William Charles Dement is the Lowell W. and Josephine Q. Berry Professor of Psychiatry and Behavioral Sciences at the Stanford University School of Medicine, and the Division Chief of the Stanford University Division of Sleep.
A native of the state of Washington, Dement received his M.D. from the University of Chicago in 1955 and his Ph.D. in Neurophysiology from the same institution in 1957. While a medical student, he began his career in sleep research when he joined the lab of Dr. Nathaniel Kleitman. There, he helped discover and describe Rapid Eye Movement (REM) sleep. From 1954 through 1957, Dement described the relationship between REM sleep and dreaming, established the all night sleep patterns in human beings, discovered REM sleep in animals and newborn babies, and demonstrated that the patterns of specific rapid eye movements are related to the visual experience of the dream.
In 1963, Dement joined the Psychiatry Department at Stanford University, where for the past thirty-five years he has continued his studies on the neurochemistry of sleep and the functional significance of the different sleep states. In 1964, Dement initiated a special narcolepsy clinic through which he demonstrated that the syndrome of narcolepsy involves disordered REM sleep processes. In 1970, Dement started the world's first Sleep Disorders Clinic which introduced all-night polysomnographic examination of patients with sleep-related complaints, medical responsibility and management of the patient, and objective assessment of the relationship between nighttime sleep and daytime function. For the latter, Dement developed the Multiple Sleep Latency Test which remains the standard diagnostic measure of daytime sleepiness. Dement and his colleagues were the first to understand the clinical implications and high prevalence of sleep apnea syndromes, periodic leg movement, narcolepsy, delayed sleep phase syndrome, psychophysiological insomnia, drug dependency insomnia, and a host of other disorders.
In 1973, Dement discovered narcolepsy in dogs and developed the world's only research colony of animals with this disease this colony represents one of a handful of animal models of a neurological disease in the world. Dement's basic research team has discovered and described neurochemical abnormalities associated with narcolepsy in dogs. Currently, the research is focusing on the biological clock -- the overseer of all the body's many rhythmic processes which is located in a single brain structure (the suprachiasmatic nucleus (SCN)) and can be kept alive in a dish, or transplanted from animal to animal. Dement's human research program elucidated sleep apnea and developed new and effective treatment strategies. Dement has conducted numerous studies on insomnia, circadian rhythms, sudden infant death syndrome (SIDS), jet lag, sleep loss, and sleep hygiene. Finally, Dement has helped develop a thorough understanding of the determinants of daytime sleepiness including the demonstration that partial sleep loss is cumulative, that the circadian curve of sleepiness is biphasic, and that sleep needs must be defined in terms of daytime alertness.
Dr. Dement was co-founder of the Sleep Research Society in 1961 and founding President of the American Sleep Disorders Association (ASDA) in 1975, a position he served for 12 years. During his Presidency, the ASDA grew from five sleep disorders centers with about twenty individual members to about 140 accredited centers with over 2,000 members.
Dement is the author or co-author of approximately 500 scientific publications, including the popular overview of sleep, Some Must Watch While Some Must Sleep, the authoritative textbook for medical professionals, Principles and Practices of Sleep Medicine, and the Portable Stanford The Sleepwatchers.
The purpose of this study is to determine the effectiveness of nasal continuous positive airway pressure (CPAP) therapy for the treatment of obstructive sleep apnea syndrome (OSAS).
Stanford is currently not accepting patients for this trial. For more information, please contact Eileen Leary, (650) 724 - 9639.
View details for DOI 10.5665/SLEEP.1296
View details for Web of Science ID 000295624800021
View details for PubMedID 22049553
Modafinil reduces the excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. In rats, modafinil promotes dose-dependent increases in wake duration. The wake-promoting activity of the R-enantiomer of modafinil (armodafinil) was evaluated in WKY rats and compared to the classical stimulant, D-methamphetamine. Electroencephalographic and electromyographic signals were assessed via a tethered cranial implant. Body temperature and locomotor activity were assessed by telemetry via intraperitoneal implant. Rats (n=60, 12 per group) were subjected to one of five parallel treatments: armodafinil at 30, 100 and 300 mg/kg i.p.; D-methamphetamine, 1 mg/kg i.p. and vehicle. Armodafinil and D-methamphetamine increased time spent awake relative to vehicle. Armodafinil-evoked increases in wake duration were dose-dependent and proportional to plasma compound exposure. Induction of wakefulness by D-methamphetamine was associated with an approximately two-fold increase in locomotor activity during the 2-h period immediately following administration relative to vehicle. D-methamphetamine also increased body temperature over the same time interval. The dose of armodafinil (100 mg/kg, i.p.) that was closest to D-methamphetamine in its wake-promoting efficacy did not produce changes in either body temperature or the intensity of locomotor activity relative to vehicle. Acute rebound hypersomnolence, characterized by increases in non-rapid eye movement sleep (NREMS) as a percentage of time and NREMS bout duration and by a decreased frequency of brief awakenings following sleep deprivation, occurred following D-methamphetamine-but not armodafinil-induced wake in this rat model which has been shown to be predictive of human drug responses.
View details for DOI 10.1016/j.pbb.2006.09.018
View details for Web of Science ID 000244122500002
View details for PubMedID 17134745
Sleeping and dreaming always have been a fundamental part of human existence. Most early writing on these subjects was almost entirely speculation. During the twentieth century, however, scientific observation and experimentation abounded. This article emphasizes the evolution of the key concepts and research findings that characterize sleep research and sleep medicine, crucial discoveries and developments in the formative years of the field, and those principles and practices that have stood the test of time.
View details for DOI 10.1016/j.ncl.2005.07.001
View details for Web of Science ID 000233258100002
View details for PubMedID 16243610
Nearly all people, whether they consider themselves sleep deprived or not, can initially obtain extra sleep. However, as accumulating extra sleep reduces carryover sleep debt, a point is reached where it is no longer possible to obtain extra sleep. If there were a practical method to make a precise measurement of a person's daily sleep requirement, it may be possible to show that most individuals are carrying a very large sleep debt. Several observations and studies demonstrate that almost everyone is sleep deprived and carries some amount of sleep debt. How long such an indebtedness will persist without change if no extra sleep is obtained is not known.
View details for DOI 10.1016/j.csm.2004.12.014
View details for Web of Science ID 000229645900005
View details for PubMedID 15892922
To measure the effects of prolonged sleep extension on daytime alertness, vigilance, and mood in healthy young adults. Little research has documented the effects of increased sleep on daytime function despite a high prevalence of daytime fatigue and sleepiness in the adult population. Past extension studies report conflicting results with regard to Multiple Sleep Latency Test (MSLT) scores, vigilance, and mood ratings. No study has challenged subjects to maximum sleep extension, defined by an MSLT score of 20.Fifteen healthy college students reporting minimal daytime sleepiness were allowed to sleep as much as possible during a sleep extension period. MSLT scores, psychomotor vigilance task (PVT) reaction times, and profile of mood states (POMS) ratings were measured at baseline, mid-extension, and end-extension.There was a significant increase in both journal and actigraphy sleep totals during all extension segments (P<0.01). MSLT scores increased significantly from baseline to both mid- and end-extension (P<0.01). Five of eight tabulated PVT measures also improved significantly at mid- and end-extension with respect to baseline (P<0.05). POMS vigor and fatigue scores showed a similar improvement (P<0.01). Seven subjects achieved an MSLT score of 20. Six subjects showed substantial improvements while two subjects obtained relatively little extra sleep and showed little or no MSLT improvement. The maximum extension group displayed exceptional improvements in vigilance and POMS ratings.Extended sleep leads to substantial improvements in daytime alertness, reaction time, and mood.
View details for DOI 10.1016/j.sleep.2004.05.003
View details for Web of Science ID 000224018100004
View details for PubMedID 15341888
View details for Web of Science ID 000224065400005
View details for PubMedID 15493538
There are relatively few studies on the prevalence of restless legs syndrome (RLS) in the general population, even fewer that used diagnostic questions covering all 4 essential diagnostic criteria defining the RLS symptom complex, and none that have reported on the 2 RLS phenotypes for patients seen by family physicians.To determine the prevalence of the symptom complex, diagnostic for RLS in a primary care patient population, a prospective population-based single-center study was performed. Every adult patient presenting for care in a small rural primary care practice with mostly white patients was surveyed for a 1-year period using a validated RLS diagnostic questionnaire.A total of 2099 patients completed the questionnaire. Analysis revealed that 24.0% of these patients were positive for all 4 of the essential symptoms used to make the diagnosis of RLS and 15.3% reported these symptoms at least weekly. In addition, the RLS symptom complex was reported significantly more often by women than men and, as a whole, patients reporting the RLS symptoms were significantly older than patients without symptoms. The prevalence of symptoms increased with age until about 60 years and then showed a steady decrease thereafter. Further, early-onset RLS was significantly more common in women than men.A high prevalence of RLS symptoms was observed in this primary care population. This finding supports the need for heightened awareness in both the medical community and general population regarding this disorder, which can often be effectively treated within the primary care practice.
View details for Web of Science ID 000186207400009
View details for PubMedID 14581252
A 3.5-hour workshop was developed to teach family medicine medical students about sleep disorders.This family medicine clerkship requirement engages students in role-plays and provides them with didactic information about common sleep problems.Fifty-one students completed questionnaires assessing their knowledge prior to the workshop, 2 weeks and 6 months after the workshop, and their clinical behavior after the workshop.A role-play-based workshop is an effective, fun way to improve students' sleep knowledge and skills. Students retain that information over a 6-month period and are able to apply it during their clinical clerkships.
View details for Web of Science ID 000185309100009
View details for PubMedID 12947515
View details for Web of Science ID 000183452600015
View details for PubMedID 12841377
A time-tested protocol for intrathoracic pressure monitoring during sleep is described. This method of esophageal manometry uses a fluid-filled catheter to measure variations in transmitted intrathoracic pressure with respiration. Esophageal manometry is an invaluable tool for the sleep specialist in the diagnosis of sleep-related breathing disorders, especially for detecting cases of upper airway resistance syndrome and for distinguishing subtle central apneas from obstructive events. The methods for scoring esophageal pressure, the indications and contraindications for esophageal manometry, the use of esophageal manometry as the 'gold standard' for the measurement of respiratory effort, and directions for future research are also discussed.
View details for Web of Science ID 000208301700014
View details for PubMedID 14592238
Comparison of polysomnography (PSG)-derived sleep parameters (total sleep time, sleep efficiency, and number of awakenings) to those derived from actigraphy and subjective questionnaires.Actigraphy is commonly used to assist sleep specialists in the diagnosis of various sleep and circadian-rhythm disorders. However, few validation studies incorporate large sample sizes, typical sleep clinic patients, or comparisons with subjective reports of sleep parameters.Clinical series with 100 consecutive sleep-disordered patients (69 men, 31 women, mean age of 49+/-14.7 years) at a tertiary sleep disorders center. Sensitivity, specificity, and accuracy measures were obtained from epoch-by-epoch comparison of PSG and actigraphic data. Subjective sleep parameter data were derived from questionnaires given to subjects in the morning following their recording night.We found that total sleep time and sleep efficiency did not significantly differ between PSG data and the combined data obtained from actigraphy and subjective reports. Using a high-threshold (low-wake-sensitivity) actigraphic algorithm, the number of awakenings was not significantly different from those detected by PSG.We recommend the use of subjective data as an adjunct to actigraphic data in estimating total sleep time and sleep efficiency in sleep-disordered patients, especially those with disorders of excessive somnolence.
View details for PubMedID 14592388
The objective of this study was to assess whether cervical positioning could improve mild to moderate cases of the obstructive sleep apnea syndrome (OSAS). Eighteen subjects recruited from a tertiary sleep disorders clinic population with mild to moderate cases of OSAS were evaluated using a custom-fitted cervical pillow designed to increase upper airway caliber by promoting head extension. The subjects used their usual pillows during two consecutive recorded baseline nights in our laboratory. They then used the cervical pillow for 5 days at home and returned for 2 consecutive recorded nights at our laboratory to use the cervical pillow. During the nights in our laboratory, the subjects completed questionnaires, were videotaped to record head and body position, and had full polysomnography. The subjects had a significant trend toward improvement in their respiratory disturbance indices with use of the cervical pillow, despite spending more time in the supine position and having similar amounts of REM sleep in the baseline and experimental conditions. They also had nonsignificant trends toward improvements in their sleep efficiency and subjective depth of their sleep as well as significantly fewer arousals and awakenings in the experimental compared with the baseline condition. We propose that cervical positioning (i.e., head extension) with a custom-fitted cervical pillow provides a simple, noninvasive, and comfortable means of reducing sleep-disordered breathing in patients with mild to moderate OSAS.
View details for PubMedID 11868144
The prevalence of sleep disorders in a primary care physician practice in Moscow, Idaho, was studied between February 7, 1997, and February 6, 1998. This primary care clinic visit population was surveyed for this 1-year period. Every patient above the age of 18 years who visited the Moscow Clinic in this time period was either approached by our on-site researcher during the patient's clinic visit or contacted via mail. Out of a total of 1249 adult patients who met with our on-site researcher during their clinic visit, 962 (77.0%) completed questionnaires and were interviewed for symptoms of sleep disorders. An additional 292 patients completed mailed questionnaires, resulting in a total of 1254 participants in the study. The percentages of patients in our sample reporting symptoms of the following sleep disorders were insomnia (32.3%), obstructive sleep apnea syndrome (23.6%), and restless legs syndrome (29.3%). This study demonstrates the need for heightened awareness and subsequent diagnosis and treatment of sleep disorders in the primary care population.
View details for PubMedID 11894194
View details for DOI 10.1007/s11325-000-0001-5
View details for PubMedID 11894193
We examined the effects of cervical position on the Obstructive Sleep Apnea Syndrome (OSAS) through the use of a custom-designed cervical pillow which promoted neck extension. Twelve subjects with OSAS were recruited from a tertiary sleep disorder clinic population. Of the twelve subjects, three had mild cases of OSAS, four had moderate cases, and the remaining five had severe cases. The subjects used their usual pillows during two consecutive recorded baseline nights in our laboratory. The subjects then used the cervical pillow for five days at home, and returned for two consecutive recorded nights at our laboratory while using the cervical pillow. During the nights in our laboratory, the subjects completed questionnaires, were videotaped to record head and body position, and had their breathing parameters recorded during sleep. Subjects with mild OSAS cases had a non-significant improvement in the severity of their snoring and a significant improvement in their respiratory disturbance index with the cervical pillow, while subjects with moderate OSAS cases showed no improvement in these parameters. Subjects with severe OSAS cases showed slight improvement in some measures of their abnormal respiratory events during the experimental period.
View details for PubMedID 11382876
View details for Web of Science ID 000076428000002
View details for PubMedID 10193352
Individual effects of corticotropin-releasing hormone (CRH) and glucocorticoids on sleep have been difficult to discern due to the feedback effects each hormone exerts on the other. In addition, it is not known whether hypothalamic-pituitary-adrenal axis hormones alter sleep homeostasis or circadian influences on sleep propensity. We therefore analyzed sleep architecture and electroencephalographic (EEG) power in freely moving rats before and after removal of corticosterone (thus elevating endogenous CRH) by surgical adrenalectomy. Adrenalectomy reduced the amplitude of the diurnal rhythms of maximal and average sleep bout lengths (P < 0.004). After adrenalectomy, power from 1 to 4 Hz decreased (P < 0.042), whereas power from 9 to 12 Hz increased in the power spectra of the EEG recording (P = 0.001). Administration of physiological corticosterone replacement reversed some of these effects. Supraphysiological corticosterone replacement in adrenalectomized rats reduced the amount of non-rapid-eye-movement sleep in the 24-h cycle (P = 0.001). During each endocrine condition, rats were sleep deprived for 6 h. Endocrine status did not alter the subsequent homeostatic response to sleep deprivation. Thus ADX and supraphysiological corticosteroid replacement each altered sleep architecture without a demonstrable effect on sleep homeostasis.
View details for Web of Science ID 000075249000028
View details for PubMedID 9688693
Forty-two genetically narcoleptic Doberman puppies [20 pure narcoleptic (N) puppies (from four narcoleptic x narcoleptic crosses) and 22 backcross narcoleptic (BN) puppies (from six narcoleptic x heterozygous crosses)] were systematically observed during the developmental period (4-24 weeks) to assess the age at onset and severity of cataplexy, a pathological manifestation of REM sleep atonia seen in narcolepsy. The mean age of onset of cataplexy was 9.69 +/- 1.15 weeks, with a median age of 7 weeks. The severity of cataplexy increased with age and reached a plateau at around 16-24 weeks. The effects of cross type (N vs BN) and sex on the development of cataplexy were analyzed. There was no difference in severity between N and BN puppies (P = 0.51). However, females had more severe cataplexy than males (P = 0.01), and this trend was preserved in five of the six litters that had both male and female puppies. These results suggest that the pathophysiological process in genetic canine narcolepsy emerges during the early developmental period and that it may involve a differential development in males and females. Furthermore, our results revealed that cataplexy onset corresponds to the emergence of adult-like REM sleep and to previously reported neuroanatomical and neurochemical abnormalities in canine narcolepsy.
View details for Web of Science ID 000075698200014
View details for PubMedID 9710528
Basal forebrain (BF) cholinergic regulation of cataplexy was investigated in narcoleptic canines. Specific cholinergic agonists and antagonists, and excitatory or inhibitory amino acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the BF of narcoleptic canines. Cataplexy was monitored using the food-elicited cataplexy test (FECT) and recordings of electroencephalogram, electrooculogram, and electromyogram. In narcoleptic canines, carbachol and oxotremorine (10(-5)-10(-3) M), but not McN-A-343 or nicotine (10(-4)-10(-3) M), produced a dose-dependent increase in cataplexy. In addition, N-methyl-d-aspartate (10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effects, while muscimol (10(-3) M) produced a weak (P < 0.10) increase in cataplexy. In control canines, carbachol (10(-5)-10(-3) M), but not oxotremorine (10(-4)-10(-3) M), produced muscle atonia after the highest concentration in one of three animals. Carbachol (10(-3) M)-induced cataplexy in narcoleptic canines was blocked by equimolar perfusion with the muscarinic antagonists atropine, gallamine, and 4-DAMP but not pirenzepine. These findings indicate that carbachol-stimulated cataplexy in the BF of narcoleptic canines is mediated by M2, and perhaps M3, muscarinic receptors. The release of acetylcholine in the BF was also examined during FECT and non-FECT behavioral stimulation in narcoleptic and control canines. A significant increase in acetylcholine release was found in both narcoleptic and control BF during FECT stimulation. In contrast, simple motor activity and feeding, approximating that which occurs during an FECT, did not affect acetylcholine release in the BF of narcoleptic canines. These findings indicate that BF acetylcholine release is enhanced during learned emotion/reward associated behaviors in canines.
View details for Web of Science ID 000073593600008
View details for PubMedID 9582257
Narcolepsy is a disabling sleep disorder of unknown aetiology. In humans, the disease is mostly sporadic, with a few familial cases having been reported. In 1973 a sporadic case of narcolepsy was reported in a poodle, and in 1975 familial cases of narcolepsy occurred in dobermanns. As with human narcoleptics, these narcoleptic dogs exhibited excessive daytime sleepiness and cataplexy. A colony of narcoleptic dogs was established at Stanford University in 1976 to study the pathophysiology of the disease. Between 1976 and 1995, a total of 669 animals of various breeds were born, of which 487 survived. Dobermanns accounted for 78 per cent of the total. The narcolepsy genotype in dobermanns had no significant influence on puppy mortality rate (numbers of stillborn and survival rate). The sex, maternal parity or the age of the sire or dam had no significant effect. The percentage of stillborn puppies increased from 6.1 per cent in outbred litters to 15.4 per cent in inbred litters (P = 0.10). Birth season also had a significant effect, and the highest survival rate (P = 0.02), and the lowest percentage of stillborn puppies (P = 0.09) occurred between April and June.
View details for Web of Science ID 000071662300006
View details for PubMedID 9481825
Photic and non-photic stimuli phase shift and entrain circadian rhythms through distinct but interacting mechanisms which impinge on the suprachiasmatic nucleus (SCN), the circadian pacemaker. Our understanding of this mechanism is incomplete. Serotonin (5-HT) injected locally at the SCN reduces light-induced glutamate release and decreases the expression of c-fos, a marker of photic transduction. Furthermore, in SCN slices, 5-HT application reduces field potentials after optic nerve stimulation. We therefore predicted that 5-HT-terminal destruction restricted to the SCN would augment phase shifts of circadian rhythms induced by light exposure. To investigate this possibility, we compared photic phase delays and Fos-like immunoreactivity in mice which had previously received bilateral infusions directed at the SCN containing either the selective 5-HT neurotoxin 5,7-dihydroxytryptamine (DHT, n = 16) or vehicle (VEH, n = 12). Phase delays after a light pulse given during the mid-subjective night (30 lux, 30 min starting at circadian time (CT) 12-20) in DHT-mice were 50% greater than in VEH-mice (P = 0.017). DHT mice (n = 5) had 76% larger Fos responses to a mid-subjective night light pulse than VEH-mice (n = 5) (P = 0.029). We conclude that 5-HT at or near the SCN in mice reduces photic phase shifts and modulates the magnitude of the photic phase response in the mouse.
View details for Web of Science ID A1997YB44200016
View details for PubMedID 9369309
The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 microg/kg, i.v.) and TA0910 (100 and 400 microg/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 microg/kg, i.v.) had no significant effect. TRH (25-1600 microg/kg, i.v.) and all three TRH analogs, CG3703 (6. 25-400 microg/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 microg/kg, i.v.), and TA0910 (25-1600 microg/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T3 and T4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.
View details for Web of Science ID A1997XU78100037
View details for PubMedID 9236248
The circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus receives serotonergic afferents from the midbrain raphe nuclei, but the functional role of this projection is unclear. In rodents, locomotor activity increases serotonin content in the SCN, and serotonergic agonists phase shift the circadian clock in a manner closely similar to voluntary bouts of vigorous exercise, suggesting that serotonergic afferents could be part of the activity-dependent entrainment mechanism. We investigated this possibility by selectively lesioning serotonin terminals within and adjacent to the SCN by local microinjection of 5,7-dihydroxytryptamine in mice pretreated with desipramine. This treatment decreased serotonin content 96 +/- 1% and 5-hydroxyindole-3-acetic acid content below levels of detection (nearly 100%) but did not decrease norepinephrine content or neuropeptide Y immunoreactivity in the SCN. These lesions did not alter subsequent running activity levels, yet rendered mice unable to synchronize to a regularly scheduled 2-h wheel running paradigm that entrained sham-lesioned controls. Serotonin afferents are thus necessary for activity-dependent entrainment in the mouse.
View details for Web of Science ID A1997XK68000034
View details for PubMedID 9249559
Like human narcoleptics, narcoleptic dogs display cataplexy, fragmented sleep and excessive daytime sleepiness. Cataplexy in dogs can easily be quantified using a simple behavioural bioassay, the Food Elicited Cataplexy Test. In contrast, daytime sleepiness and fragmented sleep are more difficult to measure, as long-term, labour-intensive polygraphic recordings in surgically-implanted animals are needed. In the current study, 24-h rest/activity patterns in genetically narcoleptic, asymptomatic heterozygous and control Dobermans were compared using small sized ambulatory activity monitoring devices under 12-h light/dark conditions. Control and heterozygous dogs were found to be more active during the light period than during the dark period, thus demonstrating a clear 24-h rest/activity cycle. In contrast, narcoleptic dogs were relatively inactive during the light period and did not show a clear rest/activity pattern, a result similar to that of human narcoleptics. Considering the fact that narcoleptic dogs show shorter sleep latency and sleep significantly more during the daytime than control dogs, the decrease in activity in narcoleptic dogs during the daytime is most likely a reflection of increased daytime napping in these animals. Ambulatory activity monitoring may be a useful non-invasive method for future pharmacological and development studies in the narcoleptic canine model.
View details for Web of Science ID A1997XL41000007
View details for PubMedID 9377531
Narcolepsy is a sleep disorder that has been shown to be tightly associated with HLA DR15 (DR2). In this study, 58 non-DR15 patients with narcolepsy-cataplexy were typed at the HLA DRB1, DQA1 and DQB1 loci. Subjects included both sporadic cases and narcoleptic probands from multiplex families. Additional markers studied in the class II region were the promoters of the DQA1 and DQB1 genes, two CA repeat polymorphisms (DQCAR and DQCARII) located between the DQA1 and DQB1 genes, three CA repeat markers (G51152, T16CAR and G411624R) located between DQB1 and DQB3 and polymorphisms at the DQB2 locus. Twenty-one (36%) of these 58 non-DR15 narcoleptic patients were DQA1*0102 and DQB1*0602, a DQ1 subtype normally associated with DRB1*15 in DR2-positive narcoleptic subjects. Additional microsatellite and DQA1 promoter diversity was found in some of these non-DR15 but DQB1*0602-positive haplotypes but the known allele specific codons of DQA1*0102 and DQB1*0602 were maintained in all 21 cases. The 37 non-DQA1*0102/DQB1*0602 subjects did not share any particular HLA DR or DQ alleles. We conclude that HLA DQA1*0102 and DQB1*0602 are the most likely primary candidate susceptibility genes for narcolepsy in the HLA class II region.
View details for Web of Science ID A1997WV41100002
View details for PubMedID 9151385
Canine narcolepsy is a unique experimental model of a human sleep disorder characterized by excessive daytime sleepiness and cataplexy. There is a consensus recognition of an imbalance between cholinergic and catecholaminergic systems in narcolepsy although the underlying mechanisms remain poorly understood. Possible substrates could be an abnormal organization, numbers and/or ratio of cholinergic to catecholaminergic cells in the brain of narcoleptic dogs. Therefore, we sought to characterize the corresponding neuronal populations in normal and narcoleptic dogs (Doberman Pinscher) by using choline acetyltransferase (ChAT), nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH). Cholinergic cell groups were found in an area extending from the central to the gigantocellular tegmental field and the periventricular gray corresponding to the pedunculopontine tegmental nucleus (PPT), the laterodorsal tegmental nucleus (LDT), and the parabrachial nucleus. An almost perfect co-localization of ChAT and NADPH-diaphorase was also observed. Catecholaminergic cell groups detected included the ventral tegmental area, the substantia nigra, and the locus coeruleus nucleus (LC). The anatomical distribution of catecholaminergic neurons was unusual in the dog in two important aspects: i) TH- and/or DBH-immunoreactive neurons of the LC were found almost exclusively in the reticular formation and not within the periventricular gray, ii) very few, if any TH-positive neurons were found in the central gray and dorsal raphe. Quantitative analysis did not reveal any significant differences in the organization and the number of cells identified in the LDT, PPT, and LC of normal and narcoleptic dogs. Moreover, the cholinergic to catecholaminergic ratio was found identical in the two groups. In conclusion, the present results do not support the hypothesis that the neurochemical imbalance in narcolepsy could result from abnormal organization, numbers, or ratio of the corresponding neuronal populations.
View details for Web of Science ID A1997WL65800002
View details for PubMedID 9050784
Several groups of investigators have assessed the impact of nasal obstruction on the obstructive sleep apnea syndrome. These studies evaluated patients with either naturally occurring partial nasal obstruction (e.g., allergic rhinitis, septal deviation) or experimentally induced nasal occlusion. The results of these studies are summarized and discussed in this article.
View details for Web of Science ID A1997WW54000003
View details for PubMedID 9134062
Thalidomide is a sedative hypnotic that was widely used in the 1950s but was withdrawn due to its teratogenic properties. The compound has recently been reintroduced as an immune modulating agent. Thalidomide significantly aggravates canine cataplexy, a pathological manifestation of rapid eye movement (RFM) sleep atonia seen in narcolepsy. This compound also increases REM sleep and slow wave sleep in these animals. In vitro receptor binding and enzyme assays demonstrate that thalidomide does not bind to or enzymatically modulate the neurotransmitter systems reported to be involved in the regulation of cataplexy. Thalidomide may therefore affect cataplexy through its immune modulation properties. Further studies on the mechanisms of action of thalidomide should increase our understanding of the pathophysiology of this disabling disorder.
View details for Web of Science ID A1996VP15900002
View details for PubMedID 8905685
Human narcolepsy is a neurological disorder known to be closely associated with HLA-DR2 and DQB1*0602. Because most autoimmune diseases are HLA-associated, a similar mechanism has been proposed for narcolepsy. However, neither systemic nor CNS evidence of an autoimmune abnormality has ever been reported. In this study, major histocompatibility (MHC) class I and class II expression was studied in the CNS of human and canine narcoleptics using immunohistochemistry and Northern analysis. Results indicated that canine narcolepsy is associated with a significant increase of MHC class II expression by the microglia. Moreover, the highest values were found between 3 and 8 months of age, strikingly concomitant to the development of narcolepsy in the canine model. In humans, class II expression was not found significantly different between control and narcoleptic subjects. This result could be explained by the old age of the subjects (69.86 +/- 5.31 and 68.36 +/- 4.74 years in narcoleptics and controls, respectively), because class II expression is significantly correlated with age in both humans and dogs. For the first time, this study demonstrated that the expression of MHC class II molecules in the CNS is age-dependent and that a consistent increase of their expression by the microglia might be critically involved in the development of narcolepsy.
View details for Web of Science ID A1996UX95500006
View details for PubMedID 8764647
View details for Web of Science ID A1996UC74600005
View details for PubMedID 8855033
The effects of modafinil and amphetamine on daytime sleep (polysomnographic recordings) and cataplexy (the food-elicited cataplexy test) were compared using the narcoleptic canine model. Results indicate that both modafinil (5 and 10 mg/kg body weight i.v.) and amphetamine (100 and 200 micrograms/kg i.v.) increase wakefulness and reduce slow-wave sleep in control and narcoleptic dogs. In contrast, the results of cataplexy testing demonstrate that amphetamine (2.5-160 micrograms/kg i.v.), but not modafinil (0.125-8.0 mg/kg i.v.) significantly suppresses canine cataplexy. These results suggest that the pharmacological property of modafinil is distinct from amphetamine. Results of polysomnographic recordings also demonstrate that narcoleptic dogs slept significantly more during the daytime than control dogs and required very high doses (10 mg/kg i.v. modafinil; 200 micrograms/kg i.v. amphetamine) of stimulants to reduce their level of sleepiness to that of control dogs. This finding is consistent with the data collected in human narcolepsy and validates the use of this canine model for the screening of stimulant compounds.
View details for Web of Science ID A1995TQ23600001
View details for PubMedID 8746387
Alpha adrenergic agonists such as clonidine are widely used for their antihypertensor effects, but they also cause sedation. The mechanisms underlying soporific effects of such compounds are poorly understood, but appear to involve the alpha-2 adrenergic receptor sub-type. To further investigate the role of this receptor in sleep-wake regulation, rats received injections i.p. either during their peak of activity (circadian time CT-18: 6 hr after lights out) or near the mid-point of their sleep-dominated phase (CT-5: 5 hr after lights on) with either the highly selective alpha-2 agonist dexmedetomidine (dMED) 0.02 to 0.04 mg/kg or the less selective alpha-2 agonist, clonidine 0.04 to 0.08 mg/kg, or vehicle. Clonidine and dMED showed remarkable overall similarities in their soporific profiles. Except for the lower dose of clonidine, both CT-5 and CT-18 treatments increased the percent of time spent in non-REM (NREM) sleep. The increase in NREM was followed by a reduction of NREM sleep that was accompanied by locomotor activity and body temperature above control levels. After CT-5 treatments, this period of reduced NREM sleep was followed by a secondary increase in NREM 7 to 10 hr posttreatment. REM sleep was markedly reduced for 9 to 10 hr after all treatments at both times of day, with elevated REM levels 18 to 30 hr posttreatment. Pre-treatment with the selective alpha-2 antagonist atipamezole (0.5 mg/kg) reversed the effects of CT-18 dMED 0.04 mg/kg except REM sleep suppression, which was only partially reversed. The NREM-inducing potency of dMED 0.02 mg/kg was greater when administered at CT-18 than at CT-5. Taken together with other evidence, these findings suggest that the profound NREM-inducing effects of dMED may be mediated by postsynaptic alpha-2 adrenoceptors. Furthermore, the pharmacodynamic action of alpha-2 adrenergic agonists, like many other sedative hypnotics (e.g., benzodiazepines), produce a hysteresis in sleep-wake regulation characterized by "rebound" waking after drug-induced sleep.
View details for Web of Science ID A1995TA46700034
View details for PubMedID 7562559
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep-related symptoms, such as cataplexy. The exact pathophysiology underlying the disease is unknown but may involve central cholinergic systems. It is known that the brainstem cholinergic system is activated during REM sleep. Furthermore, REM sleep and REM sleep atonia similar to cataplexy can be triggered in normal and narcoleptic dogs by stimulating cholinergic receptors within the pontine brainstem. The pontine cholinergic system is, therefore, likely to play a role in triggering cataplexy and other REM-related abnormalities seen in narcolepsy. The other cholinergic system that could be involved in the pathophysiology of narcolepsy is located in the basal forebrain (BF). This system sends projections to the entire cerebral cortex. Since acetylcholine release in the cortex is increased both during REM and wake, the basocortical cholinergic system is believed to be involved in cortical desynchrony. In the current study, we analyzed the effect of cholinergic compounds injected into the forebrain structures of narcoleptic and control dogs. We found that carbachol (a cholinergic agonist) injected into the BF triggers cataplexy in narcoleptic dogs while it increases wakefulness in control dogs. Much higher doses of carbachol bilaterally injected in the BF were, however, shown to trigger muscle atonia even in control dogs. These results suggest that a cholinoceptive site in the BF is critically implicated in triggering muscle atonia and cataplexy. Together with similar results previously obtained in the pontine brainstem, it appears that a widespread hypersensitivity to cholinergic stimulation may be central to the pathophysiology of canine narcolepsy.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1995RJ66200008
View details for PubMedID 7623112
We have performed a study assessing the prevalence of sleep-disordered breathing in a large US trucking company using a validated portable monitor (MESAM-4) and a validated symptom questionnaire. Three hundred eighty-eight drivers with a mean age of 36 years filled out the questionnaire. One hundred fifty-nine drivers with a mean age of 35 years spent the night at the terminal hub where they underwent monitoring for identification of sleep-disordered breathing. The drivers also had blood pressure recorded while awake, seated, and after 15 min of quiet rest. Seventy-eight percent of the drivers had an oxygen desaturation index (ODI) > or = 5 per hour of sleep; 10% had an ODI > or = 30 per hour of sleep. There was a significant difference in the body mass index (BMI) between drivers with ODI < 5 and drivers with ODI > or = 5 (25.7 +/- 6.0 kg/m2 in drivers with ODI < 5 vs 29.0 +/- 6.3 kg/m2 in drivers with ODI > or = 5, p < 0.001). Sixteen percent of all drivers tested were hypertensive. Twelve percent were unaware of their hypertension. Hypertensive drivers were significantly more overweight (p < 0.0001), slept more restlessly (p < 0.04), took more naps (p < 0.03), and woke up more frequently during the night (p < 0.005). About 20% of drivers presented symptoms indicating very regular sleep disturbances. Drivers who had been with the company for more than 1 year were more likely to present daytime fatigue, daytime tiredness, unrestorative sleep, hypertension, and higher BMI. Long-haul truck drivers have very irregular sleep/wake schedules and a high prevalence of sleep-disordered breathing. Chronic sleep/wake disruption and partial, prolonged sleep deprivation may worsen sleep-disordered breathing. This combination of problems may impact significantly on the daytime alertness of truckers.
View details for Web of Science ID A1995QY14600020
View details for PubMedID 7750318
Pharmacological studies using a canine model of narcolepsy have demonstrated that adrenergic rather than serotonergic or dopaminergic uptake inhibition is the primary mode of action of antidepressants on cataplexy, a pathological manifestation of rapid eye movement (REM) sleep atonia that occurs in narcolepsy. This result is in line with the known involvement of adrenergic systems in the regulation of REM sleep. However, the lack of anticataplectic effects of selective serotonergic compounds was puzzling as serotonergic neurons of the dorsal raphe nuclei are known to decrease activity during the REM sleep in a manner similar to the adrenergic neurons of the locus coeruleus. To further explore the role of serotonergic systems, we tested the effect on canine cataplexy of six 5-HT1A agonists and five 5-HT1A antagonists. Results indicate that 5-HT1A agonists significantly suppress cataplexy in correlation with their in vitro affinities to the canine central 5-HT1A receptors. Anticataplectic effects were, however, accompanied by various behavioral changes, such as flattened body posture, increased panting and agitation. In contrast, the selective 5-HT1A antagonist did not aggravate cataplexy, although a 5-HT1A antagonist was able to block the anticataplectic effect of a 5-HT1A agonist. These results suggest that the anticataplectic effects of 5-HT1A agonists are truly mediated by 5-HT1A receptor stimulation. It is, however, likely that anticataplectic effects occur due to the behavioral side effects rather than the direct involvement of this receptor subtype in the regulation of cataplexy. Further studies are therefore necessary to address the question of whether these 5-HT1A agonists hold promise in the pharmacological treatment of human cataplexy.
View details for Web of Science ID A1995QL99500028
View details for PubMedID 7891329
Narcolepsy is a neurological disorder known to be associated with human leukocyte antigen (HLA)-DQB1*0602 in humans. In a canine model, the disorder is also genetically linked to a gene of high homology with the human mu-switch-like immunoglobulin (Ig) gene (current LOD score 13.6 at 0% recombination). Since association with HLA or other immune function polymorphic genes (T cell receptor of Ig, mainly) is a hallmark of most autoimmune diseases, it is proposed that autoimmunity may also play a role in the development of narcolepsy. Arguments for and against this hypothesis are reviewed. It is shown that both on the basis of the most recent molecular studies, and because of some of its clinical features, narcolepsy may be an autoimmune disorder. However, neither systemic nor central nervous system (CNS) evidence of any autoimmune abnormality have ever been found. To reconcile this discrepancy, it is suggested that the pathological immune process involved in narcolepsy could be difficult to detect because it is restricted to a very small region of the brain or targets a low abundance neuroeffector. Alternatively, it is possible that a more fundamental relationship is involved between sleep generation and immune regulation. The pathophysiology of narcolepsy may then involve new CNS-immune mechanisms that may shed new light on the sleep process itself.
View details for Web of Science ID A1995QP30900004
View details for PubMedID 7795891
In the present study, we tested 19 Caucasian and 28 Black American narcoleptics for the presence of the human leucocyte antigen (HLA) DQB1*0602 and DQA1*0102 (DQ1) genes using a specific polymerase chain reaction (PCR)-oligotyping technique. A similar technique was also used to identify DRB1*1501 and DRB1*1503 (DR2). Results indicate that all but one Caucasian patient (previously identified) were DRB1*1501 (DR2) and DQB1*0602/DQA1*102 (DQ1) positive. In Black Americans, however, DRB1*1501 (DR2) was a poor marker for narcolepsy. Only 75% of patients were DR2 positive, most of them being DRB1*1503, but not DRB1*1501 positive. DQB1*0602 was found in all but one Black narcoleptic patient. The clinical and polygraphic results for this patient were typical, thus confirming the existence of a rare, but genuine form of DQB1*0602 negative narcolepsy. These results demonstrate that DQB1*0602/DQA1*0102 is the best marker for narcolepsy across all ethnic groups.
View details for Web of Science ID A1994QD08100013
View details for PubMedID 7701202
It is believed that narcolepsy involves abnormalities of rapid eye movement (REM) sleep, especially of REM sleep atonia. Compelling evidence suggests that the regulation of REM sleep and REM sleep atonia involves a reciprocal interaction of cholinergic and monoaminergic systems. Using our canine model of narcolepsy and a pharmacological approach, we have previously demonstrated a similar interaction in the regulation of cataplexy. Global activation of cholinergic or monoaminergic transmission aggravates or suppresses canine cataplexy, respectively. We have also identified the subtypes of monoaminergic and cholinergic receptors specifically involved in this interaction. Cataplexy is aggravated by activation of the cholinergic system via M2 stimulation, as well as deactivation of the catecholaminergic systems by either blockade of postsynaptic alpha-1b receptors or stimulation of alpha-2 or D2 inhibitory autoreceptors. These pharmacological results correspond to previously identified neurochemical abnormalities in canine narcolepsy, such as significant increases in M2 receptors in the pons, alpha-1 receptors in the amygdala, alpha-2 receptors in the locus coeruleus and D2 receptors in the amygdala and nucleus accumbens, when compared to control animals. Using local perfusion of active compounds, we have further demonstrated that cholinoceptive sites in the pontine reticular formation, as well as in the basal forebrain, are involved in the regulation of cataplexy. Although the specific sites of action of the monoaminergic compounds remain unknown, the results of our pharmacological and neurochemical studies to date suggest that a widespread hyperactivity of cholinergic systems within the central nervous system together with a hypoactivity of catecholaminergic systems underlie the pathophysiology of narcolepsy.
View details for Web of Science ID A1994QD08100016
View details for PubMedID 7701206
Canine narcolepsy is an animal model of the human disorder that is transmitted as a single autosomal recessive gene with full penetrance (canarc-1) in Dobermans and Labradors. In previous experiments, we have identified a very tight linkage marker for canarc-1. This marker, a 0.85-kb band cross reacting with a human mu-switch Heavy-Chain Immunoglobulin probe (maximum logarithm of odds [LOD] score Zmax = 10.8 at 0% recombination), has now been cloned and sequenced. The gene, composed of GC rich repeats, is 75% homologous to the human mu-switch gene and is similar in organization to immunoglobulin switch genes. Curiously, however, this mu-switchlike segment appears to be unlinked with other switchlike polymorphisms detected at high stringency with the human mu-switch probe. Because in most animal species all switch genes are located within 300-500 kb and show tight linkage in families, this result suggests two possible hypotheses: 1) Our 0.85 kb is a true immunoglobulin switch segment, but the map of the canine Variable Heavy-Chain loci is organized in unlinked clusters, or 2) our 0.85-kb segment is not an immunoglobulin switch segment and is located elsewhere in the genome in all species. We are now using chromosome walking and Yeast Artificial Chromosome Cloning techniques, together with corresponding studies in humans to identify the pathological gene.
View details for Web of Science ID A1994QD08100014
View details for PubMedID 7701203
This study assesses a possible independent effect of sleep-related breathing disorders on traffic accidents in long-haul commercial truck drivers. The study design included integrated analysis of recordings of sleep-related breathing disorders, self-reported automotive and company-recorded automotive accidents. A cross-sectional population of 90 commercial long-haul truck drivers 20-64 years of age was studied. Main outcome measures included presence or absence, as well as severity, of sleep-disordered breathing and frequency of automotive accidents. Truck drivers identified with sleep-disordered breathing had a two-fold higher accident rate per mile than drivers without sleep-disordered breathing. Accident frequency was not dependent on the severity of the sleep-related breathing disorder. Obese drivers with a body mass > or = 30 kg/m2 also presented a two-fold higher accident rate than nonobese drivers. We conclude that a complaint of excessive daytime sleepiness is related to a significantly higher automotive accident rate in long-haul commercial truck drivers. Sleep-disordered breathing with hypoxemia and obesity are risk factors for automotive accidents.
View details for Web of Science ID A1994PR32700008
View details for PubMedID 7846460
Both rapid eye movement sleep and cataplexy in the narcoleptic canine have been shown to increase after both systemic and local administration of cholinergic agonists in the pontine reticular formation. Furthermore, binding studies indicate an increase in the number of M2 muscarinic receptors in the pontine reticular formation of narcoleptic canines. In the present study we have investigated the receptor subtypes involved in mediating the cholinergic stimulation of cataplexy, as defined by brief periods of hypotonia induced by emotions, within the pontine reticular formation of narcoleptic canines. Specific cholinergic and monoaminergic agonists and antagonists, and excitatory or inhibitory amino-acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of narcoleptic canines, and cataplexy was monitored using the Food-Elicited Cataplexy Test and recordings of electroencephalogram, electrooculogram and electromyogram. In narcoleptic canines, bilateral perfusion with oxotremorine (M2 muscarinic) (10(-5)-10(-3) M) in the pontine reticular formation produced a dose-dependent increase in cataplexy, which reached complete muscle atonia (status cataplecticus) during the highest concentration. In control canines bilateral perfusion with oxotremorine (10(-5)-10(-3) M) did not produce any cataplectic attacks, but did produce muscle atonia after the highest concentration. Bilateral perfusion with either McN-A-343 (M1 muscarinic) or nicotine (both 10(-5)-10(-3) M) did not have any effect on cataplexy in either narcoleptic or control canines. The increase in cataplexy in narcoleptic canines produced by local perfusion with carbachol (10(-4) M) followed by equimolar perfusion with a muscarinic antagonist was rapidly reversed by atropine (muscarinic) and gallamine (M2 muscarinic), partially reversed by 4-DAMP (M3/M1 muscarinic) and completely unaffected by pirenzepine (M1 muscarinic). Bilateral perfusion with excitatory, glutamatergic receptor agonists N-methyl-D-aspartate, AMPA (both at 10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effect on cataplexy, whereas bilateral perfusion with the inhibitory GABAergic receptor agonist muscimol (10(-4)-10(-3) M) produced a moderate increase in cataplexy in the narcoleptic canines. Bilateral perfusion with numerous monoaminergic compounds, BHT-920 (alpha-2 agonist), yohimbine (alpha-2 antagonist), propranolol (beta antagonist) and prazosin (alpha-1 antagonist), did not have any effect on cataplexy. These findings demonstrate that cholinergic regulation of cataplexy in the narcoleptic canine at the level of the pontine reticular formation is mediated by M2, and possibly M3, muscarinic receptors. The effects of muscimol indicate that the stimulation of cataplexy might be elicited by local neuronal inhibition.
View details for Web of Science ID A1994PE28600005
View details for PubMedID 7991953
View details for Web of Science ID A1994PE28600006
View details for PubMedID 7991954
Cataplexy in the narcoleptic canine has been shown to increase after local administration of carbachol into the pontine reticular formation. Rapid eye movement sleep has also been shown to increase after local administration of carbachol in the pontine reticular formation, and furthermore, acetylcholine release in the pontine tegmentum was found to increase during rapid eye movement sleep in rats. Therefore, in the present study we have investigated acetylcholine release in the pontine reticular formation during cataplexy in narcoleptic canines. Extracellular acetylcholine levels were measured in the pontine reticular formation of freely moving narcoleptic and control Doberman pinschers using in vivo microdialysis probes. Cataplexy was induced by the Food-Elicited Cataplexy Test and monitored using recordings of electroencephalogram, electrooculogram and electromyogram. Basal levels of acetylcholine in the microdialysis perfusates were approximately 0.5 pmol/10 min in both control and narcoleptic canines. Local perfusion with tetrodotoxin (10(-5) M) or artificial cerebrospinal fluid without Ca2+ produced a decrease, while intravenous injections of physostigmine (0.05 mg/kg) produced an increase in acetylcholine levels, indicating that the levels of acetylcholine levels measured are derived from neuronal release. During cataplexy induced by the Food-Elicited Cataplexy Test, acetylcholine levels increased by approximately 50% after four consecutive tests in narcoleptic canines, but did not change after four consecutive tests in control canines. Motor activity and feeding behavior, similar to that occurring during a Food-Elicited Cataplexy Test, had no effect on acetylcholine levels in the narcoleptic canines.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1994NF79800004
View details for PubMedID 8008206
Cataplexy in the narcoleptic canine has been shown to increase after systemic administration of cholinergic agonists. Furthermore, the number of cholinergic receptors in the pontine reticular formation of narcoleptic canines is significantly elevated. In the present study we have investigated the effects of cholinergic drugs administered directly into the pontine reticular formation on cataplexy, as defined by brief episodes of hypotonia induced by emotions, in narcoleptic canines. Carbachol and atropine were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of freely moving, narcoleptic and control Doberman pinschers. Cataplexy was quantified using the Food-Elicited Cataplexy Test, and analysed using recordings of electroencephalogram, electrooculogram and electromyogram. Cataplexy was characterized by a desynchronized electroencephalogram and a drop in electromyogram and electrooculogram activity. In narcoleptic canines, both unilateral and bilateral carbachol (10(-5) to 10(-3) M) produced a dose-dependent increase in cataplexy, which resulted in complete muscle tone suppression at the highest concentration. In control canines, neither bilateral nor unilateral carbachol (10(-5) to 10(-3) M) produced cataplexy, although bilateral carbachol, did produce muscle atonia at the highest dose (10(-3)). The increase in cataplexy after bilateral carbachol (10(-4) M) was rapidly reversed when the perfusion medium was switched to one containing atropine (10(-4) M). Bilateral atropine (10(-3) to 10(-2) M) alone did not produce any significant effects on cataplexy in narcoleptic canines; however, bilateral atropine (10(-2) M) did reduce the increase in cataplexy produced by systemic administration of physostigmine (0.05 mg/kg, i.v.). These findings demonstrate that cataplexy in narcoleptic canines can be stimulated by applying cholinergic agonists directly into the pontine reticular formation. The ability of atropine to inhibit locally and systemically stimulated cataplexy indicates that the pontine reticular formation is a critical component in cholinergic stimulation of cataplexy. Therefore, it is suggested that the pontine reticular formation plays a significant role in the cholinergic regulation of narcolepsy.
View details for Web of Science ID A1994NF79800003
View details for PubMedID 8008205
Following a baseline night recording, 8 narcoleptic subjects and 8 sex- and age-matched controls were maintained on a 90 min sleep/wake schedule for 48-72 h. Each cycle consisted of 60 min of enforced wakefulness out of bed, followed by a 30 min "nap" period in which subjects were asked to try and fall asleep. Upon completion of the 90 min sleep/wake protocol, subjects were permitted to sleep ad libitum for 24 h. All sleep periods were monitored polygraphically; in addition, tympanic temperature and subjective sleepiness were recorded during the 90 min sleep/wake schedule. Narcoleptics and controls differed dramatically in their sleep patterns during the 90 min sleep/wake schedule. On average, narcoleptics obtained 2 more hours per day of total sleep time (TST) than did the controls, with REM sleep comprising nearly 2/3 of the incremental sleep time. The two groups did not differ with respect to the amount of slow wave sleep (stage 3 + 4; SWS). The sleep latency rhythms observed in control subjects were markedly diminished in narcoleptics; narcoleptic subjects remained objectively sleepy (i.e., had low sleep latencies) even at times corresponding to maximum alertness in the control subjects. Rhythms in subjective sleepiness and core temperature were, however, robust in both groups. Although TST in narcoleptics exceeded that of controls during the 90 min sleep/wake schedule, narcoleptics did not obtain more sleep than controls during the baseline or recovery periods. These findings suggest that the homeostatic process of sleep regulation is intact in narcoleptics. Moreover, it appears that the circadian clock itself is functioning normally in narcoleptics. An attenuated clock effector mechanism responsible for promoting alertness may, however, explain excessive daytime sleepiness in narcoleptics.
View details for Web of Science ID A1994MZ61500003
View details for PubMedID 7509271
View details for Web of Science ID A1993MW45700007
View details for PubMedID 8177995
Our series of pharmacological studies on canine narcolepsy has suggested that the adrenergic systems are more critically involved in the regulation of cataplexy than the serotonergic and dopaminergic systems. This, however, is an apparent contradiction to data obtained in human patients, which show that chronic oral administration of serotonergic uptake inhibitors, such as clomipramine, zimelidine and fluoxetine, is effective in reducing cataplexy. To explore this discrepancy, we have assessed the anticataplectic effects of various serotonergic uptake inhibitors and their active desmethyl metabolites on canine cataplexy. We found that the anticataplectic effect of the desmethyl metabolites, which are usually more potent for in vitro adrenergic uptake inhibition, was more potent and developed more rapidly than the effect of the parent compounds. Furthermore, the anticataplectic potency was positively correlated to the adrenergic uptake inhibition and was negatively correlated with serotonergic uptake inhibition among the 10 compounds tested. These results are consistent with our hypothesis of a preferential involvement of the adrenergic system in the control of cataplexy. Our results also suggest that the anticataplectic effect of "selective" serotonergic uptake inhibitors in human narcolepsy might be mediated by their less selective active metabolites.
View details for Web of Science ID A1993MV96900004
View details for PubMedID 8165384
Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.
View details for Web of Science ID A1993MG37200013
View details for PubMedID 7862832
We investigated age-related changes in a molecular mechanism associated with synchronization of circadian rhythms to the environment. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker that regulates a variety of physiological and behavioral rhythms. Recent studies have demonstrated photic induction of immediate early genes (IEGs) such as c-fos in the SCN in a circadian-phase dependent manner, suggesting that IEGs may be part of the pathway for entrainment of circadian rhythms. We find that there is a decreased response of the IEGs c-fos, and NGFI-A but not NGFI-B in the SCN of old animals after photic stimulation. Changes in gene transcription indicated by IEGs may provide insights into the molecular machinery of the biological clock and ultimately elucidate mechanisms underlying the age-dependent decay of circadian organization.
View details for Web of Science ID A1993LW58900005
View details for PubMedID 8247226
"Sundowning," a term that is sometimes equated with sleep disturbance or nocturnal delirium in dementia, is a poorly understood psychiatric phenomenon. In this study, we performed systematic, temporally specific, behavioral observations of nine profoundly demented nursing home patients 4 times an hour over a 12-hour period (1300 to 0100h) to determine whether their agitation was more likely to occur at a particular time of day. Results indicated only equivocal evidence that agitation was any worse nocturnally or during the time near sunset, thus raising the possibility that at least some components of sundowning may reflect disruptive behaviors occurring with identical frequency throughout the day but with differential impact upon nursing staff. Additional data indicated that awakening from sleep during darkness was also associated with agitation. A final result was a trend indicating the apparent worsening of agitation seasonally (greater agitation during winter), which may suggest involvement of the circadian timing system.
View details for Web of Science ID A1993MA22000009
View details for PubMedID 8272449
View details for PubMedID 11618448
View details for Web of Science ID A1993KR80300030
View details for PubMedID 8445820
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.
View details for Web of Science ID A1993KW38600002
View details for PubMedID 8490208
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.
View details for Web of Science ID A1993KT84600009
View details for PubMedID 8095546
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.
View details for Web of Science ID A1993KP71100016
View details for PubMedID 8095066
View details for PubMedID 8446072
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.
View details for Web of Science ID A1992KG17200007
View details for PubMedID 1487481
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.
View details for Web of Science ID A1992JW77400006
View details for PubMedID 1334199
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.
View details for Web of Science ID A1992JT08400005
View details for PubMedID 1455124
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)
View details for Web of Science ID A1992JN18200008
View details for PubMedID 1393593
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.
View details for Web of Science ID A1992JL38700014
View details for PubMedID 1393561
Cerebrospinal fluid from yellow-bellied marmots, Marmota flaviventris, was analysed for monoamine and monoamine metabolite content during euthermia and deep hibernation. Dopamine (DA) levels were decreased, while DA metabolite levels, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were dramatically increased in hibernating marmots. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5HIAA) levels were also greatly enhanced during hibernation while norepinephrine (NE) levels were only moderately increased. These findings demonstrate that cerebrospinal monoamine levels are dynamically altered during hibernation, such that DA versus 5-HT and NE levels undergo opposite changes. Therefore, these data indicate that DA, 5-HT and NE neuronal systems are differentially altered during hibernation in mammals.
View details for PubMedID 10607025
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.
View details for Web of Science ID A1991GU07700003
View details for PubMedID 1687464
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.
View details for Web of Science ID A1991GR67200031
View details for PubMedID 1786534
In the mouse, activity is precisely timed by the circadian clock and is normally most intense in the early subjective night. Since vigorous activity (e.g., wheel running) is thought to induce phase shifts in rodents, the temporal placement of daily exercise/activity could be a determinant of observed circadian rhythm period. The relationship between spontaneous running-wheel activity and the circadian period of free-running rhythms was studied to assess this possibility. With ad libitum access to a running wheel, mice exhibited a free-running period (tau) of 23.43 +/- 0.08 hr (mean +/- SEM). When running wheels were locked, tau increased (23.88 +/- 0.04 hr, p less than 0.03), and restoration of ad libitum wheel running again produced a shorter period (tau = 23.56 +/- 0.06 hr, p less than 0.05). A survey of free-running activity patterns in a population of 100 mice revealed a significant correlation between the observed circadian period and the time of day in which spontaneous wheel running occurred (r = 0.7314, p less than 0.0001). Significantly shorter periods were observed when running was concentrated at the beginning of the subjective night (tau = 23.23 +/- 0.04), and longer periods were observed if mice ran late in the subjective night (tau = 23.89 +/- 0.04), F (1, 99) = 34.96, p less than 0.0001. It was previously believed that the period of the circadian clock was primarily responsive to externally imposed tonic or phasic events. Systematic influences of spontaneous exercise on tau demonstrate that physiological and/or behavioral determinants of circadian timekeeping exist as well.
View details for Web of Science ID A1991GE80800001
View details for PubMedID 1773091
Circadian rhythm entrainment has long been thought to depend exclusively on periodic cues in the external environment. However, evidence now suggests that appropriately timed vigorous activity may also phase shift the circadian clock. Previously it was not known whether levels of exercise/activity associated with spontaneous behavior provided sufficient feedback to phase shift or synchronize circadian rhythms. The present study investigated this issue by monitoring the sleep-wake, drinking, and wheel-running circadian rhythms of mice (Mus musculus) during unrestricted access to running wheels and when free wheel rotation was limited to either 12- or 6-h intervals with a fixed period of 24 h. Wheel rotation was controlled remotely. Mice spontaneously ran in wheels during scheduled access, and free-running sleep-wake and drinking circadian rhythms became entrained to scheduled exercise in 11 of 15 animals. However, steady-state entrainment was achieved only when exercise commenced several hours into the subjective night. The temporal placement of running during entrainment was related (r = 0.7003, P less than 0.02) to free-running period before entrainment. Mice with a free-running period less than 23.0 h did not entrain but exhibited relative coordination between free-running variables and the wheel availability schedule. Thus the circadian timekeeping system responds to temporal feedback arising from the timing of volitional exercise/activity, suggesting that the biological clock not only is responsive to periodic geophysical events in the external environment but also derives physiological feedback from the spontaneous activity behaviors of the organism.
View details for Web of Science ID A1991GK86900072
View details for PubMedID 1928438
Narcolepsy is a sleep disorder characterized by abnormal manifestations of rapid-eye-movement (REM) sleep and excessive daytime sleepiness. Using a canine model of the disease, we found that central D2 antagonists suppressed cataplexy, a form of REM-sleep atonia occurring in narcolepsy, whereas this symptom was aggravated by D2 agonists. The effect on cataplexy was stereospecific for the S(-) enantiomer of sulpiride (a D2 antagonist) and the R(+) enantiomer of 3-PPP (a D2 agonist). There was also a significant correlation between the in vivo pharmacological potency and in vitro drug affinity for D2 receptors (but not for D1 and alpha 2 receptors) among the seven central D2 antagonists tested. Selective D1 compounds were also tested; however, the results were inconsistent because both antagonists and agonists generally suppressed cataplexy. Our current results demonstrate that central D2-type receptors are critically involved in the control of cataplexy and REM sleep. Furthermore, the finding that small doses of D2 antagonists suppressed cataplexy and induced behavioral excitation, while small doses of D2 agonists aggravated cataplexy and induced sedation, suggests that this effect is mediated presynaptically. However, considering the fact that selective dopamine reuptake inhibitors did not modify cataplexy and that our previous pharmacological results demonstrated a preferential involvement of the noradrenergic system in the control of cataplexy, we believe that the effect of D2 compounds on cataplexy is mediated secondarily via the noradrenergic systems.
View details for Web of Science ID A1991GE83100004
View details for PubMedID 1831837
Daytime residual drowsiness and psychomotor performance were assessed for two long half-life benzodiazepines, quazepam and flurazepam, in two randomized, parallel, and double-blind studies in insomniacs. Seventeen middle-aged patients took quazepam 15 mg or 30 mg, or flurazepam 30 mg; the 47-night study included 4 placebo baseline nights, 28 consecutive treatment nights, and 15 posttreatment nights. Forty-eight geriatric patients took either flurazepam 15 mg, quazepam 15 mg, or placebo; the 15-night study included 1 placebo baseline night, 7 treatment nights, and 7 posttreatment nights. The Multiple Sleep Latency Test (MSLT), an objective test for measuring daytime sleepiness, and performance tests were administered. In the first study, flurazepam patients were significantly (p less than .05) sleepier after the 7th and 14th treatment nights when compared to baseline, whereas quazepam patients were not. In the second study, flurazepam patients were sleepier at midday (p less than .10) and late afternoon (p less than .05) after 1 treatment week than were quazepam and placebo patients. Performance test results suggested quazepam has a relatively low potential for daytime impairment. Thus, quazepam 15 mg produces less daytime somnolence and fewer psychomotor performance decrements than does flurazepam.
View details for Web of Science ID A1991GJ23900007
View details for PubMedID 1680123
This study investigated whether a sensitive, physiological measure of alertness/sleepiness, the Multiple Sleep Latency Test (MSLT), was related to neuropsychological test performance in elderly individuals. We hypothesized that the greater likelihood of falling asleep during the daytime on the MSLT would be related to relatively poorer performances on a variety of neuropsychological tests. Results from a homogeneous sample of 35 relatively well-educated, high functioning, elderly community volunteers confirmed the presence of characteristic levels of daytime alertness which were stable within individuals (r = .70 to .73) and showed large variation across individuals (coefficients of variation: 54-84%). Despite this wide intersubject variability, MSLT-defined alertness/sleepiness was unrelated to neuropsychological test results. We discuss these results in terms of the performance deficits known to accompany sleepiness in experimental studies of sleep deprivation and in terms of the behavioral slowing known to occur in normal aging.
View details for Web of Science ID A1991GL95300012
View details for PubMedID 1770981
View details for Web of Science ID A1991GJ23900006
Previous studies have indicated that manipulation of activity levels can modify characteristics of sleep/wake and activity rhythms. The generality of these observations was evaluated by simultaneously measuring drinking and sleep/wake rhythms while mice had free or no access to a running wheel in constant conditions (DD). Robust circadian rhythms in all parameters were observed in the "wheel free" (unrestricted) condition. When wheels were locked, the peak amplitude of the sleep/wake circadian rhythm decreased by approximately 50% without affecting the amplitude of the drinking rhythm. Total wake time decreased 11% per circadian day when wheels were locked with increases in both NREM and REM sleep. Whereas the amplitude of the drinking waveform was unaffected, wheel restriction caused an equivalent increase in period length (tau) for both rhythms. These results indicate that, unlike the generalized effects of activity on tau, activity restriction influences on rhythm amplitude do not generalize to all behavioral and/or physiological variables. This work also supports the notion that activity influences on sleep/wake rhythm amplitude reflect behavioral "masking" rather than a fundamental change in the direct coupling mechanisms of the biological clock.
View details for Web of Science ID A1991GG61600016
View details for PubMedID 1745682
Rats with suprachiasmatic nuclei (SCN) lesions did not show increased sleep after triazolam (TRZ) injections at any dose from 0.2 to 1.6 mg/kg, whereas 0.4 mg/kg TRZ given intact rats in the middle of their activity phase significantly increased sleep. Across SCN-lesioned and intact rats, the amount of sleep before and after TRZ 0.4 mg/kg was negatively correlated. SCN-lesioned rats did not have a circadian activity-dominant period and so did not accumulate a biological sleep debt. Their lack of response to TRZ may have resulted from the absence of a sleep debt compared to intact rats injected in the middle of their activity phase. These data support our hypothesis that the homeostatic process controlling sleep gates benzodiazepine hypnotic efficacy.
View details for Web of Science ID A1991FL17600007
View details for PubMedID 1881590
Identification of genes determining narcolepsy susceptibility is important not only for understanding that disorder but also for possible clues to general sleep-control mechanisms. Studies in humans reveal at least one such gene related to the major histocompatibility complex and in dog an as-yet-unmapped single, autosomal recessive gene canarc-1. Gene markers for canarc-1 were therefore sought by DNA restriction fragment length polymorphisms in our colony of narcoleptic dogs. A human mu-switch immunoglobulin probe and the enzyme Hae III identified a gene cosegregating with canarc-1 in backcrossed animals (logarithm of odds scores: m = 24, Z max = 7.2 at theta = 0%). canarc-1 was also shown not to be tightly linked with the dog major histocompatibility complex (m = 40, Z less than -2 at theta less than 4.8%). These results represent the mapping of a non-major histocompatibility complex narcolepsy gene and strongly suggest involvement of the immune system in the pathophysiology of that disease.
View details for Web of Science ID A1991FG91300106
View details for PubMedID 1673032
The purpose of this study was to evaluate the relative validity of responses to three different questions about snoring as indicators for sleep apnea in a population referred to a sleep clinic. Secondary goals were to evaluate the meaning of a "don't know" response to these questions and to examine how the associations between snoring and sleep apnea are influenced by demographics. Results from 1,409 patients in a sleep clinic indicated that nearly all levels of estimated snoring frequency were associated with a greater likelihood of sleep apnea. In addition, a "don't know" response indicated a likelihood of sleep apnea. In the sample from this clinic, sensitivities approximating 90 percent were obtained in men, and specificities approximating 90 percent were obtained in women, but high diagnostic accuracy (high specificity in men; high sensitivity in women) could not be achieved with the three snoring questions used here. Generally, associations between snoring and sleep apnea were independent of age and sex. Single persons, persons living alone, and persons customarily sleeping alone of both sexes all showed associations between self-reported snoring and the presence of sleep apnea.
View details for Web of Science ID A1991FA84800016
View details for PubMedID 1995215
We have recently established that canine narcolepsy (an autosomal recessive genetic model of the human disorder) is dramatically improved by treatment with alpha 2 antagonists such as yohimbine (Nishino et al: J Pharmacol Exp Ther 253:1145-1152, 1990). To further investigate the role of alpha 2 adrenoceptors in narcolepsy, receptors labeled with [3H] yohimbine were examined on platelets from human and canine narcoleptic subjects. Twenty-eight Doberman pinschers were studied, 7 controls (C), 7 heterozygous (Hz), and 14 narcoleptics (N) (age and sex matched), including eight animals born in a backcross setting (narcoleptic x heterozygous; 5 narcoleptics and 3 heterozygous). The Kd and Bmax of each group respectively, were as follows: C, Kd = 2.86 +/- 0.76 nmol/L, Bmax = 295.78 +/- 31.89 fmol/mg protein; Hz, Kd = 2.06 +/- 0.23 nmol/L, Bmax = 307.02 +/- 22.21 fmol/mg protein; and N, Kd = 2.72 +/- 0.45 nmol/L, Bmax = 267.52 +/- 19.47 fmol/mg protein. No statistical differences were found between groups using nonparametric (Kruskall-Wallis) statistical procedures, and there were no correlations between any binding parameter and symptom severity within the narcoleptic group. Platelet alpha 2 receptor affinity and density also did not differ between narcoleptic and heterozygous dogs in the backcross litter (N [n = 5], Kd = 1.94 +/- 0.59 nmol/L, Bmax = 290.6 +/- 64.7 fmol/mg protein; Hz [n = 3], Kd = 2.83 +/- 0.47 nmol/L, Bmax = 294.2 +/- 42.9 fmol/mg protein). Fourteen human subjects, seven control and seven narcoleptic patients (age and sex matched), were included in the study.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1991EZ69000008
View details for PubMedID 1645207
Long-term circadian studies of sleep and wakefulness in rodents have been hindered by the labor required to analyze long polygraph records. To expedite such studies, we have designed and implemented SCORE, a microcomputer-based real-time sleep scoring system for rodents. The electroencephalograph is digitized in 10-s epochs at 100 Hz. Frequency and amplitude information from the waveform are extracted into a 48-dimension vector that is then compared to previously taught vectors representing the canonical features of four arousal states: wakefulness, theta-dominated wakefulness, rapid eye movement (REM) sleep, and nonREM (NREM) sleep. Match values are assigned for each state to each epoch; after excluding states based on wheel-running or drinking activity data, the nonexcluded state with the best match value for the epoch is scored. Analysis of over 23,000 epochs for four mice yielded an overall agreement of 94.0% between two human scorers and the program, compared with a 94.5% agreement between the two human scorers. The SCORE algorithm matched the human concensus best for wakefulness (97.8%) and NREM sleep (94.7%), but was lower for REM sleep (75.2%) and theta-dominated wakefulness (83.3%). Most errors in scoring of REM sleep were in close temporal proximity to human-scored REM epochs. SCORE is capable of scoring arousal states for eight animals simultaneously in real time on a standard IBM PC equipped with a commercially available analog-to-digital conversion board, and should considerably facilitate the performance of long-term studies of sleep and wakefulness in the rodent.
View details for Web of Science ID A1991FE62100009
View details for PubMedID 1811319
Rats entrained to 12-h on /12-h off light schedule and injected with triazolam 0.4 mg/kg at the mid-point of their activity phase (6 h after lights out: circadian time = CT-18) had a stronger hypnotic response than animals free-running in constant dark injected at the equivalent circadian time. In contrast, entrained rats injected 5 h after lights on (CT-5) showed increased wake after injection relative to baseline, largely due to REM sleep inhibition. Hypnotic efficacy was found to be inversely related to prior accumulated sleep. During the 6 h before injection, entrained rats injected at CT-18 slept significantly less than the free-running rats, which in turn slept significantly less than entrained rats injected at CT-5. Taken together, the results suggest that the amount of prior sleep was a more important influence on the response to triazolam than either light/dark per se or circadian phase. Methodologically, automated sleep scoring was found to be an efficient method for examining drug effects, particularly when corroborated by concurrent independent physiological variables and spectral analysis.
View details for Web of Science ID A1991GJ52500012
View details for PubMedID 1798833
Alertness is a vital function, and medications that do not impair this vital function are clinically desirable in terms of safety. In a comparative study to measure daytime alertness objectively, 60 men and women in good health were assigned to receive either cetirizine, 5 mg, 10 mg, or 20 mg, hydroxyzine, 25 mg, or placebo in a randomized, double-blind, parallel-group design. Subjects slept in the laboratory for 2 consecutive nights to facilitate adaptation. During the second night, the subjects' sleep patterns were recorded by electroencephalogram (EEG), electrooculogram, and chin electromyogram. After the second night, subjects were awakened at 7:30 AM and given a single dose of the assigned treatment. Multiple Sleep Latency Tests (standardized 20-minute opportunities to fall asleep in bed while EEG and eye movements are recorded) were given every 2 hours. Subjects who received cetirizine did not differ from control subjects given placebo in any measure of daytime alertness. Subjects who received hydroxyzine were significantly more sedated than were control subjects given placebo for about 4 hours after treatment. The data from this study provide evidence that cetirizine does not differ from placebo with respect to alertness. The usefulness of the specific and sensitive standardized electroencephalogram, compared with alternative assessments of daytime alertness, is discussed.
View details for Web of Science ID A1990ER13100008
View details for PubMedID 2148177
It has been shown that endogenous prostaglandin D2 and prostaglandin E2 (PGE2) are involved in sleep-wake regulation. Our recent experimental result that exogenously administered PGE2 significantly reduces canine cataplexy (a pathological equivalent of rapid-eye-movement sleep atonia and a symptom of narcolepsy) suggests that PGE2 is involved in the pathophysiology of canine narcolepsy. In order to further investigate the role of prostaglandins (PGs) in this disorder, PG levels in cerebrospinal fluid (CSF) of genetically homozygous narcoleptic, heterozygous (unaffected), and control Doberman pinschers were studied. PGE2 levels were measured by direct radioimmunoassay (RIA) and after high-grade purification using PG affinity columns and high-performance liquid chromatography. PGD2 and PGF2 alpha levels were measured by RIA after high-grade purification. There was no significant difference in PGE2 levels between homozygous narcoleptic and heterozygous or controls dogs, and PGD2 and PGF2 alpha levels were undetectable in most cases. Our results do not favor the hypothesis that central PGE2 levels are modified in canine narcolepsy, assuming that PGE2 levels in cisternal CSF properly reflect PGE2 production in the brain.
View details for Web of Science ID A1990EJ24100006
View details for PubMedID 2268692
This cross-sectional study investigated predictors of sleep/wakefulness in residents in a skilled care nursing facility. Sleep/wakefulness was defined behaviorally by observations made four times an hour over four 12-hour observation periods. Predictors studied were mental status, functional capacity, relative likelihood of cardiovascular/respiratory, musculoskeletal, and endocrine disease, psychotropic medication intake, and presence of sleep apnea. Results based on 39 residents indicated that sleep apnea was a positive consistent predictor of observed sleep in the nursing home. Apnea generally was unrelated to other predictors. We discuss these findings in terms of the viability of this technique to study sleep as well as other potential predictors of sleep/wakefulness in elderly institutionalized patients.
View details for Web of Science ID A1990DN36900007
View details for PubMedID 2365964
Recent experiments have demonstrated that pharmacological activation of central noradrenergic systems by monoaminergic stimulators or uptake blockers or through the stimulation of alpha-1 adrenergic receptors improved cataplexy, a major symptom of narcolepsy. In order to further the understanding of the control of cataplexy by noradrenergic mechanisms, the involvement of central alpha-2 adrenoceptors was examined in genetically narcoleptic Doberman pinschers using in vivo pharmacology. Yohimbine (1.5-96.0 micrograms/kg i.v.) and seven other selective and centrally acting alpha-2 adrenoceptor antagonists (rauwolscine: 1.5-96 micrograms/kg i.v.; atipemazole: 1.5-96 micrograms/kg i.v.; Wy-25309: 1.5-386 micrograms/kg i.v.; CGS-7525A: 1.5-386 micrograms/kg i.v.; idazoxan, 6-1536 micrograms/kg i.v.; piperoxan, 6-1536 micrograms/kg i.v.; and mianserin, 6-1536 micrograms/kg i.v.) significantly suppressed cataplexy. The alpha-2 mediation of this effect was demonstrated by a close correlation between drug affinities (Ki) toward the alpha-2 site (defined using [3H]yohimbine in canine cortex) and the ability of these drugs to reduce cataplexy [ED50 in nanomoles per kilogram i.v.) (r2 = 0.71, n = 8, P less than .01). The effects of six centrally acting alpha-2 agonists on canine cataplexy were also examined and two groups of compounds were distinguished on the basis of their pharmacological profile. Classical alpha-2 agonists such as clonidine (0.0625-4.0 micrograms/kg i.v.), p-aminoclonidine (0.0625-4.0 micrograms/kg i.v.) and guanfacine (0.0625-4.0 micrograms/kg i.v.) had no effect on cataplexy whereas BHT-920 (0.01875-3.0 micrograms/kg i.v.), BHT-933 (16.0-258 micrograms/kg i.v.) and xylazine (16.0-258 micrograms/kg i.v.) dramatically aggravated cataplexy.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1990DK70200035
View details for PubMedID 1972749
Sleep patterns of aged, infirm, demented, chronically institutionalized residents of a skilled-care nursing facility were studied. The purpose of this naturalistic study was to describe sleep and wakefulness (S/W) within the limits afforded by brief behavioral observations and to examine homeostasis and diurnal rhythmicity of S/W as a function of psychoactive drug intake. Observers noted S/W every 15 min, 24 hr a day for 10 days in 24 Ss. Results indicated substantial individual variation in daytime hours. Daily and weekly variation within Ss was minimal. Sleep was least likely near sunset. Ss on psychoactive drugs showed dampened diurnal variation in S/W rhythms. In Ss not on such drugs, there was a suggestion of homeostasis of S/W between sleep during the morning and evening hours. Results are discussed methodologically (viability of approach), theoretically (age-related change in sleep), and practically (potential treatments).
View details for Web of Science ID A1990CR69600003
View details for PubMedID 2317297
The heterogeneity of neural gene expression and the spatially limited expression of many low-abundance messenger RNAs in the brain has made cloning and analysis of such messages difficult. To generate amounts of nucleic acids sufficient for use in standard cloning strategies, we have devised a method for producing amplified heterogeneous populations of RNA from limited quantities of cDNA. Whole cerebellar RNA was primed with a synthetic oligonucleotide containing the T7 RNA polymerase promoter sequence 5' to a polythymidylate region. After second-strand cDNA synthesis, T7 RNA polymerase was used to generate amplified antisense RNA (aRNA). Up to 80-fold molar amplification has been achieved from nanogram quantities of cDNA. The amplified material is similar in size distribution to the parent cDNA and shows sequence heterogeneity as assessed by Southern and Northern blot analysis. Specific messages for moderate-abundance mRNAs for actin and guanine nucleotide-binding protein (G-protein) alpha subunits have been detected in the amplified material. By using in situ transcription to generate cDNA, sequences for cyclophilin have been detected in aRNA derived from single cerebellar tissue sections. cDNA derived from a single cerebellar Purkinje cell also has been amplified and yields material that hybridizes to cognate whole RNA and mRNA but not to Escherichia coli RNA.
View details for Web of Science ID A1990CR82000008
View details for PubMedID 1689846
In two separate studies a significantly greater concentration of DA (dopamine) and its metabolite, DOPAC (3,4-dihydroxyphenylacetic acid), was observed in the amygdala of narcoleptic canines. DOPAC was also significantly elevated in the reticularis parvicellularis, whereas NE (norepinephrine) was significantly elevated in the reticularis oralis, but depressed in the preoptic hypothalamus. No changes were observed in concentrations of serotonin or its metabolite, 5-HIAA (5-hydroxyindoleauric acid) in any region in the narcoleptic canine brain. Results of the two studies were similar, except that previously observed differences between narcoleptic and control canines in DOPAC levels in the caudate and reticularis oralis failed to replicate. Thus, steady state measures of neurotransmitter/metabolite tissue concentrations suggest region-specific alterations in DA and NE metabolism, rather than a global deficit in catecholamine neurotransmission in canine narcolepsy.
View details for Web of Science ID A1990CP93100028
View details for PubMedID 1689603
View details for Web of Science ID A1990CJ50400004
View details for PubMedID 2406283
alpha 2-Receptors in the canine brain were pharmacologically characterized using [3H]yohimbine binding. Competition studies revealed a single class of binding sites in frontal cortex but two distinct subtypes in nucleus caudatus. The role of central alpha 2-receptors in narcolepsy was investigated in 5 normal and 5 narcoleptic Doberman pinschers. Scatchard analysis of [3H]yohimbine binding in different brain areas revealed an increase in the number of alpha 2-binding sites limited to the locus coeruleus. This suggests that altered autoinhibition of norepinephrine release may be associated with the narcoleptic symptomatology.
View details for Web of Science ID A1989AX91400023
View details for PubMedID 2557958
Periodic leg movements during sleep (PLMs) are non-epileptiform, repetitive limb movements that are highly prevalent among the geriatric population. The mechanisms underlying these movements are poorly understood. In this study we evaluated PLMs of 24 aged volunteers. We hypothesized that the high prevalence of PLMs seen in the aged would be related to (a) lower creatinine clearance and (b) slowed velocities/delayed latencies in the nerve conduction studies of such individuals. Results did not support hypothesis (a) but offered some equivocal support for hypothesis (b), inasmuch as aged subjects with higher levels of PLMs had delayed motor and sensory latencies in the upper limbs (median n., ulnar n.). Results are discussed in terms of central vs peripheral mechanisms involved in the generation of PLMs in elderly persons.
View details for Web of Science ID A1989AQ26300004
View details for PubMedID 2768770
Disturbances of the sleep/wake cycle occur frequently in nursing home residents. Because of the many technical difficulties in studying sleep and rhythms in such patients, systematic behavioral observations offer an alternative approach. In this study we describe a method for determining interrater reliability of such observations. Two individuals observed 39 nursing home residents four times per hour during daytime and nighttime hours. Results indicated high interrater reliability for both sleep/wake and the presence of apnea during sleep. Both day and night observations were made reliably. We found only 101 discrepancies of 1.160 tandem observations. These results suggests that behavioral observations are a viable approach in the study of the sleep/wake cycle in nursing home settings.
View details for Web of Science ID A1989AG53000008
View details for PubMedID 2762690
Mental deterioration accompanying sleep apnea has been noted frequently. Because sleep apnea increases with age, such deficits raise the possibility that dementia in the elderly could be related to sleep apnea. In this study we investigated this possibility cross-sectionally by comparing respiration during sleep in 28 patients with Alzheimer's disease (AD) and 25 nondemented controls. We hypothesized that higher levels of sleep apnea would be present in AD patients. Our results indicated no significant differences between AD patients and controls but those few AD patients who desaturated during sleep experienced morning confusion. The findings imply that AD and sleep apnea are two separate conditions which may still interact in the aged.
View details for Web of Science ID A1989AK79000008
View details for PubMedID 2812195
The present study suggests the specific involvement within the central nervous system of an alpha 1 adrenoceptor subtype in a behavior, the control of cataplexy, a pathological analogue of rapid eye movement (REM) sleep atonia. Experiments have shown that prazosin, an alpha 1 antagonist, dramatically aggravates canine narcolepsy-cataplexy through a central mechanism, and that [3H]prazosin binding sites are increased in the amygdala of narcoleptic dogs. However, the corresponding Scatchard plots were curvilinear and best fit was obtained with a two-site model, suggesting the existence of two [3H]prazosin binding sites. These two sites (high and low affinity [3H]prazosin binding sites) met the criteria for authentic receptors and were respectively very similar to the alpha 1a and alpha 1b (high and low affinity for WB4101, respectively) subtypes recently described in the rat and rabbit. Our results of in vivo pharmacology and in vitro [3H]prazosin binding in canine narcolepsy now clearly implicate the low affinity [3H]prazosin binding site (alpha 1b) in canine narcolepsy: (1) Prazosin, an alpha 1 antagonist with similar affinity for both subtypes, was much more potent in increasing cataplexy than WB4101, a compound with more affinity for the alpha 1a receptor. (2) Chlorethylclonidine and phenoxybenzamine, two irreversible blockers of the alpha 1 receptors with more affinity for the alpha 1b receptors, aggravate cataplexy for up to two weeks. (3) The alpha 1 receptor upregulation previously reported by our group in the amygdala of narcoleptic dogs was due to a selective increase in the low affinity [3H]prazosin binding sites. A role for noradrenaline in REM sleep regulation has been suspected for many years, but has never been clearly elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1989AC86100027
View details for PubMedID 2569353
Human narcolepsy is almost exclusively associated with the major histocompatibility complex (MHC) class II antigen HLA-DR2 and is the strongest HLA-disease association described to date. Canine narcolepsy resembles the human disease in its behavioral manifestations and responses to therapeutic drugs. Therefore, mixed leukocyte culture (MLC) was used to study differences in the canine MHC class II (DLA-D) antigens present in narcoleptic dogs to determine whether an analogous, unique DLA-D antigen could be identified in canine narcolepsy. Results show at least five different DLA-D antigens appear in potential narcoleptic haplotypes among the 29 dogs studied. The data demonstrate that, unlike man, in dogs there is no unique D locus antigen associated with narcolepsy and further suggest that linkage disequilibrium with a specific MHC antigen is unlikely to be essential for the manifestation of canine narcolepsy. Because human narcolepsy is thought to be multigenic, the canine narcolepsy-MHC dissociation suggests that the dog model may help elucidate the non-MHC narcolepsy gene(s).
View details for Web of Science ID A1989U131500003
View details for PubMedID 2523880
Two classes of alpha 1 adrenoceptors were identified in canine brain and liver using conventional radioligand binding methods. Scatchard plots of specific [3H]prazosin binding to brain and liver membranes prepared from 100-150-day-old Doberman pinscher dogs were consistently curvilinear and best fit a two-site binding model (frontal cortex, Kd1 = 57.7 +/- 10.0 pM, Bmax1 = 64.6 +/- 17.1 fmol/mg protein, Kd2 = 1.5 +/- 0.5 nM, Bmax2 = 159 +/- 37.6 fmol/mg protein; liver, Kd1 = 82.6 +/- 36 pM, Bmax1 = 7.0 +/- 5.1 fmol/mg protein, Kd2 = 0.8 +/- 0.2 nM, Bmax2 = 62.1 +/- 8.7 fmol/mg protein). Kinetically derived affinity constants from association and dissociation experiments agreed with those obtained by Scatchard analyses of equilibrium binding data. Binding sites were saturable, heat labile, bound ligand reversibly, and appeared to be appropriately distributed in relation to endogenous catecholamine. [3H]Prazosin also bound with high affinity to two classes of binding site in porcine and bovine brain membrane but [3H]prazosin binding in monkey and rat brain was best described by a single-site binding model. Affinities obtained were in between values obtained for high and low affinity Kds in the other species. Competitions for [3H]prazosin binding sites in canine frontal cortex were conducted with the following antagonists: WB-4101, corynanthine, phentolamine, benoxathian, phenoxybenzamine, chlorethylclonidine, thymoxamine, prazosin, yohimbine and agonists: methoxamine, (-)-norepinephrine, and clonidine. All ligands but prazosin, norepinephrine and clonidine competed for specific [3H]prazosin binding in a statistically significant biphasic manner. Benoxathian and WB-4101 displayed the highest affinities (benoxathian: Ki1 = 0.26 nM, WB-4101: Ki1 = 0.20 nM) and selectivity (high affinity/low affinity: benoxathian = 1640, WB-4101 = 13204) for the high affinity [3H]prazosin binding site; chlorethylclonidine had highest affinity (Ki2 = 91 nM) and selectivity (low affinity/high affinity = 405) for the lower affinity [3H]prazosin binding site. As defined, the two sites were similar to the alpha 1a and alpha 1b recently described in the rat and rabbit. A noticeable difference was that the subtypes described in dog brain had a 30-fold difference in affinity for prazosin.
View details for Web of Science ID A1989U375200007
View details for PubMedID 2541871
The effects of intravenous administration of prostaglandins (PGs) were investigated in genetically narcoleptic Doberman pinschers. The treatment of narcoleptic dogs with PGE2 and PGE2 methyl ester, but not PGD2 and PGD2 methyl ester, induced a dose-dependent reduction of canine cataplexy, a dissociated manifestation of rapid-eye-movement sleep. The effect was specific and not associated with any change in other behavior. Furthermore, the effect was long-lasting (up to 2 hr) and could not be explained by the acute cardiovascular changes seen after intravenous PG administration. PGE2 methyl ester, a lipophilic derivative of PGE2 with more central penetration than PGE2, was 4 times more potent than PGE2. These results indicate that PGE2 modifies cataplexy through a central effect and suggest that this prostaglandin may play a role in rapid-eye-movement sleep regulation.
View details for Web of Science ID A1989U042300075
View details for PubMedID 2928344
Latency to the first episode of rapid eye movement sleep (REML) has been proposed as a potential biomarker for Alzheimer's disease (AD). In this study, we compared REML values from 28 AD patients and 28 age- and sex-matched controls. We employed multiple definitions of REML and multiple cutoffs to classify patients and controls. Results indicated that the best REML definition and optimal cutoff criterion resulted in only 65% correct classifications. We discuss the longer REML in AD patients relative to controls in terms of both overall sleep disturbance and selective deterioration of the REM-cholinergic system. As REML may be relatively short in other forms of psychopathology (e.g., affective disorders), REML may still hold promise in the differential diagnosis of dementia and pseudodementia.
View details for Web of Science ID A1989R741100008
View details for PubMedID 2914155
View details for Web of Science ID A1989R871700010
View details for PubMedID 2563354
This study investigated night-to-night variation in periodic leg movements in sleep (PLMS). PLMS are common in the elderly, but their mechanism and significance are not understood. Forty-five aged individuals (means = 69.7 years) were studied polysomnographically for 2 or 3 nights with surface electrodes placed above the anterior tibialis. Results indicated that PLMS varied considerably from night to night within individuals, though there was not a significant difference between nights for the entire group. Some evidence indicated that individuals with less severe sleep complaints showed greater nightly variation. The nightly variation in PLMS was over four times as large as the nightly variation in breathing disturbance in sleep, another condition common in the sleep of the aged. These data suggest that studies relating PLMS to other key variables (e.g. symptoms of disturbed sleep) should rely on multiple nights of data or, if single night data are used, be particularly careful to replicate findings across samples.
View details for Web of Science ID A1988R425700004
View details for PubMedID 3228331
The role of central alpha-1 adrenergic receptors in cataplexy was investigated in genetically narcoleptic Doberman pinschers. Treatment of narcoleptic dogs with 25-600 micrograms/kg prazosin, a selective alpha-1 adrenergic receptor blocker, exacerbated cataplexy, whereas treatment with the alpha-1 agonist, methoxamine, ameliorated it. Subsequent studies showed that the beneficial effects of classical treatments of human narcolepsy (amphetamines and tricyclic antidepressants) are antagonized by prazosin, suggesting that these drugs are active through an indirect alpha-1 stimulation (via an increase of norepinephrine in the synaptic cleft). Other studies confirmed that the observed effects were not due to peripheral alpha-1 cardiovascular involvement. Atropine, a central anticholinergic agent, but not methylatropine, a peripheral one, completely suppressed the prazosin effect, which suggests that adrenergic and cholinergic systems act sequentially and not independently to generate cataplexy. Little is known about the physiological role of central alpha-1 adrenoceptors. This series of experiments implicates these receptors in narcolepsy-cataplexy.
View details for Web of Science ID A1988Q160600022
View details for PubMedID 2843574
This double-blind, placebo-controlled study investigated rebound anxiety during and after 5 weeks of nightly use of triazolam 0.5 mg, a short half-life, rapidly absorbed benzodiazepine hypnotic. The study subjects were chronic insomniacs with moderate levels of psychopathology and prior use of hypnotics. Anxiety was assessed with the Profile of Mood States (POMS), instead of the anxiety scales more typically used in psychopharmacology: the Hamilton Rating Scale for Anxiety and a visual analogue scale. The POMS test was administered twice a day during the study. The results indicated that triazolam was not associated with increased anxiety the morning or the evening after previous-night drug administration. The results are discussed in view of the methodological issues in assessing anxiety in prior studies.
View details for Web of Science ID A1988Q239100004
View details for PubMedID 3047100
Sleep characteristics were compared in young adult and aged cats over a range of environmental temperatures from 5 to 35 degrees C. Although both groups exhibited sleep disruptions as ambient temperatures decreased, transient arousals were increased at temperature extremes in the aged group compared to young adults. Declining efficiency of thermoregulatory control and increased sensitivity to environmental temperature in the elderly may contribute to the changes in sleep quality which occur during the aging process.
View details for Web of Science ID A1988P672600027
View details for PubMedID 3167566
To investigate determinants of daytime sleepiness in obstructive sleep apnea syndrome (OSAS), we studied 100 unselected OSAS patients by nocturnal polygraphic recording and the Multiple Sleep Latency Test (MSLT). Data obtained were submitted to three types of analysis. Respiratory disturbance index, oxygen saturation indices, body mass index, and total nocturnal sleep time did not significantly correlate with daytime sleepiness, as measured by the MSLT. Analysis of subgroups based on weight and degree of alertness also showed a nonsignificant correlation with daytime sleepiness. The best predictor of the excessive daytime sleepiness (EDS) frequently found in OSAS patients was the nocturnal polygraphic recording of the sleep disturbances and sleep structure anomalies that reflect the brain's overall dysfunction in OSAS. Understanding why an electroencephalogram arousal response occurs during sleep in association with abnormal breathing and how this response can become blunted may help us to better predict the development of EDS.
View details for Web of Science ID A1988P190000009
View details for PubMedID 3383654
Brains from breed and age-matched canines stored at -80 degrees C for between 3 and 44 months showed a time-dependent decline in the concentration of norepinephrine in the amygdala and dopamine and norepinephrine in the caudate. No changes were seen in the density or ligand affinities of prazosin or spiperone binding sites in the same areas nor were there changes in quinuclidinyl benzylate binding sites in the frontal cortex. The changes in dopamine concentrations in the caudate were not accompanied by changes in the concentrations of dopamine metabolites. The chromatograms from which the dopamine and norepinephrine concentrations were estimated contained several unidentified, amperometrically detectable, extraneous peaks which increased in size in the older tissue samples. These results suggest that the decline in dopamine and norepinephrine concentrations was not the result of enzymatic breakdown, but probably the result of chemical decomposition. These findings have significance for the measurement of dopamine and norepinephrine concentrations in autopsied brains kept frozen in storage.
View details for Web of Science ID A1988N627300024
View details for PubMedID 2841003
In the aged, sleep may be a vulnerable period for death from cardiovascular causes. Because of its high prevalence in the elderly, sleep apnea has been suggested to be one mechanism contributing to such sleep-related mortality. In this study, a cohort of 198 non-institutionalized elderly individuals (mean age at entry = 66) were followed for periods up to 12 years after initial polysomnography. The mortality ratio for sleep apnea (defined as a Respiratory Disturbance Index of over 10 events per sleep hour) was estimated to be 2.7 (95% CI = .95, 7.47). Multiple regression with the Cox proportional hazards model suggested that cardiovascular death was most clearly associated with age in this cohort. These results raise the possibility that "natural" death during sleep in the elderly may be associated with specific pathophysiological events during sleep.
View details for Web of Science ID A1988P186100012
View details for PubMedID 3354738
The role of central alpha 1-adrenergic receptors in cataplexy was investigated in 4 narcoleptic poodles and 6 genetically narcoleptic Doberman pinschers. Treatment of narcoleptic dogs with prazosin, a selective alpha 1-adrenergic receptor blocker, exacerbated cataplexy in both narcoleptic dog breeds. Control and heterozygous Dobermans were not affected by the drug. Binding studies using [3H]prazosin revealed an increase in alpha 1-receptor binding apparently limited to the amygdala. The present study suggests that central alpha 1-adrenoceptors, whose role is still mostly unknown, play a fundamental role in controlling mechanisms involved in cataplexy and REM sleep.
View details for Web of Science ID A1988M418200022
View details for PubMedID 2834022
Sleep/wake expression in mice varies predictably with circadian phase. Such circadian rhythms are known to depend on intact suprachiasmatic nuclei (SCN) in the hypothalamus, but the mechanism by which SCN activity modulates sleep/wake expression is unknown. This paper examines the possibility that circadian patterns of sleep/wake derive partly from circadian timing of waking behaviors that are incompatible with sleep, such as locomotor activity. Voluntary locomotor activity was restricted in five mice adapted to a running wheel by locking the wheel in place. Continuous electrographic monitoring of sleep and wakefulness over multiple circadian cycles revealed: (1) during the active phase, shorter wake bouts and more frequent bouts of sleep, resulting in greater sleep/wake fragmentation and more time spent asleep; (2) during the rest phase, a small compensatory reduction in NREM sleep; (3) reduced amplitude of circadian sleep/wake rhythms and a greater amount of sleep overall. Thus, voluntary locomotor activity has an important influence on sleep/wake expression in mice, and the normal circadian pattern of sleep/wake depends on circadian timing of activity. Previous reports of damped circadian sleep/wake rhythms in rodents may therefore be explained by coincident diminutions in locomotor activity associated with age or health status. Our results also support analogous findings in human subjects, and we propose that elderly humans may benefit from therapies that augment daytime activity.
View details for Web of Science ID A1988Q210300012
View details for PubMedID 3237790
Sixty healthy men and women with no sleep complaints, 21 to 45 years of age (mean age 28), were randomly assigned to one of five parallel groups that received one of the following: cetirizine 5 mg (n = 13), 10 mg (n = 13), or 20 mg (n = 11); hydroxyzine 25 mg (n = 12); or placebo (n = 11). After one adaptation night in the lab, the subjects' sleep patterns were recorded from 2300 to 0730 hours. Subjects were in bed during this period. When they awoke at 0730, a test agent was administered according to double-blind technique. Multiple Sleep Latency Tests (MSLT: 20-minute opportunities to fall asleep in bed while EEG and eye movements are recorded) were given at two-hour intervals throughout the day, and a 30-minute vigilance performance test was given at 1000 and 1600 hours. Subjects receiving cetirizine in doses of 5 to 20 mg did not differ from placebo controls in any objective or subjective measure of daytime alertness. Subjects receiving hydroxyzine were significantly more sedated and showed slower reaction times than the placebo control group for at least four hours after treatment. Self-rated feelings of sleepiness, impairment, and fatigue did not differ significantly between groups. This suggests that hydroxyzine subjects may not have been aware of their sleepiness and slower reaction times.
View details for Web of Science ID A1987L492900012
View details for PubMedID 2892452
View details for Web of Science ID A1987J662300010
View details for PubMedID 3659737
Seventeen white patients from the Stanford Sleep Disorders Clinic complaining of excessive daytime somnolence (EDS) were selected for restriction-fragment-length polymorphism (RFLP) studies. Fourteen of the patients with clinically diagnosed narcolepsy were seropositive for DR2. RFLP analysis of these patients compared with a homozygous DR2-Dw2 cell line failed to reveal any polymorphism when digested with six restriction endonucleases and hybridized with three different cDNA probes. None of the three patients with central nervous system hypersomnia, a syndrome similar to narcolepsy, were DR2-positive. We conclude that any polymorphism of the DR beta, DQ alpha, or DQ beta genes of DR2 narcoleptics that might distinguish them from DR2 normals cannot be resolved through RFLP analysis.
View details for Web of Science ID A1987K676800031
View details for PubMedID 2890770