Then, Morris water maze (MWM) test was used to assess learning and memory performance of the rats. The rats were sacrificed and the brain was harvested for immunohistochemistry and Western blot analysis. RESULTS: MWM test found that REM sleep deprivation significantly impaired learning and memory performance without defect in locomotor function associated with a significant increase in hippocampus DREAM protein expression in CA1, CA2, CA3, and DG regions and the mean relative level of DREAM protein compared to other experimental groups. Treatment with acute nicotine significantly prevented these effects and decreased expression of DREAM protein in all the hippocampus regions but only slightly reduce the mean relative level of DREAM protein. CONCLUSION: This study suggests that changes in DREAM protein expression in CA1, CA2, CA3, and DG regions of rat's hippocampus and mean relative level of DREAM protein may involve in the mechanism of nicotine treatment-prevented REM sleep deprivation-induced learning and memory impairment in rats.
Assuntos
Hipocampo , Proteínas Interatuantes com Canais de Kv/metabolismo , Nicotina/farmacologia , Proteínas Repressoras/metabolismo , Privação do Sono , Animais , Modelos Animais de Doenças , Estimulantes Ganglionares/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Ratos , Ratos Sprague-Dawley , Privação do Sono/tratamento farmacológico , Privação do Sono/metabolismo , Privação do Sono/psicologia , Sono REM/efeitos dos fármacos , Sono REM/fisiologiaRESUMO
Sleep has been postulated to promote brain energy restoration. It is as yet unknown if increasing the energy availability within the brain reduces sleep need. The guanidine amino acid creatine (Cr) is a well-known energy booster in cellular energy homeostasis. Oral Cr-monohydrate supplementation (CS) increases exercise performance and has been shown to have substantial effects on cognitive performance, neuroprotection and circadian rhythms. The effect of CS on cellular high-energy molecules and sleep-wake behaviour is unclear. Here, we examined the sleep-wake behaviour and brain energy metabolism before and after 4-week-long oral administration of CS in the rat. CS decreased total sleep time and non-rapid eye movement (NREM) sleep significantly during the light (inactive) but not during the dark (active) period. NREM sleep and NREM delta activity were decreased significantly in CS rats after 6 h of sleep deprivation. Biochemical analysis of brain energy metabolites showed a tendency to increase in phosphocreatine after CS, while cellular adenosine triphosphate (ATP) level decreased. Microdialysis analysis showed that the sleep deprivation-induced increase in extracellular adenosine was attenuated after CS. These results suggest that CS reduces sleep need and homeostatic sleep pressure in rats, thereby indicating its potential in the treatment of sleep-related disorders.
Assuntos
Creatina/farmacologia , Homeostase/efeitos dos fármacos , Sono/efeitos dos fármacos , Sono/fisiologia , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Creatina/administração & dosagem , Eletroencefalografia , Metabolismo Energético/efeitos dos fármacos , Masculino , Microdiálise , Fosfocreatina/metabolismo , Ratos , Ratos Sprague-Dawley , Privação do Sono/tratamento farmacológico , Privação do Sono/metabolismo , Sono REM/efeitos dos fármacos , Sono REM/fisiologiaRESUMO
BACKGROUND: Radix Polygalae, the dried root of Polygala tenuifolia, has been extensively used as a traditional Chinese medicine for promoting intelligence and tranquilization. Polygalasaponins extracted from the root of P. tenuifolia possess evident anxiolytic and sedative-hypnotic activities. Previous studies have reported that tenuifolin was a major constituent of polygalasaponins. PURPOSE: The currently study aims to investigate the hypnotic effect and possible mechanism of tenuifolin in freely moving mice. DESIGN/METHODS: The hypnotic effects of tenuifolin (20, 40 and 80mg/kg, p.o.) were assessed by electroencephalographic (EEG) and electromyographic (EMG) analysis. Double-staining immunohistochemistry test was performed to evaluate the neuronal activity of sleep-wake regulating brain areas. High performance liquid chromatograph- electrochemical detection (HPLC-ECD) and ultrafast liquid chromatography-mass spectrometry (UFLC-MS) were used for the detection of neurotransmitters. Locomotor activity was measured by Open-field Test. RESULTS: Tenuifolin at doses of 40 and 80mg/kg (p.o.) significantly prolonged the total sleep time by increasing the amount of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, associated with the significant increase in the bouts of episodes respectively. After administration of tenuifolin, the cortical EEG power spectral densities during NREM and REM sleep were similar to that of natural sleep (vehicle) and thus compatible with physiological sleep. Double-immunohistochemistry staining test showed that tenuifolin increased the c-Fos positive ratios of GABAergic NREM sleep-promoting neurons in ventrolateral preoptic area (VLPO), cholinergic REM sleep-promoting neurons in laterodorsal tegmental area (LDT) and pontomesencephalic tegmental area (PPT) and decreased the c-Fos positive ratios in wake-promoting neurons (locus coeruleus (LC) and perifornical area (Pef)). Neurotransmitter detections revealed that tenuifolin significantly reduced the noradrenaline (NA) levels in LC, VLPO, PPT and LDT, elevated the GABA levels in VLPO, LC and Pef and increased the acetylcholine (Ach) levels in LDT and PPT. In addition, tenuifolin did not cause any change to locomotor activity. CONCLUSION: Taken together, these results provide the first experimental evidence of the significant sleep-enhancing effect of tenuifolin in mice. This effect appears to be mediated, at least in part, by the activation of GABAergic systems and/or by the inhibition of noradrenergic systems. Moreover, this study adds new scientific evidence and highlights the therapeutic potential of the medicinal plant P. tenuifolia in the development of phytomedicines with hypnotic properties.
Assuntos
Encéfalo/efeitos dos fármacos , Diterpenos do Tipo Caurano/farmacologia , Hipnóticos e Sedativos/farmacologia , Extratos Vegetais/farmacologia , Polygala/química , Saponinas/farmacologia , Sono/efeitos dos fármacos , Acetilcolina/metabolismo , Animais , Ansiolíticos/farmacologia , Encéfalo/metabolismo , Eletroencefalografia , Masculino , Camundongos Endogâmicos ICR , Neurotransmissores/metabolismo , Raízes de Plantas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Sono REM/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P < 0.021). The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD.
Assuntos
Melatonina/administração & dosagem , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Privação do Sono/patologia , Sono REM/efeitos dos fármacos , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/farmacocinética , Hipocampo/metabolismo , Masculino , Melatonina/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neurais/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Distribuição Aleatória , Privação do Sono/tratamento farmacológico , Privação do Sono/metabolismo , Proteína bcl-X/metabolismoRESUMO
The circadian clock maintains appropriate timing for a wide range of behaviors and physiological processes. Circadian behaviors such as sleep and wakefulness are intrinsically dependent on the precise oscillation of the endogenous molecular machinery that regulates the circadian clock. The identical core clock machinery regulates myriad endocrine and metabolic functions providing a link between sleep and metabolic health. The REV-ERBs (REV-ERBα and REV-ERBß) are nuclear receptors that are key regulators of the molecular clock and have been successfully targeted using small molecule ligands. Recent studies in mice suggest that REV-ERB-specific synthetic agonists modulate metabolic activity as well as alter sleep architecture, inducing wakefulness during the light period. Therefore, these small molecules represent unique tools to extensively study REV-ERB regulation of sleep and wakefulness. In these studies, our aim was to further investigate the therapeutic potential of targeting the REV-ERBs for regulation of sleep by characterizing efficacy, and optimal dosing time of the REV-ERB agonist SR9009 using electroencephalographic (EEG) recordings. Applying different experimental paradigms in mice, our studies establish that SR9009 does not lose efficacy when administered more than once a day, nor does tolerance develop when administered once a day over a three-day dosing regimen. Moreover, through use of a time response paradigm, we determined that although there is an optimal time for administration of SR9009 in terms of maximal efficacy, there is a 12-hour window in which SR9009 elicited a response. Our studies indicate that the REV-ERBs are potential therapeutic targets for treating sleep problems as those encountered as a consequence of shift work or jet lag.
Assuntos
Terapia de Alvo Molecular , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Sono/fisiologia , Vigília/fisiologia , Animais , Ritmo Circadiano/efeitos dos fármacos , Eletroencefalografia , Luz , Masculino , Camundongos Endogâmicos C57BL , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacologia , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Tiofenos/administração & dosagem , Tiofenos/farmacologia , Fatores de Tempo , Vigília/efeitos dos fármacosRESUMO
STUDY OBJECTIVES: To examine the REM sleep response to stress and fearful memories as a potential marker of stress resilience and vulnerability and to assess the role of the basolateral amygdala (BLA) in mediating the effects of fear memory on sleep. METHODS: Outbred Wistar rats were surgically implanted with electrodes for recording EEG and EMG and with bilateral guide cannulae directed at the BLA. Data loggers were placed intraperitoneally to record core body temperature. After recovery from surgery, the rats received shock training (ST: 20 footshocks, 0.8 mA, 0.5-s duration, 60-s interstimulus interval) and afterwards received microinjections of the GABAA agonist muscimol (MUS; 1.0 µM) to inactivate BLA or microinjections of vehicle (VEH) alone. Subsequently, the rats were separated into 4 groups (VEH-vulnerable (VEH-Vul; n = 14), VEH-resilient (VEH-Res; n = 13), MUS-vulnerable (MUS-Vul; n = 8), and MUS-resilient (MUS-Res; n = 11) based on whether or not REM was decreased, compared to baseline, during the first 4 h following ST. We then compared sleep, freezing, and the stress response (stress-induced hyperthermia, SIH) across groups to determine the effects of ST and fearful context re-exposure alone (CTX). RESULTS: REM was significantly reduced on the ST day in both VEH-Vul and MUS-Vul rats; however, post-ST MUS blocked the reduction in REM on the CTX day in the MUS-Vul group. The VEH-Res and MUS-Res rats showed similar levels of REM on both ST and CTX days. The effects of post-ST inactivation of BLA on freezing and SIH were minimal. CONCLUSIONS: Outbred Wistar rats can show significant individual differences in the effects of stress on REM that are mediated by BLA. These differences in REM can be independent of behavioral fear and the peripheral stress response, and may be an important biomarker of stress resilience and vulnerability.
Assuntos
Adaptação Psicológica/fisiologia , Tonsila do Cerebelo/fisiologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Individualidade , Resiliência Psicológica , Sono REM/fisiologia , Estresse Psicológico/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Animais , Modelos Animais de Doenças , Eletroencefalografia , Eletromiografia , Medo/efeitos dos fármacos , Febre/fisiopatologia , Reação de Congelamento Cataléptica/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Muscimol/administração & dosagem , Muscimol/farmacologia , Ratos , Ratos Wistar , Sono REM/efeitos dos fármacosRESUMO
The detailed molecular mechanisms underlying the regulation of sleep duration in mammals are still elusive. To address this challenge, we constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep and awake states. Comprehensive bifurcation analysis predicted that a Ca(2+)-dependent hyperpolarization pathway may play a role in slow-wave sleep and hence in the regulation of sleep duration. To experimentally validate the prediction, we generate and analyze 21 KO mice. Here we found that impaired Ca(2+)-dependent K(+) channels (Kcnn2 and Kcnn3), voltage-gated Ca(2+) channels (Cacna1g and Cacna1h), or Ca(2+)/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca(2+) ATPase (Atp2b3) increases sleep duration. Pharmacological intervention and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Based on these results, we propose a hypothesis that a Ca(2+)-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals.
Assuntos
Sinalização do Cálcio/genética , Cálcio/metabolismo , Sono/genética , Animais , Canais de Cálcio Tipo T/genética , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Simulação por Computador , Maleato de Dizocilpina/farmacologia , Eletroencefalografia , Eletromiografia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais da Membrana/genética , Camundongos , Camundongos Knockout , Fenciclidina/farmacologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Sono REM/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Fatores de TempoRESUMO
Rapid eye movement sleep (REMS) modulates Na-K ATPase activity and maintains brain excitability. REMS deprivation (REMSD)-associated increased Na-K ATPase activity is mediated by noradrenaline (NA) acting on α1-adrenoceptor (AR) in the brain. It was shown that NA-induced increased Na-K ATPase activity was due to allosteric modulation as well as increased turnover of the enzyme. Although the former has been studied in detail, our understanding on the latter was lacking, which we have studied. Male Wistar rats were REMS deprived for 4-days by classical flower-pot method; suitable control experiments were conducted. In another set, α1-AR antagonist prazosin (PRZ) was i.p. injected 48 h REMSD onward. At the end of experiments rats were sacrificed by cervical dislocation and brains were removed. Synaptosomes prepared from the brains were used to estimate Na-K ATPase activity as well as protein expressions of different isoforms of the enzyme subunits using western blot. REMSD significantly increased synaptosomal Na-K ATPase activity and that was due to differential increase in the expressions of α1-, α2- and α3-isoforms, but not that of ß1- and ß2-isoforms. PRZ reduced the REMSD-induced increased Na-K ATPase activity and protein expressions. We also observed that the increased Na-K ATPase subunit expression was not due to enhanced mRNA synthesis, which suggests the possibility of post-transcriptional regulation. Thus, the findings suggest that REMSD-associated increased Na-K ATPase activity is due to elevated level of α-subunit of the enzyme and that is induced by NA acting on α1-AR mediated mRNA-stabilization.
Assuntos
Encéfalo/enzimologia , Norepinefrina/farmacologia , Subunidades Proteicas/biossíntese , Receptores Adrenérgicos alfa 1/biossíntese , Privação do Sono/enzimologia , Sono REM/fisiologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Masculino , Norepinefrina/fisiologia , Ratos , Ratos Wistar , Sono REM/efeitos dos fármacosRESUMO
Nicotine and alcohol co-abuse is highly prevalent, although the underlying causes are unclear. It has been suggested that nicotine enhances pleasurable effects of alcohol while reducing aversive effects. Recently, we reported that nicotine acts via the basal forebrain (BF) to activate nucleus accumbens and increase alcohol consumption. Does nicotine suppress alcohol-induced aversive effects via the BF? We hypothesized that nicotine may act via the BF to suppress sleep-promoting effects of alcohol. To test this hypothesis, adult male Sprague-Dawley rats were implanted with sleep-recording electrodes and bilateral guides targeted toward the BF. Nicotine (75 pmol/500 nL/side) or artificial cerebrospinal fluid (ACSF; 500 nL/side) was microinjected into the BF followed by intragastric alcohol (ACSF + EtOH and NiC + EtOH groups; 3 g/kg) or water (NiC + W and ACSF + W groups; 10 mL/kg) administration. On completion, rats were killed and processed to localize injection sites in the BF. The statistical analysis revealed a significant effect of treatment on sleep-wakefulness. While rats exposed to alcohol (ACSF + EtOH) displayed strong sleep promotion, nicotine pre-treatment in the BF (NiC + EtOH) attenuated alcohol-induced sleep and normalized sleep-wakefulness. These results suggest that nicotine acts via the BF to suppress the aversive, sleep-promoting effects of alcohol, further supporting the role of BF in alcohol-nicotine co-use.
Assuntos
Prosencéfalo Basal , Depressores do Sistema Nervoso Central/antagonistas & inibidores , Depressores do Sistema Nervoso Central/farmacologia , Etanol/antagonistas & inibidores , Etanol/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Sono/efeitos dos fármacos , Animais , Ritmo Delta/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Masculino , Microinjeções , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Sono REM/efeitos dos fármacos , Vigília/efeitos dos fármacosRESUMO
To evaluate the antinociceptive and hypnotic effects of pregabalin, we established a neuropathic pain-like model in mice using partial sciatic nerve ligation (PSNL), and examined thermal hyperalgesia, mechanical allodynia, electroencephalogram, rota-rod testing, and c-Fos expression in the anterior cingulate cortex. Gabapentin was used as a reference drug in the study. Pregabalin administered i.g. at 12.5 and 25mg/kg prolonged the duration of thermal latencies by 1.4- and 1.6-fold and increased the mechanical threshold by 2.2- and 3.1-fold 3h after administration, respectively, but did not affect motor coordination in PSNL mice, compared with vehicle control. Pregabalin (12.5 and 25mg/kg) given at 6:30 increased the amount of non-rapid eye movement sleep in a 4-h period by 1.3- and 1.4-fold, respectively, in PSNL mice. However, pregabalin (25mg/kg) given at 20:30 did not alter the sleep pattern in normal mice. Immunohistochemical study showed that PSNL increased c-Fos expression in the neurons of anterior cingulate cortex by 2.1-fold, which could be reversed by pregabalin. These results indicate that pregabalin is an effective treatment for both neuropathic pain and sleep disturbance in PSNL mice.
Assuntos
Analgésicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Neuralgia/tratamento farmacológico , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Aminas/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ácidos Cicloexanocarboxílicos/farmacologia , Eletroencefalografia/efeitos dos fármacos , Gabapentina , Genes fos/efeitos dos fármacos , Temperatura Alta , Hiperalgesia/tratamento farmacológico , Hiperalgesia/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor/efeitos dos fármacos , Estimulação Física , Equilíbrio Postural/efeitos dos fármacos , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/psicologia , Transtornos do Sono-Vigília/induzido quimicamente , Transtornos do Sono-Vigília/psicologia , Sono REM/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologiaRESUMO
Our recent study indicates that the lesions of the prefrontal cortex in rats result in depressive-like behavior in forced swim test and REM sleep alterations, two well-established biomarkers of depression disorder. We hypothesized that antidepressants may target the PFC to reverse depression. Systemic injections of antidepressants: the tricyclic antidepressant desipramine (DMI), the selective serotonin reuptake inhibitor fluoxetine, and the NMDA-antagonist ketamine selectively increased cFos expression (a marker of neuronal activity) in the deep layers of the ventromedial PFC (vmPFC) in rats. Of the vmPFC's limbic system targets, only the nucleus accumbens (NAc) was also activated by DMI. Using a retrograde tracer and a neuronal toxin, we also found that DMI-activated vmPFC neurons project to the NAc and that NAc activation by DMI was lost following vmPFC lesion. These results suggest that the vmPFC may be an essential target of antidepressant drugs, its projections to the NAc may be a key circuit regulating antidepressant action, and dysfunction of this pathway may contribute to depression.