Narcolepsy in animals and man.
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Animals↗
Biomedical subjects
W C Dement
Publications and source records attributed to W C Dement.
Serotonin and the mammalian circadian system: II. Phase-shifting rat behavioral rhythms with serotonergic agonists.
The suprachiasmatic nuclei (SCN) receive primary afferents from the median and dorsal raphe, but the role of these projections in circadian timekeeping is poorly understood. Studies of the SCN in vitro suggest that quipazine, a general serotonin (5-HT) receptor agonist, can produce circadian time-dependent phase advances and phase delays in circadian rhythms of neuronal activity. The present study addresses whether quipazine and the selective 5-HT1A receptor agonist 8-OH-DPAT are similarly effective in vivo. Drinking and wheel-running patterns of male Wistar rats individually housed in constant darkness were monitored before and after subcutaneous administration of quipazine (5-10 mg/kg) at either circadian time (CT) 6 or CT 18, with and without running wheels available. Dose-dependent phase advances (20-180 min) were produced at CT 6. Significant phase shifts were not observed at CT 18. CT 6 quipazine-treated animals also showed a sustained and significant shortening of rhythm period (tau) following treatment (-0.28 hr; p < 0.002). tau shortening was inconsistently observed in CT 18 quipazine-treated rats. Neither quipazine-induced phase shifts nor tau effects were dependent on wheel-running activity per se. 8-OH-DPAT delivered via intracerebral ventricular treatment into the third ventricle (5 microliters at 100 microM in saline) produced slightly smaller phase advances (20-90 min) at CT 6, but did not produce phase delays at CT 18 or changes in tau. These findings support in vitro evidence that 5-HT-ergic agonists can phase-shift the circadian pacemaker.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Heterozygosity at the canarc-1 locus can confer susceptibility for narcolepsy: induction of cataplexy in heterozygous asymptomatic dogs after administration of a combination of drugs acting on monoaminergic and cholinergic systems.
Narcolepsy is a genetically determined disorder of sleep characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep that affects both humans and animals. Although its exact pathophysiologic mechanisms remain undetermined, recent experiments have demonstrated that in both humans and canines, susceptibility genes are linked with immune-related genes. A striking difference, however, is that the genes thought to be involved in the human pathology are autosomal dominant, whereas canine narcolepsy in Dobermans is transmitted as a single autosomal recessive gene with full penetrance (canarc-1). In this study, we have examined the development of narcoleptic symptoms in homozygous narcoleptic, heterozygous, and control Dobermans. Animals were behaviorally observed until 5 months of age and then treated at weekly intervals with cataplexy-inducing compounds that act on cholinergic or monoaminergic systems (alone and in combination). Our data indicate that cataplexy can be induced in 6-month-old asymptomatic heterozygous animals, but not in control canines, with a combination of drugs that act on the monoaminergic and cholinergic systems. This demonstrates that disease susceptibility may be carried by heterozygosity at the canarc-1 locus. Our data further suggest that cataplexy, a model of REM sleep atonia, is centrally regulated by a balance of activity between cholinergic and monoaminergic neurons.
Aging↗
Further characterization of the alpha-1 receptor subtype involved in the control of cataplexy in canine narcolepsy.
We have demonstrated previously that central noradrenergic mechanisms, especially postsynaptic alpha-1 receptors, are critically involved in the regulation of cataplexy, a pathological manifestation of rapid eye movement sleep atonia in narcolepsy. However, it has been shown recently that alpha-1 receptors constitute a heterogeneous population of binding sites, which is encoded by several distinct genes. In light of these findings, we investigated the possibility that the effect of alpha-1 compounds on cataplexy found in our previous study is mediated more specifically by certain alpha-1 receptor subtypes than by other subtypes. We therefore examined the effects of eight selective alpha-1 antagonists and five agonists on canine cataplexy and compared these with the affinities of the same compounds for the canine central alpha-1a and alpha-1b subtypes. The affinities of the compounds for the alpha-1 receptor subtypes were assessed by using [3H]prazosin receptor binding in combination with a 5-methylurapidil (an alpha-1a selective ligand) mask. Six of the eight alpha-1 antagonists tested exacerbated canine cataplexy, whereas all five agonists tested suppressed cataplexy. Furthermore, the potency (ED50 values) of the compounds on cataplexy significantly correlated with the affinity of the compounds for the alpha-1b binding site. These results are consistent with our earlier implication of the alpha-1 receptor mechanisms in the control of cataplexy and further suggest a specific involvement of the alpha-1b receptor subtype in these mechanisms.
Adrenergic alpha-Agonists↗
Sleep apnea and hypertension in commercial truck drivers.
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Adult↗
Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation.
Sleep and wakefulness are governed by both the suprachiasmatic nuclei of the hypothalamus (SCN), and a sleep homeostatic process; however, the interaction of these control systems is not well understood. From rodent studies it has been assumed that the SCN promote neither wake nor sleep but gate the homeostatic sleep-promoting process. Yet in humans sleep tendency is lowest during the later waking hours of the day, and sleep duration can be predicted because of the precise circadian timing of waking. Thus in primates, the SCN could assure sleep-wake cycle consolidation by actively promoting or facilitating wakefulness. To evaluate this hypothesis, we examined the sleep-wake and sleep-stage patterns of intact and SCN-lesioned (SCNx) squirrel monkeys maintained in constant light. This diurnal primate has consolidated sleep and wake patterns more similar to man than rodents. Sleep-wake, sleep stages, brain temperature, and drinking circadian rhythms were eliminated, and total sleep time was significantly increased (4.0 hr, P < 0.01) in SCNx monkeys. However, total times in deeper stages of non-rapid eye movement (non-REM; e.g., delta sleep) and REM sleep were not significantly affected by SCN lesions. Increased total sleep time was associated with a reduction in subjective day wake consolidation, as evidenced by substantially shorter wake bout lengths in SCNx monkeys (15 +/- 6 min) as compared to intact monkeys (223 +/- 10 min; P < 0.0001, ANOVA). These findings show that the SCN influence the regulation of daily total wake and sleep times, and implicate an alternative sleep-wake regulatory model in which an SCN-dependent process actively facilitates the initiation and maintenance of wakefulness and opposes homeostatic sleep tendency during the subjective day in diurnal primates.
Analysis of Variance↗
Sleep homeostasis in suprachiasmatic nuclei-lesioned rats: effects of sleep deprivation and triazolam administration.
The electroencephalogram (EEG) and electromyogram of rats with lesions in the suprachiasmatic nuclei (SCNx) were recorded during two series of 24-h baseline, 6-h sleep deprivation (SD), and 24-h recovery. At recovery onset, rats were injected i.p. with vehicle (VEH) control solution or 0.4 mg/kg triazolam (TRZ) in a balanced crossover design. Consecutive 10-s epochs were scored for vigilance states and EEG power spectra were computed. Arousal states were uniformly distributed during 24-h baseline (wake 47% of recording time, non-rapid-eye movement sleep (nonREMS) 47%, REMS 7%), and EEG spectra (0-25 Hz) were devoid of significant trends. State-specific EEG power spectra profiles in SCNx rats were similar to those of intact animals reported previously. However, EEG delta power (0.5-3.5 Hz) of nonREMS was markedly lower in SCNx rats. Recovery from 6-h SD was characterised by a short-lasting reduction of REMS, and a long-lasting increase of nonREMS time at the cost of wakefulness. EEG delta power rebounded during the first 8 h in recovery, and fell below baseline level after 12 h in recovery. During 0-2 h TRZ recovery, rats spent more time in nonREMS with higher EEG slow wave activity as compared to the corresponding VEH recovery period. EEG slow wave activity fell below baseline levels 10 h after TRZ injection and termination of SD. We conclude that major features of homeostatic sleep EEG regulation are present in SCNx rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Monoaminergic uptake in synaptosomes prepared from frozen brain tissue samples of normal and narcoleptic canines.
Canine narcolepsy, a model of the human disorder, is associated with altered catecholamine but not serotonin (5-HT) metabolism in some brain areas, particularly the amygdala. A possible explanation for these global changes could be the existence of specific defects in monoamine uptake processes. We have studied the uptake of [3H]norepinephrine (NE), [3H]dopamine (DA) and [3H]5-HT in synaptosomes prepared from cortex and amygdala of narcoleptic and control Doberman pinscher brains. Since narcoleptic canines are relatively few in number, we have used a specific brain freezing procedure that has been reported to allow restoration of metabolically functional tissue upon thawing. Preliminary studies comparing monoamine uptake in fresh and frozen brain samples of both groups of dogs were carried out and demonstrated that this procedure significantly altered serotoninergic but not noradrenergic and dopaminergic uptake. All further investigations were then done on synaptosomes prepared from frozen samples. Our results demonstrate that synaptosomal uptake of [3H]NE, [3H]DA and [3H]5-HT in cortex and amygdala are not altered in narcolepsy.
Amygdala↗
DQ (rather than DR) gene marks susceptibility to narcolepsy.
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Black People↗
Melatonin influences Fos expression in the rat suprachiasmatic.
Administration of the pineal hormone melatonin to rats induces expression of Fos, the protein product of the c-fos proto-oncogene, in the suprachiasmatic nucleus (SCN), the putative biological clock of mammals. Expression of the Fos protein is dependent on circadian phase: injections in the late subjective night (circadian time (CT) 22) induce Fos expression in cells within the ventral SCN whereas injections during the subjective day are ineffective. Since melatonin injections in the late subjective day have previously been shown to phase advance circadian rhythms, these results indicate that phase-advances of the circadian system can occur without increased expression of Fos protein in the SCN, at least at levels detectable by immunohistochemistry. In support of in situ hybridization histochemical evidence obtained previously, immunocytochemical data from vehicle-injected control rats suggest that the Fos protein undergoes an endogenous fluctuation with peak levels in the SCN occurring during the subjective night. These observations indicate that melatonin can affect immediate early gene expression within the SCN.
Animals↗
Multiple sleep latency tests during the constant routine.
The "post-lunch dip" is a common behavioral phenomenon, though perhaps a misnomer. Biphasic models of the human sleep tendency rhythm suggest an alternative explanation for the afternoon decline in alertness. Sleep tendency was measured with the Multiple Sleep Latency Test (MSLT) at 2-hour intervals in 16 volunteers from three age groups (ages 10-12, ages 16-17, ages 62-74 years) during a constant routine in which small meals were given each hour. Baseline scores showed no significant Time of Day effect, although a trend for an afternoon dip was present in the eldest group. During the constant routine, a significant Time of Day effect was found for the two older groups and not for the prepubertal group. The results indicate a midday increase in sleep tendency that is unrelated to food intake but that may be related to developmental or maturational processes.
Adolescent↗
DQB1-0602 (DQw1) is not present in most nonDR2 Caucasian narcoleptics.
Human narcolepsy is a genetically determined disorder of sleep strongly associated with the human leucocyte antigens (HLA) DR2 and DQw1. In black narcoleptic patients, susceptibility for narcolepsy is more closely related to a specific gene subtype of DQw1, DQB1-0602, than to DR2. About 30% of black narcoleptic patients are nonDR2, but all carry the HLA DQB1-0602 gene. In the present study, we have tested caucasian nonDR2 cataplectic patients (6 sporadic cases and 7 familial cases from 3 multiplex families) for the presence of the HLA DQB1-0602 and DQA1-0102 (DQw1) using a specific polymerase chain reaction (PCR)-oligotyping technique. None of the patients was DQB1-0602 or DQA1-0102 positive, thus proving that, in caucasians, DQB1-0602 and DQA1-0102 (DQw1) are not prerequisites for the diagnosis of narcolepsy. Further studies with more patients are warranted to exclude the possibility that a few caucasian patients carry rare haplotypes with DQB1-0602 independently of DR2.
Amino Acid Sequence↗
Serum prolactin response to a D2 antagonist in narcoleptic and control canines.
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Animals↗
The proper use of sleeping pills in the primary care setting.
Insomnia is a highly prevalent problem occurring in about 35% of the adult population. The complaint can be divided into temporary insomnia and persistent insomnia. A 1983 NIMH/OMAR Consensus Development Conference on drugs and insomnia issued guidelines for the use of sleep-promoting medications. There was a consensus that hypnotic medication is indicated for the treatment of temporary insomnia. Temporary insomnia, in response to external circumstances, is real and can have very serious consequences. This paper reviews the proper use of sleeping pills in the primary care setting in the context of current controversy involving benzodiazepines in general and benzodiazepine hypnotics in particular. It is concluded if the physician feels a patient's temporary insomnia warrants symptomatic relief with medication, it is appropriate to prescribe use of the lowest effective dose of a benzodiazepine hypnotic for several nights. Depending on the circumstances, the physician can specify either a short-acting or a long-acting hypnotic. The patient should be firmly instructed to call the clinic or office the next day to report results.
Drug Prescriptions↗
Activity of medial mesopontine units during cataplexy and sleep-waking states in the narcoleptic dog.
Narcolepsy has been hypothesized to be a disease of rapid eye movement (REM) sleep. According to this hypothesis, cataplexy is a result of the triggering during waking of the mechanism that normally serves to suppress muscle tone in REM sleep. REM sleep control mechanisms have been localized to the pons. Narcoleptic dogs have increased numbers of cholinergic receptors in the medial pons. These findings suggest that neurons mediating the triggering of cataplexy might be located in medial pontine regions. In the present study, this hypothesis has been investigated by recording the discharge of units in the medial mesopontine region of the narcoleptic dog. Unit activity was examined in the nucleus reticularis pontis oralis, caudalis, and central gray, with each cell being recorded during both cataplexy and sleep states. Maximal discharge rates were observed, in all of these regions, during active waking states (mean rate, 45.3/sec) and REM sleep (16.0/sec), with minimal discharge rates in non-REM sleep (8.3/sec). Unit discharge was reduced in cataplexy relative to precataplexy periods. Cataplexy discharge rates were 8.3/sec, 52% of the mean REM sleep rate. Cataplexy discharge rates were also significantly lower than those at REM sleep onset. Cataplexy discharge rates were comparable to rates in quiet waking and non-REM sleep. While medial mesopontine neurons discharge at high rates in REM sleep, they have little or no activity in cataplexy. We interpret the lack of activation of medial mesopontine units in cataplexy as indicating that the characteristic phasic motor activation of REM sleep does not occur in this state.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of SDZ NVI-085, a putative subtype-selective alpha 1-agonist, on canine cataplexy, a disorder of rapid eye movement sleep.
Canine narcolepsy is an animal model of the human rapid eye movement sleep disorder. Dogs exhibit bouts of sleep attacks and muscle atonia (cataplexy) that are induced by emotions and thought to be abnormal rapid eye movement sleep episodes. We have previously demonstrated that cataplexy is strongly inhibited by increases in noradrenergic activity. This effect is mediated through central alpha 1-adrenoceptors, presumably of the alpha 1B subtype. In this study, we demonstrate with the canine model that SDZ NVI-085, a new compound with alerting effects, is a potent anticataplectic agent that may act through stimulation of an alpha 1-adrenoceptor subtype.
Adrenergic alpha-Agonists↗
Regional changes in central monoamine and metabolite levels during the hibernation cycle in the golden-mantled ground squirrel.
We assayed various brain regions for levels of monoamines and their metabolites throughout the hibernation cycle of the golden-mantled ground squirrel Spermophilus lateralis. The tissue concentrations of serotonin, dopamine, norepinephrine and their metabolites were determined in the parietal cortex, striatum, midbrain, hippocampus, hypothalamus, and pons. Telencephalic regions exhibited the most significant variations in biogenic amine content. Cortical serotonin (5-HT) levels increased significantly at entrance (P less than 0.0001) relative to other periods of the hibernation cycle, suggesting a role for 5-HT in the initiation of hibernation. Among striatal dopamine (DA) metabolites, 3-methoxytyramine was detectable only during euthermia and arousal; from entrance through arousal, homovanillic acid (HVA) levels were half that found during euthermia (P = 0.0001); and dihydroxyphenylacetic acid (DOPAC) levels increased during day 1 of hibernation (P less than 0.0005). Midbrain DA (P = 0.0295) and hippocampal HVA (P = 0.0194) levels also changed significantly across the hibernation bout. The absence of a consistent change in any monoamine or metabolite throughout the brain precludes the possibility of preferential temperature-dependent impairment of an enzyme involved in biogenic amine synthesis or degradation and suggests that the levels observed reflect changes in neural activity specific to each brain region. Together with previous studies of brain 2-deoxyglucose uptake throughout the hibernation cycle, these data indicate that a transient change in afferent monoaminergic metabolism and neurotransmission in the forebrain is a necessary component for the entrance to hibernation.
Action Potentials↗
Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla.
Narcolepsy is a neurological disorder characterized by sleepiness and episodes of cataplexy. Cataplexy is an abrupt loss of muscle tone, most often triggered by sudden, strong emotions. A subset of cells in the medial medulla of the narcoleptic dog discharged at high rates only in cataplexy and rapid eye movement (REM) sleep. These cells were noncholinergic and were localized to ventromedial and caudal portions of the nucleus magnocellularis. The localization and discharge pattern of these cells indicate that cataplexy results from a triggering in waking of the neurons responsible for the suppression of muscle tone in REM sleep. However, most medullary cells were inactive during cataplexy but were active during REM sleep. These data demonstrate that cataplexy is a distinct behavioral state, differing from other sleep and waking states in its pattern of brainstem neuronal activity.
Animals↗