A single dose of hypnotic corrects sleep and EEG abnormalities in symptomatic Huntington's disease mice.

Sleep and electroencephalogram abnormalities are prominent early features of Huntington's disease (HD) that typically appear before the onset of characteristic motor symptoms. The changes in sleep and electroencephalogram seen in HD patients are largely recapitulated in mouse models of HD such as transgenic R6/2 lines. To test whether or not drugs with hypnotic properties can correct the sleep and electroencephalogram abnormalities seen in HD mice, we treated male wild-type (WT; N = 7) and R6/2 mice (N = 9) acutely with intraperitoneal injections of vehicle, zolpidem (5, 10 or 20 mg/kg) or amitriptyline (5, 10 or 20 mg/kg), and then monitored their sleep-wake behavior. In R6/2 mice, both zolpidem and amitriptyline suppressed the abnormally high REM sleep amount and electroencephalographic gamma (30-46 Hz) oscillations in a dose-dependent manner. Amitriptyline's effect on sleep was similar in both genotypes, whereas zolpidem showed significant genotype differences. Zolpidem exerted a strong hypnotic effect in WT mice by increasing electroencephalographic delta power, doubling the mean bout duration and the total amount of non-rapid eye movement sleep. However, no such effect was seen in R6/2 mice. Our study demonstrates that the pathophysiological changes seen in sleep and electroencephalogram are not 'hard-wired' in HD brain and can be reversed even at late stages of the disease. The diminished hypnotic effect of zolpidem suggests that the GABAergic control of sleep-wake states is impaired in HD mice. A better understanding of the neurochemical basis underlying these abnormalities should lead to more effective and rational therapies for HD.This work was supported by a grant from CHDI Foundation, Inc.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.neuropharm.2016.01.02

MANAGEMENT OF SEPTIC SHOCKAND HYPOXIA INDUCED CONJUGATED HYPERBILIRUBINAEMIA IN CASE OF MAJOR CHEST TRAUMA – CASE REPORT

This case report describes a 50-year-old male trauma patient with multiple crushed thoracic lesions: flail chest, bilateral hemopneumothorax, myocardial infarction and pulmonary contusion. In the ICU he developed ARDS and pulmonary infection which lead to septic shock. Hypoxia due to inadequate ventilation and reduced visceral perfusion due to shock induced elevated levels of conjugated bilirubin. Continuous veno-venous hemofiltration (CVVH) sessions in combination with CytoSorb® filters and MARS® were needed. After surgical fixation of the flail segment ventilatory parameters improved significantly

Decrease in REM latency and changes in sleep quality parallel serotonergic damage and recovery after MDMA: a longitudinal study over 180 days

The recreational drug ecstasy [3,4-methylenedioxymethamphetamine (MDMA)], has been found to selectively damage brain serotonin neurons in experimental animals, and probably in human MDMA users, but detailed morphometric analyses and parallel functional measures during damage and recovery are missing. Since there is evidence that serotonin regulates sleep, we have compared serotonergic markers parallel with detailed analysis of sleep patterns at three time-points within 180 d after a single dose of 15 mg/kg MDMA in male Dark Agouti rats. At 7 d and 21 d after MDMA treatment, significant (30-40%), widespread reductions in serotonin transporter (5-HTT) density were detected in the cerebral cortex, hippocampus, most parts of the hypothalamus, and some of the brainstem nuclei. With the exception of the hippocampus, general recovery was observed in the brain 180 d after treatment. Transient increases followed by decreases were detected in 5-HTT mRNA expression of dorsal and median raphe nuclei at 7 d and 21 d after the treatment. Significant reductions in rapid eye movement (REM) sleep latency, increases in delta power spectra in non-rapid eye movement sleep and increased fragmentation of sleep were also detected, but all these alterations disappeared by the 180th day. The present data provide evidence for long-term, albeit, except for the hippocampus, transient changes in the terminal and cellular regions of the serotonergic system after this drug. Reduced REM latency and increased sleep fragmentation are the most characteristic alterations of sleep consistently described in depression using EEG sleep polygraphy

Effects of the fatty acid amide hydrolase inhibitor URB597 on coping behavior under challenging conditions in mice

RATIONALE: Recent evidence suggests that in addition to controlling emotional behavior in general, endocannabinoid signaling is engaged in shaping behavioral responses to challenges. This important function of endocannabinoids is still poorly understood. OBJECTIVES: Here we investigated the impact of blockade of fatty acid amide hydrolase (FAAH), the degrading enzyme of anandamide on behavioral responses induced by challenges of different intensity. METHODS: Mice treated with FAAH inhibitor URB597 were either manually restrained on their backs (back test) or received foot-shocks. RESULTS: The behavior of mice showed bimodal distribution in the back test: they either predominantly showed escape attempts or equally distributed time between passivity and escape. URB597 increased escapes in animals with low escape scores. No effects were noticed in mice showing high escape scores, which is likely due to a ceiling effect. We hypothesized that stronger stressors would wash out individual differences in coping; therefore, we exposed mice to foot-shocks that decreased locomotion and increased freezing in all mice. URB597 ameliorated both responses. The re-exposure of mice to the shock cage 14 days later without delivering shocks or treatment was followed by reduced and fragmented sleep as shown by electrophysiological recordings. Surprisingly, sleep was more disturbed after the reminder than after shocks in rats receiving vehicle before foot-shocks. These reminder-induced disturbances were abolished by URB597 administered before shocks. CONCLUSIONS: These findings suggest that FAAH blockade has an important role in the selection of behavioral responses under challenging conditions and-judging from its long-term effects-that it influences the cognitive appraisal of the challenge

Ketamine supresses REM sleep and markedly increases EEG gamma oscillations in the Wistar Kyoto rat model of treatment-resistant depression

© 2023 Published by Elsevier. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.bbr.2023.114473Wistar–Kyoto (WKY) rats exhibit depression-like characteristics and decreased sensitivity to monoamine-based antidepressants, making them a suitable model of treatment-resistant depression (TRD). Ketamine has emerged recently as a rapidly acting antidepressant with high efficacy in TRD. Our aim was to determine whether subanaesthetic doses of ketamine can correct sleep and electroencephalogram (EEG) alterations in WKY rats and whether any ketamine-induced changes differentially affect WKY rats compared to Sprague-Dawley (SD) rats. Thus, we surgically implanted 8SD and 8 WKY adult male rats with telemetry transmitters and recorded their EEG, electromyogram, and locomotor activity after vehicle or ketamine (3, 5 or 10mg/kg, s.c.) treatment. We also monitored the plasma concentration of ketamine and its metabolites, norketamine and hydroxynorketamine in satellite animals. We found that WKY rats, have an increased amount of rapid eye movement (REM) sleep, fragmented sleep-wake pattern, and increased EEG delta power during non-REM sleep compared to SD rats. Ketamine suppressed REM sleep and increased EEG gamma power during wakefulness in both strains, but the gamma increase was almost twice as large in WKY rats than in SD rats. Ketamine also increased beta oscillations, but only in WKY rats. These differences in sleep and EEG are unlikely to be caused by dissimilarities in ketamine metabolism as the plasma concentrations of ketamine and its metabolites were similar in both strains. Our data suggest an enhanced antidepressant-like response to ketamine in WKY rats, and further support the predictive validity of acute REM sleep suppression as a measure of antidepressant responsiveness.Peer reviewe

Increased wakefulness, motor activity and decreased theta activity after blockade of the 5-HT(2B) receptor by the subtype-selective antagonist SB-215505

1. Serotonin-2 receptor antagonists, like ritanserin, greatly enhance deep slow wave sleep (SWS-2) and low-frequency EEG power in humans and rodents. 5-HT(2A) and 5-HT(2C) receptors may be involved in these effects, but the role of the 5-HT(2B) receptor is still unclear. 2. To investigate the role of the 5-HT(2B) receptor in regulation of the sleep–wake cycle, the subtype-selective antagonist SB-215505 (0.1, 0.3 and 1.0 mg kg(−1) i.p.) was administered to Sprague–Dawley rats at light onset (beginning of passive phase). EEG, EMG and motor activity were recorded during the subsequent 8 h. 3. SB-215505 dose-dependently increased wakefulness (W) at the expense of the intermediate stage of sleep, paradoxical sleep (PS) and SWS-2 in the first hour. Parallel to increased W, significantly increased motor activity was found. Spectral analysis of the EEG in W showed a dose-dependent decrease in power density in the 3–8 Hz frequency range (maximum effect at 6 Hz). In light slow wave sleep and SWS-2, the drug reduced low-frequency (<8 Hz) EEG power, suggesting decreased sleep intensity after SB-215505 treatment. In PS, the drug dose-dependently decreased EEG power solely in the theta (6–9 Hz) band, primarily affecting the peak power value (7 Hz). 4. The well-known SWS-2 enhancing effect of 5-HT(2) receptor antagonists is mediated by 5-HT(2A) and/or 5-HT(2C) receptors. In contrast, blockade of 5-HT(2B) receptors increases motor activity and W along with decreased theta activity during W and PS. Activation of 5-HT(2B) receptors may contribute to initiation of sleep and to theta generation during W and PS under physiological conditions

Expression of FcγRIII defines distinct subpopulations of fetal liver B cell and myeloid precursors

International audienceWe have isolated four distinct fetal liver (FL) populations based on the expression of AA4.1 and the low-affinity Fc gamma receptors type II and III (Fc gamma RII/III), and characterized them with respect to B cell, T cell, and myeloid precursor content. Polymerase chain reaction analysis revealed that the prevalent Fc gamma R isoform at this stage of FL development (day 12 of gestation) was Fc gamma RIII. Two of the four populations, one which expressed AA4.1 but little if any Fc gamma RII/III (AA4.1+), and one which expressed abundant levels of both markers (AA4.1+/FcR+), contained B cell precursors that grew and differentiated to generate VHDJH-rearranged B-lineage cells on S-17 stromal cells in the presence of IL-7. When cultured on FLST2 stromal cells only the AA4.1+ cells generated VHDJH-rearranged B-lineage cells. T cell precursors as assayed by their ability to repopulate fetal thymi in organ culture were found only in the AA4.1+ fraction. In contrast to the lymphoid precursors, myeloid precursors able to generate colonies in methyl cellulose cultures were found in all four fractions including the one which expressed Fc gamma RII/III but no AA4.1 (FcR+) and the one which expressed neither marker (AA4.1-/FcR-). The AA4.1+ population which contained both B cell and T cell precursors was enriched for precursors from many myeloid lineages including the most immature ones which generated multilineage colonies. In contrast, the AA4.1+/FcR+ population, which also contained B cell precursors, was almost devoid of myeloid precursors and the few that were detected were committed to the macrophage lineage. The population defined as FcR+ was also enriched for precursors; however, the majority of these were committed to the erythroid, the macrophage and the mast cell lineage. The fourth population which expressed neither marker (AA4.1-/FcR-) was enriched for relatively mature erythroid precursors which were not present in any of the other fractions. Together, these findings demonstrate that fractionation of FL cells on the basis of AA4.1 and Fc gamma RII/III expression distinguishes subpopulations of B cell and myeloid precursors and suggests that the low-affinity Fc gamma RIII could play a role in the development of early hematopoietic cells at this stage of ontogeny