中枢组胺能神经系统调节睡眠-觉醒机制研究进展

哺乳动物组胺能神经元集中分布于下丘脑后部的结节乳头核(tuberomammillary nucleus,TMN),其神经纤维投射至全脑。研究发现,中枢组胺的释放与觉醒时相呈正相关,觉醒期的释放量是睡眠期的4倍;内源性物质前列腺素E2和神经肽阿立新(orexin)激活TMN组胺能神经元,增加组胺释放,促进觉醒;前列腺素D2和腺苷抑制组胺能神经元活性,诱导睡眠。本文综述组胺能神经系统调节睡眠-觉醒研究进展,讨论拟(抗)组胺类药物用于促觉醒或(和)镇静催眠的可能性。     

Role of spinal 5-HT receptors in cutaneous hypersensitivity induced by REM sleep deprivation

Previous studies indicate that rapid eye movement (REM) sleep deprivation facilitates pain sensitivity. Since serotoninergic raphe neurons are involved both in regulation of sleep and descending pain modulation, we studied whether spinal 5-HT receptors have a role in sleep deprivation-induced facilitation of pain-related behavior. REM sleep deprivation of 48h was induced by the flower pot method in the rat. The pain modulatory influence of various serotoninergic compounds administered intrathecally was assessed by determining limb withdrawal response to monofilaments. REM sleep deprivation produced a marked hypersensitivity. Sleep deprivation-induced hypersensitivity and normal sensitivity in controls were reduced both by a 5-HT(1A) receptor antagonist (WAY-100635) and a 5-HT(2C) receptor antagonist (RS-102221). An antagonist of the 5-HT(3) receptor (LY-278584) failed to modulate hypersensitivity in sleep-deprived or control animals. Paradoxically, sensitivity in sleep-deprived and control animals was reduced not only by a 5-HT(1A) receptor antagonist but also by a 5-HT(1A) receptor agonist (8-OHDPAT). The results indicate that serotoninergic receptors in the spinal cord have a complex role in the control of sleep-deprivation induced cutaneous hypersensitivity as well as baseline sensitivity in control conditions. While endogenous serotonin acting on 5-HT(1A) and 5-HT(2C) receptors may facilitate mechanical sensitivity in animals with a sleep deprivation-induced hypersensitivity as well as in controls, increased activation of spinal 5-HT(1A) receptors by an exogenous agonist leads to suppression of mechanical sensitivity in both conditions. Spinal 5-HT(3) receptors do not contribute to cutaneous hypersensitivity induced by sleep deprivation.     

Protective effect of St. John's wort (Hypericum perforatum) extract on 72-hour sleep deprivation-induced anxiety-like behavior and oxidative damage in mice

Sleep disruption or poor quality of sleep is a common problem associated with depression. Antidepressant drugs have been reported to improve the quality of sleep and behavior. The present study was undertaken to explore the therapeutic potential of Hypericum perforatum (St. John's wort) on behavioral alterations and oxidative damage induced by sleep deprivation in mice. Male laca mice (n = 6 - 10 in each group) were sleep deprived for 72 hours using the grid suspended over water method. Standardized Hypericum perforatum extract and imipramine were administered for five days, starting two days before sleep deprivation. Alterations in body weight, motor activity, anxiety like behavior (mirror chamber, plus maze, zero maze) and oxidative stress parameters (reduced glutathione, catalase, lipid peroxidation and nitrite levels) were observed after drug treatment in sleep-deprived animals. 72-hour sleep deprivation significantly altered body weight, locomotor activity and produced anxiety-like behavior and oxidative damage (depleted reduced glutathione, catalase activity and increased lipid peroxidation and nitrite activity) as compared to the na?ve (placed on sawdust) animals (P < 0.05). Treatment with either St. John's wort (200 and 400 mg/kg, P. O.) or with imipramine (10 mg/kg, I. P.) significantly improved body weight, locomotor activity, antianxiety and antioxidant effect as compared to the control group (sleep deprived) (P < 0.05). Co-administration of John's wort (200 mg/kg, P. O.) with imipramine (10 mg/kg, I. P.) further improved body weight, locomotor activity, antianxiety effect as well as reduced oxidative damage in sleep-deprived animal as compared to their effect per se (P < 0.05). The present study suggests that there is therapeutic potential of St. John's wort in the management of sleep deprivation-induced anxiety-like behavior and oxidative damage.     

Total sleep deprivation decreases immobility in the forced-swim test.

Sleep deprivation can exert antidepressant effects in humans in less than 24 h, making it the fastest acting antidepressant treatment. However, it is rarely used clinically because the effect disappears once the subject goes back to sleep. An understanding of the neurobiological mechanisms underlying the antidepressant effect of sleep deprivation should help to develop new rapidly acting antidepressant strategies. In the present report, an animal model of depression (the forced-swim test) was used to determine whether the effects of total sleep deprivation parallel those obtained with antidepressant drugs. Using the disk-over-water method, rats deprived of sleep for 24 h exhibited increased swimming behavior when compared to cage control rats, mimicking the effects of serotonergic antidepressants. After 48 h, sleep-deprived rats exhibited increased swimming when compared to both cage control and stimulus control rats, demonstrating that the effect is due to sleep deprivation per se, and not to extraneous factors inherent in the sleep deprivation protocol (such as stress and movement). We believe that this paradigm can be used to study the neurobiological mechanisms of rapid antidepressant effects induced by sleep deprivation.     

Histamine content and synthesis in central and pheripheral nerve structures during stress.

Histamine content and histidine decarboxylase activity in cortex and hypothalamus, together with histamine content in peripheral nervous structures were examined in normal and electrically stressed guinea-pigs. A significant increase in histidine decarboxylase activity in hypothalamus and cortex together with concomitant decrease in histamine content in hypothalamus have been found. Electric shock causes also a decrease in histamine content in spinal cord, spinal ganglia, dorsal roots and sensory nerve. The function of histamine in nervous system is discussed.     

The Effects of Drugs Acting at GABA-Benzodiazepine-Barbiturate Receptor Complex on the Behaviour of Sleep-Deprived Mice

Abstract: The effects of the benzodiazepine receptor agonist diazepam, the benzodiazepine receptor antagonist flumazenil and the benzodiazepine receptor inverse agonist ethyl-8-azido-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo-[1, 5-a] [1-4] benzo-diazepine-3-carboxylate (RO 15-4513) on the locomotor activity and the behaviour of animals in the plus-maze test were studied in sleep-deprived mice. The effects of convulsants acting at GABA-benzodiazepine-barbiturate receptor complex-bicuculline, picrotoxin and pentylenetetrazole, were also studied. Sleep deprivation of mice for 24 hr using the platform technique caused behavioural excitation that was reflected by an increase in the locomotor activity. Administration of diazepam (0.5 and 2.0 mg/kg), flumazenil (5.0 and 10.0 mg/kg) and RO 15-4513 (1.0, 2.0 and 3.0 mg/kg) either did not affect (in low doses) or inhibited (in high doses) locomotions of control animals. The inhibition of locomotor activity by these drugs was greater in sleep-deprived animals. In the plus-maze test, diazepam in a dose of 2.5 mg/kg had an anxiolytic effect in control mice that was reflected by an increase in the percentage of entries onto and the percentage of time spent on the open arms of the plus-maze. In contrast, in sleep-deprived animals, diazepam did not induce anxiolytic action at any dose tested. In the highest dose (2.5 mg/kg) diazepam produced a sedative effect that was reflected by a decrease in the total number of entries made onto the open and into the closed arms of the plus-maze. The convulsive actions of bicuculline (2.0–4.0 mg/kg) and picrotoxin (2.5–4.0 mg/kg) were considerably more pronounced in sleep-deprived mice as compared to control animals. The effect of pentylenetetrazole (60–100 mg/kg) was not changed in sleep-deprived mice. These data suggest that sleep deprivation induced a sensitization of mice to the motor depressant effect of benzodiazepine receptor agonists, antagonists and inverse agonists and to the convulsive action of bicuculline and picrotoxin. At the same time sleep deprivation induces a hyposensitivity of mice to the anxiolytic effect of diazepam. It is proposed that the hyposensitivity to the anxiolytic effect of diazepam as well as the hypersensitivity to the convulsions induced by bicuculline and picrotoxin in sleep-deprived mice might be due to the alterations in the function of GABA-benzodiazepine-barbiturate complex induced by sleep deprivation.     

Effects of REMS deprivation on striatal dopamine and acetylcholine in rats.

Changes in the concentration of striatal dopamine (DA) and acetylcholine (ACh) in rats deprived of REM sleep for 10 days were compared with those obtained after a 4 day deprivation procedure. Animals placed on small (7 cm dia.) islands surrounded by water were completely deprived of REM sleep but able to obtain some slow-wave sleep. Concentration of striatal DA was significantly increased after 4 days and 10 days of REM sleep deprivation by 73 and 133%, respectively when compared to controls. Levels of ACh in the striatum were significantly enhanced (by 28%) after 10 day, but failed to show significant change after 4 day REM sleep deprivation procedure. The short term locomotor activity was significantly higher in REM sleep-deprived animals. Our data indicate that REM sleep deprivation results in marked alterations of both cholinergic and dopaminergic mechanisms in the rat striatum.     

REM sleep deprivation decreases apomorphine-induced stimulation of locomotor activity but not stereotyped behavior in mice.

1. Effects of rapid eye movement (REM) sleep deprivation on central dopaminergic system were investigated by testing the behavioral responses to apomorphine and brain dopamine metabolism in mice. 2. REM sleep deprivation for 48 hr significantly suppressed apomorphine.HCl (3.0 and 6.0 mg/kg, i.p.)-stimulated spontaneous locomotor activity without affecting the intensity of stereotyped behavior. 3. Neither the latency of nociceptive response in a hot-plate test nor the duration of pentobarbital-induced sleep was changed by REM sleep deprivation. 4. Dopamine turnover in the striatum and the nucleus accumbens of REM sleep-deprived mice was significantly higher than that of control animals. 5. These results suggest that REM sleep deprivation may decrease the function of postsynaptic dopamine receptor in the mesolimbic but not nigrostriatal dopaminergic system.     

Possible mechanism involved in sleep deprivation-induced memory dysfunction

Sleep deprivation disrupts various vital biological and metabolic processes that are necessary for health. The present study was designed to investigate the possible mechanisms of sleep deprivation-induced memory dysfunction by using different behavioral, biochemical and neurochemical parameters. Male Wistar rats were sleep deprived for 72 h using a grid suspended over water. Elevated plus maze, passive avoidance and Morris water maze tests were used to assess memory retention in 72-h sleep-deprived animals. Various electrophysiological (sleep-wake cycle), biochemical (lipid peroxidation, reduced glutathione, nitrite, catalase, acetylcholinesterase) and neurochemical parameters (norepinephrine, dopamine and serotonin) were also assessed. Sleep deprivation resulted in memory dysfunction in all the behavioral paradigms, alteration in the sleep-wake cycle (delayed sleep latency, shortening of rapid eye movement [REM] and non-REM [NREM] sleep and increased waking period) and oxidative stress (increased lipid peroxidation and nitrite levels, depletion of reduced glutathione and catalase activity). In addition, increased levels of acetylcholinesterase (AChE; the enzyme responsible for the degradation of acetylcholine) and reduction in norepinephrine and dopamine levels were seen in 72-h sleep-deprived animals. In conclusion, sleep deprivation-induced memory deficits may possibly be due to the combined effect of oxidative damage and alterations in neurotransmitter levels.     

Influence of low dietary histamine on seizure development of chemical kindling induced by pentylenetetrazol in rats

Aim: To determine the role of dietary low histamine on the seizure development of pentylenetetrazol (PTZ)-induced kindling in rats. Methods: After 14d of feeding on a low histamine diet (LH, containing 0.145μmol/g of histamine), the rats were chemically kindled by repeated intraperitoneal injection of a subconvulsant dose of PTZ (35mg/kg) once every 48h, and seizure activity of kindling was recorded for 30min. Histamine in brain samples was analyzed using a high performance liquid chromatography system with a fluorescence spectrofluorometer. Results:The LH diet induced an increase in seizure response (seizure susceptibility) to the first trial of PTZ, and resulted in facilitation of subsequent PTZ kindling process (seizure development). The histamine levels in the cortex, hippocampus, and hypothalamus of LH-treated rats decreased significantly and these changes correlated well with seizure behavior (r=0.875,0.651, and 0.796, respectively). In addition, chronic kindled seizures resulted in a significant increase of the histamine content in the cortex and hypothalamus in the LH-fed groups. Conclusion: These findings indicate that the histamine in daily food could influence the brain histaminergic function, and play an important role in regulating seizure susceptibility.     

Orexin‐A and respiration in a rat model of smoke‐induced chronic obstructive pulmonary disease

1. Orexins are neuropeptides synthesized in the hypothalamus that regulate many physiological functions, including energy homeostasis, stress responses, sleep/wake states etc. It is now emerging that orexins may also regulate breathing, but little is known as to how they do this, particularly in chronic obstructive pulmonary disease (COPD). In the present study, we used a rat model of cigarette smoke‐induced COPD to investigate orexin‐A expression in the hypothalamus and medulla and its effect on respiration. 2. Sprague‐Dawley rats were exposed to cigarette smoke (1 h twice daily) for 12 weeks. Lung function and pathological changes associated with inflammation and emphysema were determined to confirm the validity of the COPD model. 3. Hypothalamic and medullary orexin‐A levels, as determined by radioimmunoassay, were higher in smoke‐exposed than control rats. Furthermore, the expression of prepro‐orexin (PPO) mRNA in the hypothalamus and orexin OX₁ receptor mRNA in the medulla, as determined by real‐time quantitative polymerase chain reaction, was higher in smoke‐exposed than control rats. 4. The number of orexin‐A‐positive neurons in the hypothalamus and OX₁ and OX₂ receptor‐positive neurons in the ventrolateral medulla was higher in smoke‐exposed than control rats. 5. Microinjection of orexin‐A (1 μmol/L, 0.1 μL) into the pre‐Bötzinger complex enhanced phrenic nerve discharge to a greater extent in smoke‐exposed compared with control rats (61% vs 36%, respectively). 6. The findings of the present study demonstrate that the increased respiratory activity in smoke‐exposed rats is due to an increase in orexin‐A as well as upregulation of orexin receptors in the ventrolateral medulla.     

Modafinil restores memory performance and neural activity impaired by sleep deprivation in mice

The original aims of our study have been to investigate in sleep-deprived mice, the effects of modafinil administration on spatial working memory, in parallel with the evaluation of neural activity level, as compared to non-sleep-deprived animals. For this purpose, an original sleep deprivation apparatus was developed and validated with continuous electroencephalography recording. Memory performance was evaluated using spontaneous alternation in a T-maze, whereas the neural activity level was estimated by the quantification of the c-Fos protein in various cerebral zones. This study allowed altogether: First, to evidence that a diurnal 10-h sleep deprivation period induced an impairment of spatial working memory. Second, to observe a decrease in c-Fos expression after sleep deprivation followed by a behavioural test, as compared to non-sleep-deprived mice. This impairment in neural activity was evidenced in areas involved in wake-sleep cycle regulation (anterior hypothalamus and supraoptic nucleus), but also in memory (frontal cortex and hippocampus) and emotions (amygdala). Finally, to demonstrate that modafinil 64 mg/kg is able to restore on the one hand memory performance after a 10-h sleep deprivation period, and on the other hand, the neural activity level in the very same brain areas where it was previously impaired by sleep deprivation and cognitive task.     

Influence of sleep deprivation and morphine on the expression of inducible nitric oxide synthase and cyclooxygenase-2 in skin of hairless mice

Skin performs a host of primordial functions that keep the body alive. Morphine is a drug with immunosuppressant properties whose chronic use may lead to increased infection and delayed wound healing. Sleep is a fundamental biological phenomenon that promotes the integrity of several bodily functions. Sleep deprivation adversely affects several systems, particularly the immune system. The aim of this study was to perform an immunohistochemical evaluation on the expression of inducible nitric oxide synthase and cyclooxygenase-2 in skin of sleep-deprived mice and mice chronically treated with morphine. Adult hairless male mice were distributed into the following groups: Control, morphine, sleep-deprived, and morphine + SD. Morphine (10?mg/kg, subcutaneous) was injected every 12?h for 9 days. Morphine induced immunoexpression of cyclooxygenase-2 and nitric oxide synthase. Sleep deprivation did not modulate outcomes induced by morphine. Morphine, not sleep loss, induces cyclooxygenase-2 and nitric oxide synthase immunoexpression in the skin of hairless mice.     

Cocaine effects in sleep-deprived humans

Eight normal healthy volunteers were tested in a reaction-time task and a work-output task after 24 and 48 h of sleep deprivation with and without 96 mg of inhaled cocaine. Cardiovascular changes and verbal report of mood change and drug effect were also monitored. Sleep deprivation produced a decrement in reaction-time performance which was reversed by inhalation of cocaine. Heart rate increased after cocaine both under non sleep-deprived conditions and sleep-deprived conditions. The magnitude of the drug-induced heart rate was, however, lower when subjects were deprived of sleep for 48 h. Verbal reports of cocaine effects were similar to those reported for amphetamine, with no evidence supporting the idea of a postdrug depression immediately after the acute effects of the drug dissipated, although some rebound effects were noted 8 h after drug administration.     

Effect of total parenteral nutrition on histamine in the rat brain and other tissues.

The effects of a constant infusion of total parenteral nutrition on the histamine content of the hypothalamus was studied in adult male rats. Histamine content of the stomach, kidney, liver, and heart was also determined. The relationship between tissue histamine levels and duration of the infusion was examined. Rats receiving intravenous infusions of total parenteral nutrition had significantly higher (p less than 0.001) histamine levels in the hypothalamus than did orally-fed control rats. No difference was observed in the histamine level in the remainder of the brain. Animals receiving parenterally infused nutrient solutions had a higher histamine content in the kidneys but lower histamine levels in the stomach than did the control rats. No changes in the histamine content of liver or heart were observed. It appears that increases in histamine levels in the kidney and hypothalamus of rats given total parenteral nutrition persist up to 5 days and 9 days, respectively. The mechanisms responsible for and the consequences of the alterations of histamine content of these tissues remain to be established.     

Innervation of histamine neurons in the caudal part of the arcuate nucleus of hypothalamus and their activation in response to food deprivation under scheduled feeding

It has been well established that histaminergic neurons innervate densely the anterior hypothalamus and regulate several functions through the histamine H? receptor (H1R). However, the physiological function of the histaminergic neurons in other regions including the posterior hypothalamus has not been fully investigated. Recently, we have found a selective c-Fos expression in the caudal part of the arcuate nucleus of the hypothalamus (cARC) by food deprivation under scheduled feeding in rats. In this study, we histochemically examined the correlation of this c-Fos expression with the activation of histaminergic neurons in this region using an anti-H1R antibody. Strong H1R immunoreactivity was observed in the perikarya of the c-Fos positive cells. Abundant histamine-containing fibers were also found in the cARC and in the area between the cARC and the tuberomammillary nucleus (TM), where the histaminergic neuronal cell bodies are exclusively distributed. Our morphological observations suggest that c-Fos expression in the cARC by food deprivation under scheduled feeding is caused by the activation of histaminergic neurons projected from the TM.     

Mast cell degranulation in hemorrhagic shock in rats and the effects of vasoactive intestinal peptide, aprotinin and H1 and H2-receptor blockers on degranulation.

Various stressful stimuli cause mast cell degranulation. Hemorrhagic shock is one such stressful stimulus which may cause mast cell degranulation and histamine release. Histamine may be involved in the pathophysiology of hemorrhage. It was reported that there are large amounts of histamine in the anterior and posterior lobes of the pituitary and the adjacent median eminence of the hypothalamus. Most of the histamine in the posterior pituitary is in mast cells. In addition, both vasoactive intestinal peptide (VIP) and histamine-containing neurons are available in the hypothalamus. It therefore seems reasonable to suppose that these three systems (i.e., mast cells, VIP-containing neurons, and histamine-containing neurons) may play an important role in the progression of hemorrhagic shock. 66 albino rats (200-250 g) of either sex were used. The presence of mast cells was examined by light microscopy. Hemorrhage caused mast cell degranulation in a correlation with the amount of blood loss. In all cases, the most intense degranulation was observed in the hypothalamus, especially the nucleus arcuatus, and in the subcutaneous tissue. The intensity of degranulation gradually decreased in the peripheral blood vessel, peritoneum and omentum, in this order. VIP prevented degranulation, but aprotinin and H1 and H2 receptor blockers did not.     

Activation of orexin neurons by acute nicotine

The hypothalamus is a prominent central site of action of nicotine but the phenotype of nicotine-sensitive neurons in this region has not been fully described. Hypothalamic orexin neurons are important regulators of state-dependent behavior, arousal and feeding. Here, we treated rats with acute nicotine and quantitated Fos expression as a marker of neuronal activation. Nicotine increased the percentage of orexin neurons expressing Fos without a significant effect on non-orexin neurons. This effect was attenuated by the nicotinic antagonists mecamylamine and dihydro-beta-erythroidine, implicating alpha4beta2-containing nicotinic receptors. The orexin system is likely to play an important role in the coordination of physiological and behavioral responses to acute nicotine treatment.     

Differential effects of total sleep deprivation on contextual and spatial memory: modulatory effects of modafinil

The aim of the present work was to investigate in mice the effects of a total 10-hr sleep deprivation on contextual (episodic-like) and spatial (reference) memory tasks. For that purpose, mice learned two consecutive discriminations (D1 and D2) in a 4-hole board involving either identical (Serial Spatial Discrimination, SSD) or distinct (Contextual Serial Discrimination, CSD) internal contextual cues. In a second step, we intended to assess the corrective effect of modafinil on memory impairments generated by sleep deprivation. Sleep deprivation was triggered through an alternative platform apparatus (water box), previously validated using EEG recording and spectral analysis.We showed that a 10-hr total sleep deprivation impaired the CSD task but not the SSD one. Moreover, the impairment of contextual memory in sleep-deprived animals was dose-dependently corrected by modafinil. Indeed, modafinil administered after the sleep deprivation period and 30 min before the test session restored a memory retrieval pattern identical to non sleep-deprived animals at the doses of 32 and 64 mg/kg, however not at 16 mg/kg.Results hereby evidence that the vigilance-enhancing drug modafinil is able to restore the contextual memory performance at a low dose as compared to other memory tasks, possibly by an enhancement of hippocampal activity known to be both involved in the processing of contextual information and impaired following our sleep deprivation procedure.     

The effect of clomipramine on wake/sleep and orexinergic expression in rats

We have previously found that neonatal treatment with clomipramine (CLI) induced a decrease in brain orexins during the juvenile period and that these changes were reversed at adulthood. This study investigated the effect of CLI on the orexinergic component and sleep/wake states. Two groups of adult male rats were conducted for 48-h polysomnographic recording. One group of rats was treated with CLI (20 mg/kg every 12 h), and a second group was treated with equivolume of saline (SAL) simultaneously after the first 24 h of polysomnographic recording. Rats were killed 2 h after the third dose of treatment. Brain tissues were collected for radioimmunoassay quantification of orexins and real-time PCR analysis of prepro-orexin and orexin receptor mRNA. The CLI group had significantly shorter rapid eye movement (REM) sleep and longer REM latency compared with both the baseline day and the SAL group and had significantly less active wake and more quiet wake. Compared with the control rats, the CLI rats had significantly higher mRNA expression of prepro-orexin in the hypothalamus and the frontal cortex, but not in the hippocampus. The CLI rats also had significantly less orexin B in the hypothalamus than the control rats. These results suggest that suppression of active wake and orexin B by CLI may be a factor responsible for CLI-induced depression and that the increase of prepro-orexin mRNA may be a sign of increased brain orexins found in this model.