Sleep loss and recovery after administration of drugs related to different arousal systems in rats.

Sleep is homeostatically regulated suggesting a restorative function. Sleep deprivation is compensated by an increase in length and intensity of sleep. In this study, suppression of sleep was induced pharmacologically by drugs related to different arousal systems. All drugs caused non-rapid eye movement (NREM) sleep loss followed by different compensatory processes. Apomorphine caused a strong suppression of sleep followed by an intense recovery. In the case of fluoxetine and eserine, recovery of NREM sleep was completed by the end of the light phase due to the biphasic pattern demonstrated for these drugs first in the present experiments. Yohimbine caused a long-lasting suppression of NREM sleep, indicating that either the noradrenergic system has the utmost strength among the examined systems, or that restorative functions occurring normally during NREM sleep were not blocked. Arousal systems are involved in the regulation of various wakefulness-related functions, such as locomotion and food intake. Therefore, it can be hypothesized that activation of the different systems results in qualitatively different waking states which might affect subsequent sleep differently. These differences might give some insight into the homeostatic function of sleep in which the dopaminergic and noradrenergic systems may play a more important role than previously suggested.

EEG effect of orexin A in freely moving rats.

Orexin A and orexin B are neuropeptides produced by a group of neurons located in the lateral hypothalamus which send widespread projections virtually to the whole neuraxis. Several studies indicated that orexins play a crucial role in the sleep-wake regulation and in the pathomechanism of the sleep disorder narcolepsy. As no data are available related to the EEG effects of orexin A in healthy, freely moving rats, the aim of the present experiments was to analyze EEG power changes in the generally used frequency bands after intracerebroventricular orexin A administration.Orexin A administration (0.84 and 2.8 nM/rat) differently affected fronto-occipital EEG waves in the different frequency bands recorded for 24 hours. Delta (1-4 Hz) and alpha (10-16 Hz) power decreased, while theta (4-10 Hz) and beta (16-48 Hz) power increased. Decrease of the delta power was followed by a rebound in case of the higher orexin A dose. This complex picture might be explained by the activation of several systems by the orexin A administration. Among these systems, cortical and thalamic circuits as well as the role of the neurons containing corticotrophin-releasing factor might be of significant importance.

Atonia-related regions in the rodent pons and medulla.

Electrical stimulation of circumscribed areas of the pontine and medullary reticular formation inhibits muscle tone in cats. In this report, we present an analysis of the anatomical distribution of atonia-inducing stimulation sites in the brain stem of the rat. Muscle atonia could be elicited by electrical stimulation of the nuclei reticularis pontis oralis and caudalis in the pons as well as the nuclei gigantocellularis, gigantocellularis alpha, gigantocellularis ventralis, and paragigantocellularis dorsalis in the medulla of decerebrate rats. This inhibitory effect on muscle tone was a function of the intensity and frequency of the electrical stimulation. Average latencies of muscle-tone suppressions elicited by electrical stimulation of the pontine reticular formation were 11.02 +/- 2.54 and 20.49 +/- 3.39 (SD) ms in the neck and in the hindlimb muscles, respectively. Following medullary stimulation, these latencies were 11.29 +/- 2.44 ms in the neck and 18.87 +/- 2. 64 ms in the hindlimb muscles. Microinjection of N-methyl-D-aspartate (NMDA, 7 mM/0.1 microliter) agonists into the pontine and medullary inhibitory sites produced muscle-tone facilitation, whereas quisqualate (10 mM/0.1 microliter) injection induced an inhibition of muscle tone. NMDA-induced muscle tone change had a latency of 31.8 +/- 35.3 s from the pons and 10.5 +/- 0. 7 s from the medulla and a duration of 146.7 +/- 95.2 s from the pons and 55.5 +/- 40.4 s from the medulla. The latency of quisqualate (QU)-induced reduction of neck muscle tone was 30.1 +/- 37.9 s after pontine and 39.5 +/- 21.8 s after medullary injection. The duration of muscle-tone suppression induced by QU injection into the pons and medulla was 111.5 +/- 119.2 and 169.2 +/- 145.3 s. Smaller rats (8 wk old) had a higher percentage of sites producing muscle-tone inhibition than larger rats (16 wk old), indicating an age-related change in the function of brain stem inhibitory systems. The anatomical distribution of atonia-related sites in the rat has both similarities and differences with the distribution found in the cat, which can be explained by the distinct anatomical organization of the brain stem in these two species.

Neurotoxic N-methyl-D-aspartate lesion of the ventral midbrain and mesopontine junction alters sleep-wake organization.

The dorsal regions of the midbrain and pons have been found to participate in sleep regulation. However, the physiological role of the ventral brainstem in sleep regulation remains unclear. We used N-methyl-D-aspartate-induced lesions of the ventral midbrain and pons to address this question. Unlike dorsal mesencephalic reticular formation lesions, which produce somnolence and electroencephalogram synchronization, we found that ventral midbrain lesions produce insomnia and hyperactivity. Marked increases in waking and decreases in slow wave sleep stage 1 (S1), stage 2 (S2) and rapid eye movement sleep were found immediately after the lesion. Sleep gradually increased, but never returned to baseline levels (baseline/month 1 post-lesion: waking, 30.6 +/- 4.58%/62.3 +/- 10.1%; S1, 5.1 +/- 0.74/3.9 +/- 1.91%; S2, 46.2 +/- 4.74%/23.1 +/- 5.47%; rapid eye movement sleep, 14.1 +/- 3.15%/7.2 +/- 5.42%). These changes are comparable in magnitude to those seen after basal forebrain lesions. Neuronal degeneration was found in the ventral rostral pons and midbrain, including the substantia nigra, ventral tegmental area, retrorubral nucleus, and ventral mesencephalic and rostroventral pontine reticular formation. We conclude that nuclei within the ventral mesencephalon and rostroventral pons play an important role in sleep regulation.

Differential EEG effects of the anxiolytic drugs, deramciclane (EGIS-3886), ritanserin and chlordiazepoxide in rats.

The influence of serotonergic and benzodiazepine type anxiolytic drugs on the cortical activation and sleep-wakefulness cycle were compared by evaluating the effects of ritanserin and deramciclane (EGIS-3886), two 5-HT2 receptor antagonists, and chlordiazepoxide on the electroencephalogram (EEG) in freely moving rats. Following drug administration (1, 3, and 10 mg/kg, PO for all drugs), EEG was continuously sampled for 6 h and power spectra were calculated for every 5 s to assess changes in slow wave activity and sleep phases. In a separate test, anticonvulsant effects of the drugs were examined in mice. Both deramciclane and ritanserin slightly increased total time spent in deep sleep (DS) and lengthened sleep episodes. In contrast, chlordiazepoxide had a strong inhibitory action on DS, sleep time being shifted to more superficial light sleep (LS). The incidence and length of the high voltage spindle (HVS) episodes characteristic for the motionless, awake rat were increased at the highest dose of both deramciclane and ritanserin, while it was decreased by chlordiazepoxide. In mice, chlordiazepoxide had a marked anticonvulsant effect, while deramciclane was moderately effective and ritanserin ineffective. In conclusion, the 5-HT2 receptor antagonist anxiolytic drugs seem to be superior compared to the benzodiazepine type anxiolytic drug, chlordiazepoxide, as ritanserin and deramciclane improved sleep quality by increasing sleep episode length and time spent in DS, while chlordiazepoxide enhanced sleep fragmentation and decreased DS.

Long-term sleep deprivation by hypothalamic stimulation in cats.

Several techniques were developed to prevent sleep in animals in order to examine the biological role fulfilled by sleep; however, most were either stressful or difficult to accomplish routinely, especially in such a large animal as the cat. Electrical stimulation of activating structures in the brain presents a very attractive alternative to peripheral stimulation used by the usual sleep deprivation methods although it has been rarely tried. The paper describes a microcomputer-based system used to achieve sleep deprivation in cats by stimulating the hypothalamic predatory area with short trains. During control days and deprivation the electrocorticogram (EEG), electromyogram (EMG) and electrooculogram (EOG) were continuously digitalized by the computer in 5 s epochs and the integrated power of the 4 usual frequency bands of the EEG (alpha, beta, delta, theta) as well as the variance of EMG and EOG signals were calculated. Criteria for stimulus delivery were based on the integrated power of the delta band and on the variance of EMG but the flexibility of the computer ensures that any other parameter can be used to achieve total or selective sleep deprivation.