No abstract

Numerous animal studies suggest that cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) mediate increased sleep amount and intensity observed during infection and are, moreover, involved in physiological sleep regulation. In humans the role of cytokines in sleep-wake regulation is largely unknown. In a single-blind, placebo-controlled study, we investigated the effects of granulocyte colony-stimulating factor (G-CSF, 300 μg sc) on the plasma levels of cytokines, soluble cytokine receptors, and hormones as well as on night sleep. G-CSF did not affect rectal temperature or the plasma levels of cortisol and growth hormone but did induce increases in the plasma levels of IL-1 receptor antagonist and both soluble TNF receptors within 2 h after injection. In parallel, the amount of slow-wave sleep and electroencephalographic delta power were reduced, indicating a lowered sleep intensity. We conclude that G-CSF suppresses sleep intensity via increased circulating amounts of endogenous antagonists of IL-1β and TNF-α activity, suggesting that these cytokines are involved in human sleep regulation.

Haloperidol is unlikely to confound the results of studies investigating disease-related alterations in the levels of a broad range of cytokines and soluble cytokine receptors in schizophrenia.

The antipsychotic drug clozapine frequently induces transient increases in white blood cell counts that have been found to be sensitive, but non-specific, predictors of subsequent life-threatening agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) is an endogenous hematopoietic growth factor that plays a pivotal role in granulopoiesis. In addition, G-CSF has successfully been used to treat clozapine-induced agranulocytosis. We performed a longitudinal investigation of the plasma levels of G-CSF in 20 schizophrenic patients during six weeks of clozapine treatment. Clozapine transiently increased plasma G-CSF levels in 55% of the subjects studied. This effect was most prominent at the end of the second week of treatment. Increased G-CSF levels were accompanied by increased granulocyte and monocyte counts, increased rectal temperature and increased plasma levels of other cytokines and cytokine receptors. The results presented suggest that G-CSF is involved in clozapine-induced increases in granulocyte counts seen early during treatment. Like granulocytosis, granulocytopenia is known to occur in conjunction with increased systemic G-CSF levels. Therefore, we hypothesize that a persistent increase along with a decline in white cell counts following an early spike during clozapine treatment might predict the occurrence of agranulocytosis.

BackgroundIn humans, rapid eye movements (REM) density during REM sleep plays a prominent role in psychiatric diseases. Especially in depression, an increased REM density is a vulnerability marker for depression. In clinical practice and research measurement of REM density is highly standardized. In basic animal research, almost no tools are available to obtain and systematically evaluate eye movement data, although, this would create increased comparability between human and animal sleep studies.MethodsWe obtained standardized electroencephalographic (EEG), electromyographic (EMG) and electrooculographic (EOG) signals from freely behaving mice. EOG electrodes were bilaterally and chronically implanted with placement of the electrodes directly between the musculus rectus superior and musculus rectus lateralis. After recovery, EEG, EMG and EOG signals were obtained for four days. Subsequent to the implantation process, we developed and validated an Eye Movement scoring in Mice Algorithm (EMMA) to detect REM as singularities of the EOG signal, based on wavelet methodology.ResultsThe distribution of wakefulness, non-REM (NREM) sleep and rapid eye movement (REM) sleep was typical of nocturnal rodents with small amounts of wakefulness and large amounts of NREM sleep during the light period and reversed proportions during the dark period. REM sleep was distributed correspondingly. REM density was significantly higher during REM sleep than NREM sleep. REM bursts were detected more often at the end of the dark period than the beginning of the light period. During REM sleep REM density showed an ultradian course, and during NREM sleep REM density peaked at the beginning of the dark period. Concerning individual eye movements, REM duration was longer and amplitude was lower during REM sleep than NREM sleep. The majority of single REM and REM bursts were associated with micro-arousals during NREM sleep, but not during REM sleep.ConclusionsSleep-stage specific distributions of REM in mice correspond to human REM density during sleep. REM density, now also assessable in animal models through our approach, is increased in humans after acute stress, during PTSD and in depression. This relationship can now be exploited to match animal models more closely to clinical situations, especially in animal models of depression.