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Decreased susceptibility to local anesthetics-induced convulsions after paradoxical sleep deprivation.

The effect of 50% convulsant (CD50) and 50% lethal (LD50) doses of lidocaine, bupivacaine and pentylenetetrazol were determined in mice stressed by paradoxical sleep deprivation (PSD). The results showed a reduced mortality after high doses of local anesthetics and decreased seizure susceptibility induced by bupivacaine after 48 h and 72 h of PSD. On the other hand this stressful manipulation increased the susceptibility to pentylenetetrazol-induced convulsions. These data may suggest a different mechanism of action for these drugs. Possible alterations in drug metabolism or on aminergic transmission after PSD may be involved in the protection to the toxic effect of the local anesthetics.

Anesthetics, Local↗

Challenging the sleep homeostat does not influence the thermoregulatory system in men: evidence from a nap vs. sleep-deprivation study.

The purpose of our study was to understand the relationship between the components of the three-process model of sleepiness regulation (homeostatic, circadian, and sleep inertia) and the thermoregulatory system. This was achieved by comparing the impact of a 40-h sleep deprivation vs. a 40-h multiple nap paradigm (10 cycles with 150/75 min wakefulness/sleep episodes) on distal and proximal skin temperatures, core body temperature (CBT), melatonin secretion, subjective sleepiness, and nocturnal sleep EEG slow-wave activity in eight healthy young men in a "controlled posture" protocol. The main finding of the study was that accumulation of sleep pressure increased subjective sleepiness and slow-wave activity during the succeeding recovery night but did not influence the thermoregulatory system as measured by distal, proximal, and CBT. The circadian rhythm of sleepiness (and proximal temperature) was significantly correlated and phase locked with CBT, whereas distal temperature and melatonin secretion were phase advanced (by 113 +/- 28 and 130 +/- 30 min, respectively; both P < 0.005). This provides evidence for a primary role of distal vasodilatation in the circadian regulation of CBT and its relationship with sleepiness. Specific thermoregulatory changes occur at lights off and on. After lights off, skin temperatures increased and were most pronounced for distal; after lights on, the converse occurred. The decay in distal temperature (vasoconstriction) was significantly correlated with the disappearance of sleep inertia. These effects showed minor and nonsignificant circadian modulation. In summary, the thermoregulatory system seems to be independent of the sleep homeostat, but the circadian modulation of sleepiness and sleep inertia is clearly associated with thermoregulatory changes.

Body Temperature↗

Paradoxical sleep-promoting effects of brain extract from paradoxical sleep-deprived rats.

Brain extract was obtained from whole brains of donor rats following four days of paradoxical sleep deprivation (PSD). Intraperitoneal injection of this brain extract in normal (i.e., not pretreated) recipient rats led to a significant increase of paradoxical sleep (PS) which was beginning at the third hour postinjection and still present on the day after treatment. Both PS episode number and PS episode duration were increased by the PSD extract, whereas slow-wave sleep was not influenced. Brain extract of nondeprived control rats, on the other hand, had no significant effects. In the present experiments, an extract volume obtained from two donor brains was transferred to one recipient. Compared to our earlier investigations (one donor brain/one recipient) this higher "dose" of PSD extract exerted a more pronounced and prolonged effect. These results support the idea that some PS-inducing factor(s) accumulating in the brain during PS deprivation may be involved in the regulation of paradoxical sleep.

Animals↗

Effects of REM sleep deprivation on cholinergic receptor sensitivity and passive avoidance behavior in clomipramine model of depression.

This study investigated the effects of REM (rapid eye movement) sleep deprivation (RSD) on the activity of central cholinergic receptors and passive avoidance retention in rats treated neonatally with clomipramine. Male rat pups treated with clomipramine (15 mg/kg, s.c.) twice daily from postnatal day 5 to 21 were subjected to RSD procedure at three months of age, for 4 days consecutively. In the post-RSD phase, RSD-control rats showed a significantly enhanced cholinomimetic-induced hypothermia and an improved retention in passive avoidance task. However, these measures were not significantly different in RSD-experimental group as compared to rats treated neonatally with saline. These results suggest that RSD reverses the sensitivity of central cholinergic receptors in rats given clomipramine neonatally, and this mechanism may be involved in mediating the antidepressant effects of RSD treatment in clomipramine model of depression.

Animals↗

Sleep deprivation impairs object recognition in mice.

Many studies in animals and humans suggest that sleep facilitates learning, memory consolidation, and retrieval. Moreover, sleep deprivation (SD) incurred after learning, impaired memory in humans, mice, rats, and hamsters. We investigated the importance of sleep and its timing in an object recognition task in OF1 mice subjected to 6h SD either immediately after the acquisition phase (0-6 SD) or 6h later (7-12 SD), and in corresponding undisturbed controls. Motor activity was continuously recorded with infrared sensors. All groups explored two familiar, previously encountered objects to a similar extent, both at the end of the acquisition phase and 24h later during the test phase, indicating intact familiarity detection. During the test phase 0-6 SD mice failed to discriminate between the single novel and the two familiar objects. In contrast, the 7-12 SD group and the two control groups explored the novel object significantly longer than the two familiar objects. Plasma corticosterone levels determined after SD did not differ from time-matched undisturbed controls, but were significantly below the level measured after learning alone. ACTH did not differ between the groups. Therefore, it is unlikely that stress contributed to the memory impairment. We conclude that the loss of sleep and the activities the mice engaged in during the SD, impaired recognition memory retrieval, when they occurred immediately after acquisition. The delayed SD enabled memory consolidation during the 6h when the mice were allowed to sleep, and had no detrimental effect on memory. Neither SD schedule impaired object familiarity processing, suggesting that only specific cognitive abilities were sensitive to the intervention. Sleep may either actively promote memory formation, or alternatively, sleep may provide optimal conditions of non-interference for consolidation.

Adrenocorticotropic Hormone↗

Sleep deprivation as a predictor of response to light therapy in major depression.

BACKGROUND: While the majority of depressed patients benefit from total sleep deprivation (TSD), light therapy is regarded as a first-line treatment only for seasonal affective disorder (SAD). The results of light therapy in nonseasonal major depressive disorder have been non-conclusive. We examined the correlation of TSD response and light therapy response in major depressed patients. METHODS: 40 inpatients with major depressive disorder (seven with seasonal pattern, 33 without seasonal pattern) were deprived of a night's sleep. The TSD responders, as well as the TSD nonresponders, were randomly assigned to receive adjunct light therapy either with bright white light (2500 lux) or dim red light (50 lux) during 2 weeks beginning on the third day after TSD. RESULTS: The 20 TSD responders improved significantly better under the light therapy than the 20 TSD nonresponders (according to the Hamilton Depression Rating Scale and the self-rating depression scale Bf-S; v. Zerssen). LIMITATIONS: No significant difference could be found between the two light intensities. Since the patients were additionally treated with medication an interaction with the two adjunctive therapies cannot be excluded. CONCLUSION: Our results indicate that a positive TSD response in major depressed patients can be predicative of beneficial outcome of subsequent light therapy.

Adult↗

Single-case evaluation of sleep-deprivation effects by means of nonparametric time-series analysis (according to the HTAKA model)

Modern statistical approaches to the analysis of single cases have so far been rarely employed in psychiatric therapy research. The recently developed Hierarchical Trend-Segment Component Analysis (HTAKA) seems to be an adequate and practicable method for the field of therapy evaluation, not only under sophisticated research conditions, but also under routine treatment conditions, but analysis data of the effects of sleep-deprivation therapy as an example, the results of nonparametric time-series analyses performed according to HTAKA are presented. The statistical agglomeration of the single case results demonstrated that in most cases undergoing repeated sleep deprivation a long-term antidepressive effect related to this therapy could be proven.

Adult↗

Response to total sleep deprivation and clomipramine in endogenous depression.

In 44 endogenously depressed patients, response to total sleep deprivation (TSD) was investigated as a function of several biographical and clinical variables. All patients were subjected to a schedule of sleep-TSD-sleep-TSD. Antidepressant drug treatment (clomipramine) was started on the day before the first TSD. Sex, age, educational status, number of previous hospitalizations and duration of the current depressive episode were not related to the response to either the first or the second TSD. Likewise, no significant differences were found in the responses of unipolar and bipolar patients. In contrast, diurnal variation appeared to be positively correlated with response to TSD. Depressives with psychotic features reacted more favourably than non-psychotic depressives.

Adult↗

Instrumental REM sleep deprivation in neonates leads to adult depression-like behaviors in rats.

STUDY OBJECTIVES: Previous studies have demonstrated that neonatal suppression of rapid eye movement (REM) sleep by pharmacologic agents, particularly clomipramine, produces adult depressive behavior. These findings suggest the hypothesis that REM sleep deprivation (RSD) mediates the depressogenic behaviors of neonatally administered antidepressant drugs. Drug suppression of RSD, however, was thought to be confounded by the other effects of the drugs. The current study was aimed to show the adult effect of neonatal RSD in rats by instrumental means, ie, a computer-controlled shaking method. DESIGN: Three treatment groups were studied: an instrumental RSD group, a yoked control group, and a nonshaken, maternally separated, control group. All treatments began at the age of 14 days and lasted for 7 days. Adult behavior measurements including tests of sexual activity, locomotor activity, shock-induced fighting, and sleep recording were subsequently performed. MEASUREMENTS AND RESULTS: The major findings of our investigation were that rats subjected to neonatal instrumental RSD demonstrated diminished sexual activity, decreased aggressive behavior, increased percentage of REM sleep, and decreased wake-REM sleep ratio compared with yoked control rats. These data are compatible with the findings from adult rats subjected to neonatal treatment with the REM-sleep suppressant, clomipramine, and supports the hypothesis that neonatal RSD results in adult depressive abnormalities. CONCLUSION: Neonatal RSD induced by a nondrug method results in adult depression-like changes similar to those induced by a REM-sleep suppressant drug, although the extent of these changes varies.

Age Factors↗

Disruption of passive avoidance memory by REM sleep deprivation: methodological and pharmacological considerations.

The present experiments were designed to examine more closely the variables responsible for the disruption of passive avoidance memory produced by REM sleep deprivation. In the pharmacological study it was found that imipramine could reverse the memory disruption exhibited by rats maintained on large platforms (presumably not REM-deprived) while both imipramine and physostigmine were required to reverse the memory disruption exhibited by rats maintained on small platforms. In the methodological study it was found that those animals maintained on the smallest platforms and therefore having the largest weight to area ratio exhibited the greatest degree of memory disruption. It is concluded that further modification and verification of the platform techniques of REM deprivation is required before firm conclusions about its neurochemical basis and behavioural functions can be made.

Animals↗

Apomorphine does not mimic the effects of REM-sleep deprivation on cortical spreading depression.

The propagation of cortical spreading depression (SD) and the incidence of "spontaneous" SD were enhanced in rats after rapid-eye-movement sleep deprivation (REMD) as compared to control animals. Pseudo-deprived rats were similar to controls, suggesting that the facilitatory effect on SD is due to REMD rather than to the stress accompanying deprivation. In control rats, apomorphine (0.5 to 8 mg/kg) failed to reproduce the effects of REMD and also failed to enhance the REMD effects in deprived rats, suggesting that the dopaminergic system does not play an important role in propagation of cortical SD.

Animals↗

Enhanced slow-wave activity within NREM sleep in the cortical and subcortical EEG of the cat after sleep deprivation.

Electroencephalograms (EEGs) of the cortex and of seven subcortical structures were recorded during two baseline days and during a recovery day following a 12-hour period of sleep deprivation (SD) in eight cats. The EEGs were analyzed by visual scoring and by spectral analysis. The following subcortical structures were studied: hippocampus, amygdala, hypothalamus, nucleus centralis lateralis of the thalamus, septum, nucleus caudatus and substantia nigra. The EEGs of all brain structures exhibited sleep state-dependent changes. In general, slow-wave activity (SWA, 0.5-4.0 Hz) during nonrapid eye movement (NREM) sleep exceeded that of REM sleep. The power spectra (0.5-24.5 Hz) in NREM, as well as the relationship between the power spectra of NREM and REM sleep, differed between the recording sites. Moreover, the rate of increase of SWA in the course of an NREM episode and the rate of decrease of SWA at the transition from NREM to REM sleep differed between the brain structures. During the first 12 hours following SD, the duration of NREM increased due to a prolongation of the NREM episodes. REM increased by a rise in the number of REM episodes. During the same period, the NREM EEG power density in the delta and theta frequencies was enhanced in all brain structures. Furthermore, in all structures the enhancement of SWA was most pronounced at the beginning of the recovery period and gradually declined thereafter. SD also induced a rise in the rate of increase of SWA in the NREM episodes in all recording sites. This indicates that the enhancement of EEG power density was not only due to prolongation of the NREM episodes. The EEG activity during REM was barely affected by the SD. It is concluded that, in all brain structures studied, the EEG during NREM is characterized by high levels of SWA. Furthermore, in each brain structure, SWA within NREM sleep is enhanced after a prolonged vigil. These data may indicate that SWA reflects a recovery process in cortical and subcortical structures.

Animals↗

Thyroid hormones in the rat amygdala as common targets for antidepressant drugs, mood stabilizers, and sleep deprivation.

BACKGROUND: There have been repeated reports of antidepressant effects of thyroid hormones. In this study, we investigated whether antidepressant treatments enhance the concentrations of thyroid hormones in rat brain. METHODS: Each of the groups of rats was treated for 14 days with one of the following: an antidepressant drug (desipramine, paroxetine, venlafaxine, or tianeptine); a mood stabilizer (lithium or carbamazepine); or 8 hours' partial sleep deprivation. Thyroid hormone concentrations were quantified in homogenates, nuclei, mitochondria, synaptosomes, myelin, and microsomes in 11 rat brain areas. RESULTS: No drug effects were seen on nuclear triiodothyronine (T(3)) concentrations in any brain area. In the amygdala, all antidepressant drugs enhanced the levels of T(3) in the myelin fraction. Triiodothyronine molecules were identified in the myelin by immunogold labeling. Quantification of the major lipid components showed a selective decrease in cholesterol in the myelin of the amygdala after desipramine treatment. Desipramine induced an increase in protein concentrations, 3,5-diiodothyronine levels, and the activity of the mitochondrial enzyme succinate dehydrogenase in the mitochondria of the amygdala. Lithium, carbamazepine, and partial sleep deprivation raised the levels of T(3) in synaptosomes of the amygdala. CONCLUSIONS: These results demonstrate that thyroid hormones in the amygdala are a common target of different antidepressant and mood-stabilizing therapies.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

Sleep deprivation and adaptive hormonal responses of healthy men.

To study the effects of sleep deprivation on the pituitary-testis axis physiology, we measured the circulating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), testosterone (T), androstanedione (A), dihydrotestosterone (DHT), estradiol (E2), and cortisol (C) in eight healthy men as follows: phase I (control), phase II (24-h restless period), phase III (48-h restless period), and phase IV (24-h recovery period). All samples were taken at 8:00 a.m. There was a significant decrease of T, A, DHT, and E2 in phase II but no decrease in FHS, LH, PRL, or C. In phase III there was no further decrease in any androgen, although E2 decreased along with the increase of PRL. In phase IV E2 and PRL tended to return to baseline values, and the androgens were very similar to the controls. FHS, LH, and C showed no change under the effects of phase III. These data extend the adaptive androgenic response and the association of the role of E2 and PRL to restricted or disturbed sleep in men.

Adult↗

Motor reactivity, pain threshold and effects of sleep deprivation in unipolar depressives.

The authors studied the motor reactivity by means of serial choice reaction, electromyography of simple reactions, and defense reflexes in normal and in depressed patients. Significant differences were observed between normal and depressed patients, especially in those with retardation. The 'retarded' depressives exhibited higher pain threshold values, a lower number of motor reactions, and more prolonged reaction times. 2 normal and 4 depressed patients were submitted to the same tests after 1 night's total sleep deprivation. In normals negative effects were found in the levels of vigilance and endurance. In depressed patients, at variance with normals, the number of motor reactions increased, the reaction time decreased, and the rate of basal motor innervation improved, tending to normalization. On the contrary, pain threshold underwent the same type of changes as in controls. Sleep deprivation seemed to specifically reduce retardation phenomena in depressives, thus strongly improving motor reactivity.

Adult↗

Effects of benzodiazepines, sleep and sleep deprivation on vigilance and memory.

Anterograde amnesia is one of the troublesome adverse effects of the benzodiazepines, especially when they are used as tranquillizers. Interestingly, benzodiazepines also produce retrograde facilitation. In this review, a unifying hypothesis concerning both the cognitive enhancement and the cognitive decrement is discussed: the decrease in vigilance or sedative-hypnotic properties of the benzodiazepines induces a superficial type of encoding and consolidation. This is expressed in anterograde amnesia. The shallower encoding also causes less retrograde interference and retrograde facilitation is the result. In this way also the positive effect of sleep on memory is explained. In a series of experiments, this hypothesis was investigated. Anterograde amnesia and retrograde facilitation was demonstrated after benzodiazepine intake in healthy, volunteers. It was striking that amnestic effects and retrograde facilitation were most prominent when memory was tested one week after drug intake. A decrease in vigilance was also obtained by sleep deprivation and an increase by the gavage of the central stimulant methylphenidate. The latter vigilance increasing drug did not change memory aspects. Also memory effects were hardly present in sleep deprived subjects with low levels of vigilance and the performance on memory tests were not changed. This jeopardizes the vigilance hypothesis of the memory effects of the benzodiazepines. However, amnesia under the influence of benzodiazepines was less for semantic related words than for unrelated words. This suggests that information might be stored without appropriate contextual cues. Only under special circumstances this information can be retrieved. It is further speculated that this storage costs less efforts leading to less retrograde interference and consequently retrograde facilitation.

Amnesia↗

Cytophotometric study of ATPase activity in brain neurons and gliocytes of paradoxical sleep-deprived rats.

Conditions were chosen for optimal demonstration of ATPases in brain slices by a modified method of Wachstein and Meisel, and the reaction was shown to obey the Bouguer-Beer laws, confirming that ATPase activity can be determined quantitatively in single cells by cytophotometry. In rats in a state of relative physiological rest specific activity of both Na+, K+-ATPase and Mg++-ATPase in gliocytes of the hippocampus and dorsal raphe was found to be considerably higher than in neurons. Deprivation of the paradoxical phase of sleep of the rats for 24 h led to a significant increase in Na+, K+-ATPase activity in hippocampal neurons and to a decrease in its activity in gliocytes of the hippocampus and dorsal nucleus raphe. It is suggested that these changes in Na+, K+-ATPase activity may be due to some extent to a change in excitability of neurons and depolarization of the glia when sleep is disturbed.

Adenosine Triphosphatases↗