Wesley F. Seidel

Sleep homeostasis in suprachiasmatic nuclei-lesioned rats: effects of sleep deprivation and triazolam administration.

The electroencephalogram (EEG) and electromyogram of rats with lesions in the suprachiasmatic nuclei (SCNx) were recorded during two series of 24-h baseline, 6-h sleep deprivation (SD), and 24-h recovery. At recovery onset, rats were injected i.p. with vehicle (VEH) control solution or 0.4 mg/kg triazolam (TRZ) in a balanced crossover design. Consecutive 10-s epochs were scored for vigilance states and EEG power spectra were computed. Arousal states were uniformly distributed during 24-h baseline (wake 47% of recording time, non-rapid-eye movement sleep (nonREMS) 47%, REMS 7%), and EEG spectra (0-25 Hz) were devoid of significant trends. State-specific EEG power spectra profiles in SCNx rats were similar to those of intact animals reported previously. However, EEG delta power (0.5-3.5 Hz) of nonREMS was markedly lower in SCNx rats. Recovery from 6-h SD was characterised by a short-lasting reduction of REMS, and a long-lasting increase of nonREMS time at the cost of wakefulness. EEG delta power rebounded during the first 8 h in recovery, and fell below baseline level after 12 h in recovery. During 0-2 h TRZ recovery, rats spent more time in nonREMS with higher EEG slow wave activity as compared to the corresponding VEH recovery period. EEG slow wave activity fell below baseline levels 10 h after TRZ injection and termination of SD. We conclude that major features of homeostatic sleep EEG regulation are present in SCNx rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study

We studied sleep and daytime function in insomniac patients who took either flurazepam, 30 mg, triazolam, 0.5 mg, or placebo 30 minutes before bedtime. Subjects were 21 patients with either a primary or a secondary diagnosis of chronic psychophysiological insomnia or insomnia associated with personality disorder. Seven subjects were randomly assigned to each condition. The study used a three group by 9 week, double-blind design with three nocturnal sleep recordings each week. During week 1, subjects took no capsules; week 2, subjects took placebo; weeks 3 to 7, flurazepam, triazolam, or placebo; weeks 8 and 9, placebo. Daytime tests for alertness and performance were administered during weeks 1, 3, 5, 7, and 8. Flurazepam showed hypnotic efficacy for weeks 3 to 5. Triazolam showed hypnotic activity for weeks 3 to 7. Although not significant overall, discontinuation of flurazepam produced rebound insomnia in six of seven subjects sometime during the two withdrawal weeks. The relationship between plasma concentration of desalkylflurazepam, the principal active metabolite of flurazepam, and sleep disturbance suggested that the onset of the rebound insomnia depended on the rate of drug washout. Discontinuation of triazolam produced a significant rebound insomnia on the first and second nights of drug withdrawal. Placebo subjects showed improved sleep throughout weeks 2 to 9 of the study. Daytime testing revealed significantly decreased daytime alertness and decreased performance for flurazepam subjects during weeks 3 to 7, although these effects reverted toward baseline despite continued drug administration.

Risk Factors for Sleep Disordered Breathing in Heterogeneous Geriatric Populations

This cross‐sectional, multivariate study investigated associations between sleep disordered breathing (SDB) and putative risk factors in a heterogeneous group of 720 individuals over the age of 50 years studied during all‐night in‐lab polysomnography. Results indicated that: 1) aged men were more likely to show impaired respiration during sleep than aged women; 2) excessive daytime somnolence and parasomniac symptoms (snoring, gasping during sleep) were associated with SDB but insomnia was not; 3) obesity accounted for more variance in SDB than age per se, implying that the prevalence of SDB in some elderly persons could be related to the deposition of body fat seen as individuals grow older. All four risk factors (age, sex, obesity, and symptomatic status) were statistically significant and independent predictors of impaired respiration in sleep in the elderly.

N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a Novel Metabotropic Glutamate 2 Potentiator with Potential Anxiolytic/Antidepressant Properties: In Vivo Profiling Suggests a Link between Behavioral and Central Nervous System Neurochemical Changes

The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC50 = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.

Buspirone: an anxiolytic without sedative effect.

Twelve volunteers with a complaint of chronic insomnia participated in a placebo-controlled, doubleblind, crossover study of the effects of buspirone t.i.d. on sleep pattern and daytime function. The drug was tested alone and in combination with flurazepam or triazolam. Buspirone alone did not impair objective measures of daytime wakefulness or performance. Impaired alertness was seen the day after bedtime administration of flurazepam but not after triazolam; buspirone did not alter these effects. Buspirone did not affect the Multiple Sleep Latency Test, a sensitive measure of changes in daytime alertness.

Sleep spindle and delta changes during chronic use of a short-acting and a long-acting benzodiazepine hypnotic

Twenty-one medically screened insomniacs were studied over 59 nights in a double-blind, parallel groups design study. The 7 patients receiving a short-acting (triazolam) and the 7 receiving a long-acting (flurazepam) benzodiazepine hypnotic showed a similar pattern and magnitude of sleep EEG changes, especially during the latter part of the 37-night treatment period. Both groups significantly increased sleep spindle rate and decreased delta count per minute. The patterns of withdrawal were also similar. Plasma levels of N-desalkylflurazepam were not significantly related to the magnitude of EEG changes.

Periodic leg movements during sleep in the elderly

Periodic leg movements in sleep (PLMS) occur frequently in the sleep of elderly persons but their significance is unknown. In this study, 63 elderly persons with symptoms of insomnia but without history of renal disease were evaluated polysomnographically. All received laboratory evaluations for blood urea nitrogen (BUN) and creatinine and completed a questionnaire on sleep complaints. Results indicated a positive relationship between PLMS and urea nitrogen in elderly women. In addition, symptoms of leg twitching and prolonged sleep latency could distinguish arbitrarily formed high and low PLMS groups. These results suggest that PLMS could be a window on the age-related decline in renal function and that these movements are related to several highly specific symptoms of geriatric insomnia.

Triazolam-induced sleep in the rat : influence of prior sleep, circadian time, and light/dark cycles

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.

MSLT-defined sleepiness and neuropsychological test performance do not correlate in the elderly

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.

Issues in the Diagnosis and Treatment of Insomnia

Most people attribute a restorative function to sleep. This is because experimental or clinical sleep disturbance is usually followed by annoying symptoms of fatigue and sleepiness the following day. Can these daytime changes be documented objectively? In the past several years, the Multiple Sleep Latency Test (MSLT) has been developed and validated as an objective quantitative measure of sleepiness. Multiple assessments of sleep latency yield a profile of sleepiness across the day. This profile changes in the predicted direction with acute total and partial sleep deprivation, chronic sleep deprivation, sleep satiation, and in comparisons between hypersomnia patients and controls. Sleep and wakefulness are complementary phases in the daily cycle of human existence. Adequacy of sleep and energetic wakefulness next day are interacting phases in this cycle. Insomnia can be seen as a perception of disturbed sleep with daytime consequences, but is essentially also a symptom. This paper reviews a number of issues in the diagnosis and treatment of insomnia. The dimensions, daytime consequences and longitudinal aspects of insomnia are considered. Most investigations to date have been geared towards the problem of chronic insomnia and yet we are all likely to suffer from transient insomnia at some point. Psychiatric and psychophysiological disorders have been shown to be the most frequent causes of disorders of initiating and maintaining sleep. Moreover, there is an apparent disparity between subjective and objective sleep parameters with, for example, objectively disturbed sleep in noncomplaining subjects. The criteria of hypnotic efficacy and the effects of triazolam and flurazepam on sleep and daytime alertness have been investigated in normals, chronic insomniacs and the elderly. In general, chronic insomniacs showed all degrees of daytime alertness regardless of nocturnal sleep parameters. About one-third could be classified as fully alert all day long in spite of their complaints. The effect of flurazepam and triazolam on sleep (improvement) was essentially the same. Daytime effects were most closely related to half-life. The long-acting benzodiazepine, flurazepam, impaired daytime alertness although nocturnal sleep was improved. Triazolam improved not only nighttime sleep but also daytime alertness.