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Biomedical subjects

W B Mendelson

Publications and source records attributed to W B Mendelson.

At least 91 records · Page 5Linked to original sources

Enhancement of sleep by microinjection of triazolam into the medial preoptic area.

A growing literature suggests that the basal forebrain may contain structures involved in the regulation of sleep. As part of a series of studies designed to locate the site(s) of hypnotic action of benzodiazepines, we have injected triazolam into the medial preoptic area (MPA) of the hypothalamus of rats. Total sleep time was increased, due primarily to an increase in non-rapid eye movement (non-REM) sleep and a trend toward a decrease in intermittent waking time. A previous study from this laboratory reported that injections into the raphe nucleus decreased sleep, whereas injections at adjacent sites were without effect. These studies indicate the selectivity with which different brain regions respond to triazolam in terms of actions on sleep.

Animals↗

Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy?

High affinity recognition sites for benzodiazepines are part of the gamma-aminobutyric acid (GABA) supramolecular complex on the plasma membrane of neurons in the mammalian brain. Synthetic agonist benzodiazepines promote GABA-ergic neurotransmission, and hence the hypnotic and anxiolytic effects of this class of drugs, by binding to these sites. A normal physiological role for these binding sites is unknown, and an endogenous ligand for benzodiazepine receptors has not been definitely identified in normal animals. In animals and human beings with hepatic encephalopathy, however, benzodiazepine receptor antagonists have induced amelioration of the encephalopathy, and an endogenous substance that competitively binds to benzodiazepine receptors has been found in cerebrospinal fluid. These findings suggest that an endogenous ligand for the benzodiazepine receptor with agonist properties contributes to hepatic encephalopathy by promoting GABA-ergic neurotransmission.

Benzodiazepines↗

Effects of flurazepam on sleep, arousal threshold, and the perception of being asleep.

This study examined the effects of flurazepam on arousal threshold and on quality of sleep during nights in which arousal threshold studies were performed. Ten patients with subjective insomnia received 30 mg flurazepam or placebo on nights in which arousal thresholds in response to electronic tones or a recording of the subjects' names were determined. Arousal thresholds differed across waking and sleep stages, but there was less difference in response to the subjects' names than to electronic tones. Flurazepam raised arousal thresholds to both stimuli, but did not selectively influence response in any individual sleep stage. Flurazepam did not alter subjects' estimates of elapsed time or duration of sleep between tests.

Adult↗

Periodic cessation of respiratory effort during sleep in adult rats.

Using a noninvasive technique which measures respiration as a function of chest and abdominal movement, it was found that adults rats have periodic cessations of respiratory effort during the daytime. In a preliminary study, male Fischer-344 rats had respiratory pauses of 2.4-2.6 seconds duration, which tended to be more frequent in older (22-month) compared to young adult (3-month) rats. Respiratory rate was lower and respiratory volume greater in the 22-month-old animals. In a more detailed study of 3-month-old male Sprague-Dawley rats, respiratory pauses were divided into two types: those preceded by a large inspiration ("sighs") and those which were not. The latter, which appear to be most analogous to human apneas of clinical interest, occurred in all animals studied, with a frequency of 13 to 26 events during six hour recordings. These pauses varied in duration from 2.0 to 6.1 seconds and were most frequent and longest in REM sleep.

Aging↗

Sleep induction by an adrenal steroid in the rat.

The ring A reduced metabolites of deoxycorticosterone and progesterone, 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) and 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-DHP) have been shown to be potent barbiturate-like ligands of the benzodiazepine receptor complex. The former has also been reported to have anxiolytic effects in mice and rats. In the present study, sleep recordings were obtained on rats given 5 and 10 mg/kg of these steroids alone and in combination with flurazepam. THDOC, but not 3 alpha-OH-DHP, had potent dose-dependent sleep-inducing properties and increased nonREM sleep. Flurazepam had similar hypnotic effects and also reduced REM sleep. There were no significant interactions between THDOC and flurazepam, except in the case of REM latency, which tended to increase when the two compounds were given together. In summary, THDOC, a mineralocorticoid metabolite found in brain, has sedative properties and could conceivably play a role in stress responses.

Animals↗

Sleep and benzodiazepine receptor sub-types.

CL 218,872, which preferentially binds to benzodiazepine (BZ) type 1 receptors, and flurazepam, which is thought to bind to both types 1 and 2, were given alone and in combination to rats. CL 218,872 had little effect on sleep latency, but significantly increased total sleep time. As expected, flurazepam both shortened sleep latency and prolonged total sleep. Pretreatment with CL 218,872 had no effect on these alterations in sleep induced by flurazepam. The implications for possible significance of sub-typing of BZ receptors are discussed.

Animals↗

Frequency analysis of the sleep EEG in depression.

Eight patients with major depressive disorder (seven bipolar and one unipolar) and matched controls had sleep studies, on which frequency analysis of the electroencephalogram (EEG) was performed. Total sleep and sleep efficiency were decreased in the patients, but there was no significant difference in rapid eye movement (REM) latency between the two groups. Frequency analysis revealed no group differences in power in the delta band (0.23-2.5 Hz) or the whole EEG spectrum (0.23-25 Hz). These findings suggest that mean REM latencies are not always shorter in major depression. The results are discussed in light of a previous report of decreased delta energy in the sleep EEG of unipolar patients.

Adult↗

The effect of melatonin on normal sleep.

We examined the effect of 1-mg and 5-mg oral dosages of melatonin on the electroencephalogram-recorded sleep of ten normal subjects in a randomized, double-blind design. Although high dosages of melatonin have previously been reported to be a sedative and to have behavioral effects, we could not find any change in onset or duration of sleep, or any effect on mood or alertness the following day using these low dosages. An increase in rapid eye movement (REM) latency was noted at the 5-mg dose, but no other parameter of REM sleep was changed.

Adult↗

Arousal induced by injection of triazolam into the dorsal raphe nucleus of rats.

In order to explore the possible sites at which benzodiazepines alter sleep, we have performed sleep studies following administration of 0.5 microgram of triazolam into the dorsal raphe nucleus of rats. Triazolam significantly increased sleep latency and decreased non-rapid eye movement (REM) sleep, with an effect greatest in the first 2 hours after injection. Total REM sleep time was not significantly affected, although there was a modest trend toward reduction in the first 2 hours. In contrast to the decreased sleep resulting from injection into the dorsal raphe nucleus, triazolam did not significantly alter sleep in animals in whom it was injected into surrounding areas. Similarly, the low dose employed in this study did not significantly affect sleep when injected into the lateral ventricle. These data are reminiscent of studies showing transient decreases in sleep following lesions of the dorsal raphe nucleus.

Animals↗

Pharmacotherapy of insomnia.

Sleep disturbance is often the result of specific pathophysiologies of sleep or of psychiatric illness. When this is the case, specific treatment of these conditions is indicated. When such disorders are not found, hypnotics often play a useful role, particularly as adjunctive treatment while the patient receives behaviorally-oriented therapy. Considerations in choosing a hypnotic should include issues of residual daytime effects, special problems of the elderly, interaction with alcohol, dependence, and effects on respiration.

Aged↗

Cholinergic induction of seizures in the rat prefrontal cortex.

Intracerebral microinjection of the cholinergic agonist, carbachol, into the medial prefrontal cortex of the rat, induced a profound behavioral syndrome consisting of repetitive, stereotyped forepaw treading in an upright posture. Electroencephalographic analysis revealed multiple bursts of sharp waves, 200-300 microV, accompanying the carbachol-elicited motor behavior. Pretreatment with intraperitoneal doses of three anticonvulsant drugs, clonazepam, diazepam, and pentobarbital, blocked the manifestation of the motor behavior. These observations suggest that activation of cholinergically innervated regions of the rat medial prefrontal cortex induces an atypical form of seizures.

Animals↗

A psychophysiological study of insomnia.

Ten insomniacs with age- and sex-matched controls had studies of baseline sleep, relation of polygraphically defined sleep to retrospective reports, and arousal thresholds to electronic tones or to a recording of a voice calling out the subject's name. The two groups differed in 10 out of 13 questions about habitual sleep and daytime feelings. In contrast, polygraphic measures of baseline sleep indicated only that insomniacs tended to have slightly less total sleep and had a small but significant increase in early morning awakening time. Unlike the descriptions of habitual sleep, the subjects' retrospective reports of the previous night's sleep differed significantly only for the variable of total sleep time, and there were virtually no differences in the description of their status at a given moment. Auditory arousal thresholds were similar in the two groups, and both went back to sleep and stayed asleep with equal facility. These findings suggest that subjectively poor sleep is not necessarily "light" sleep. For both groups, arousal thresholds differed across the sleep stages, and thresholds to hearing the subject's name were lower than those in response to electronic tones. Although insomniacs had as much polygraphically defined sleep as controls between the forced awakenings of the arousal threshold studies, they perceived their sleep to be only approximately half as long. Insomniacs described themselves as having been awake more frequently than controls in 8 out of 10 forced awakening situations. In one case, insomniacs also overestimated the time between awakenings. In both groups, there was little relationship between reported habitual aspects of sleep and baseline polygraphically defined sleep variables. On questionnaires the following mornings, however, in both groups there was a positive correlation of subjective quality of sleep on the baseline nights with percentage of rapid eye movement sleep, and a negative correlation to various aspects of slow-wave sleep.

Adult↗

Are the toxicities of pentobarbital and ethanol mediated by the GABA-benzodiazepine receptor-chloride ionophore complex?

Both barbiturates and ethanol have been reported to interact with the GABA-benzodiazepine receptor-chloride ionophore 'supramolecular complex'. These observations raise the possibility that some of the pharmacologic actions of barbiturates and ethanol may be mediated through this complex. In this study we have administered a series of drugs which bind to various components of the complex in an attempt to antagonize the lethality of sodium pentobarbital, and ethanol-induced loss of righting reflex in mice. It was found that isopropylbicyclophosphate (IPPO), a cage convulsant which binds at or near the chloride ionophore, greatly reduces the overall mortality (and increases latency to death) of animals pretreated with a lethal dose of pentobarbital. Picrotoxin also decreases pentobarbital lethality, but only at doses which were usually lethal when given alone. Picrotoxin shortened, rather than increased, latency to death. Strychnine did not prevent pentobarbital lethality, suggesting that the IPPO effect is not shared by convulsants in general. IPPO did not prevent ketamine-induced deaths, which supports the notion that the protective actions of IPPO are specific for depressant drugs which act at the chloride ionophore. IPPO also significantly reduced the duration of loss of righting reflex induced by ethanol. These observations suggest that the use of compounds which have a high affinity for the chloride ionophore in vitro might be fruitful in developing a clinical treatment for barbiturate or ethanol toxicity.

Animals↗

Sleep and circadian rhythms in affective patients isolated from external time cues.

Sleep electroencephalographic activity, circadian rhythms in motor activity and rectal temperature, and clinical state were monitored longitudinally in four affectively ill patients (two depressed, one manic, and one rapidly cycling between depression and mania) who lived in isolation from external time cues (zeitgebers) for 3 to 4 weeks. In these conditions it was possible to observe the intrinsic or free-running behavior of circadian pacemakers and thereby to test several hypotheses about the role of sleep and circadian rhythms in the pathogenesis of depression. No hypothesis was consistently supported by the results. We found that the intrinsic rhythm of a circadian pacemaker appeared to free-run with an abnormally fast frequency in one patient. No patient remained stably depressed during temporal isolation. Our experience suggests that this type of study can be carried out safely with appropriate precautions. Temporal isolation is a means to test decisively predictions of several chronobiological hypotheses about affective illness and should be applied to additional patients.

Adult↗

Antidepressant effects of light in seasonal affective disorder.

The authors treated winter depression in 13 patients with typical seasonal affective disorder by extending the length of winter days with bright and dim light in the morning and evening in a balanced-order crossover study. Bright light had a marked antidepressant effect, whereas the dim light did not. This response could not be attributed to sleep deprivation. Subsequent pilot studies indicated that bright evening light alone is probably also effective. Several patients were able to maintain the antidepressant response throughout the winter months by continuing daily light treatments.

Adult↗

Diazepam-stimulated increases in the synaptosomal uptake of 45Ca2+: reversal by dihydropyridine calcium channel antagonists.

Pharmacologically relevant concentrations of benzodiazepines have previously been reported to increase 45Ca2+ uptake into synaptosomes. This observation, coupled with the recent report that nifedipine may block the hypnotic effect of flurazepam, led us to study the effects of nifedipine and nitrendipine on 45Ca2+ uptake into synaptosomes. Diazepam (1 microM) significantly increased the uptake of 45Ca2+ to a crude synaptosomal fraction (P2) prepared from rat cerebral cortex and depolarized with 55 mM K+. Nifedipine (1 microM) did not alter the uptake of Ca2+, while nitrendipine (1 microM) reduced uptake by 37%. Both nifedipine and nitrendipine completely antagonized the ability of diazepam to increase 45Ca2+ uptake following K+ depolarization. These observations support the notion that the pharmacologic actions of benzodiazepines may be mediated through effects on a calcium channel.

Animals↗

The experience of insomnia and daytime and nighttime functioning.

Ten insomniacs and matched control subjects, in whom major physiologic disorders such as sleep apnea and nocturnal myoclonus were ruled out, underwent studies of sleep, temperature, motor activity, cognitive performance, and perception of depth of sleep. Subjective descriptions of sleep differed significantly between insomniacs and normals on a variety of variables. In contrast, polysomnographic evaluation showed increased intermittent waking time and decreased sleep efficiency, and only a tendency toward decreased total sleep and increased sleep latency. Minnesota Multiphasic Personality Inventory (MMPI) evaluation revealed that insomniacs had higher scores on the F, D, and SI scales, and lower values on the K scale. On cognitive testing, insomniacs did well on tests of episodic (recent) memory, but displayed major deficits in accessing semantic memory (retrieval of material already known). Compared to normals, insomniacs described rapid eye movement (REM) sleep as relatively "light" sleep.

Adult↗