Wallace B. Mendelson

Positive Correlations Between Cerebral Protein Synthesis Rates and Deep Sleep in Macaca mulatta

Local rates of cerebral protein synthesis (ICPSleu), were determined with the autoradiographic L‐[1‐14C]leucine method in seven awake and seven asleep, adult rhesus monkeys conditioned to sleep in a restraining chair in a darkened, ventilated chamber while EEG, EOG, and EMG were monitored. Prior to the period of measurement all animals slept for 1–4 h. Controls were awakened after at least one period of rapid‐eye‐movement (REM) sleep. Experimental animals were allowed to remain asleep, and they exhibited non‐REM sleep for 71–99% of the experimental period. Statistically significant differences in ICPSleu between control and experimental animals were found in four of the 57 regions of brain examined, but these effects may have occurred by chance. In the sleeping animals, however, correlations between ICPSleu, and percent time in deep sleep were positive in all regions and were statistically significant (P≤ 0.05) in 35 of the regions. When time in deep sleep was weighted for the integrated specific activity of leucine in grey matter, positive correlations were statistically significant (P≤ 0.05) in 18 regions in the experimental animals. These results suggest that rates of protein synthesis are increased in many regions of the brain during deep sleep compared with light sleep.

The sleep of patients with panic disorder: A preliminary report

Electroencephalographic sleep recordings were compared in patients with panic disorder and normal controls. Correlation coefficients of standard sleep parameters versus ratings of anxiety, depression, and panic attack frequency were calculated in the panic-anxious patients. Overall findings are discussed in the context of previous sleep studies in patients with depressive, anxiety, and obsessive-compulsive disorders.

Speaking, thinking, and blinking

The effect of several mental tasks on the spontaneous eye blink rate in 36 normals was examined. The blink rate during silence was 19.0 blinks/minute. This was significantly lower than the mean blink rate during speech (24.7 blinks/minute) and while listening to a paragraph to be memorized (27.6 blinks/minute). Reading reduced the blink rate to 12.3 blinks/minute. Men were more able to suppress and speed up blinking than women.

Methscopolamine Inhibition of Sleep-Related Growth Hormone Secretion: EVIDENCE FOR A CHOLINERGIC SECRETORY MECHANISM

We have examined the effects of cholinergic blockade with 0.5 mg methscopolamine bromide, intramuscularly, on sleep-related and insulin-induced growth hormone (GH) secretion. 17 normal young men were studied; 8 had sleep studies, and 12 (including 3 who also had sleep studies) had insulin tolerance tests (ITT) with 0.1 U/kg of regular insulin. After an adjustment night in the sleep laboratory, saline control night and methscopolamine night studies were done in random sequence; study procedures included electroencephalographic, electromyographic, and electrooculographic recordings, and blood sampling every 20 min for hormone radioimmunoassays. Prolactin levels were also measured during sleep. For methscopolamine night studies, the mean overall control GH level of 2.89+/-0.44 ng/ml and the mean peak control GH level of 11.09+/-3.11 ng/ml were dramatically reduced to 0.75+/-0.01 and 1.04+/-0.25 ng/ml, respectively (P<0.0001 and <0.001). Despite virtual absence of GH secretion during the night in every study subject, no measured sleep characteristic was affected by methscopolamine, including total slow-wave sleep (12.1+/-2.6% control vs. 10.3+/-2.5% drug, P>0.2). Sleep prolactin levels were not changed by methscopolamine. In contrast to the abolition of sleep-related GH secretion, administration of methscopolamine had only a marginal effect on the GH response to insulin hypoglycemia. None of nine time points differed significantly, as was also the case with peak levels, mean increments, and areas under the curves (P>0.2). Analysis of variance did, however, indicate that the lower GH concentrations achieved during ITT after methscopolamine (average 31.7% below control) were significantly different than control concentrations. We conclude that the burst of GH secretion which normally occurs after sleep onset is primed by a cholinergic mechanism which does not influence slow-wave sleep. Cholinergic mechanisms do not appear to play an important role in sleep-related prolactin secretion. The contrast between the complete suppression of sleep-related GH release and the relatively small inhibitory effect on ITT-induced GH secretion suggests that the neurotransmitter mechanisms, and presumably the pathways, which subserve sleep-related GH secretion in man may be different from those which mediate the GH response to pharmacologic stimuli such as insulin.

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.

Effects of melatonin and propranolol on sleep of the rat.

Melatonin and L-propranolol, which inhibits melatonin synthesis, were administered to rats at 07.45 h and 19.45 h. Melatonin given in the morning decreased non-REM sleep, but when given at night had no effect on sleep stages. L-propranolol given in the morning had no effect on non-REM sleep, but increased it at night. L-propranolol produced decreased in percentage REM sleep at both times.

Flurazepam-induced sleep apnea syndrome in a patient with insomnia and mild sleep-related respiratory changes.

Sleep EEG and respiratory measures were examined in a 38-year-old man with a long-standing history of insomnia and daytime sleepiness. He was found to have seven to 18 primarily obstructive apneas per night on four baseline recordings, a finding not generally considered to be indicative of pathology. On the first two nights on which he received 30 mg of the benzodiazepine hypnotic flurazepam, there were 22 and 100 apneas, and during the daytime he became extremely sleepy. Upon cessation of medication, his clinical condition improved, and the number of apneas decreased to 11 and 6 on withdrawal nights 4 and 6. Although respiratory depression is neither invariable nor unique to flurazepam, this case suggests that it may be a clinically significant problem with recommended oral doses in some individuals.

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.

Physostigmine alters onset but not duration of REM sleep in man

Physostigmine (1.0 mg) or placebo were administered intravenously over 1-h period to seven male normal volunteers beginning 35 min after sleep onset. The results indicate that physostigmine induced the onset of REM sleep but did not significantly alter the duration of individual REM sleep periods. Physostigmine significantly shortened the REM latency and the duration of the second non REM period. After inducing the onset of the first REM period(s), physostigmine also appeared to advance succeeding REM-nonREM sleep cycles relative to sleep onset even when the duration of each cycle was unaffected.

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.