Narcolepsy is a chronic sleep disorder, likely with an autoimmune component. During 2009 and 2010, a link between A(H1N1)pdm09 Pandemrix vaccination and onset of narcolepsy was suggested in Scandinavia. In this study, we searched for autoantibodies related to narcolepsy using a neuroanatomical array: rat brain sections were processed for immunohistochemistry/double labeling using patient sera/cerebrospinal fluid as primary antibodies. Sera from 89 narcoleptic patients, 52 patients with other sleep-related disorders (OSRDs), and 137 healthy controls were examined. Three distinct patterns of immunoreactivity were of particular interest: pattern A, hypothalamic melanin-concentrating hormone and proopiomelanocortin but not hypocretin/orexin neurons; pattern B, GABAergic cortical interneurons; and pattern C, mainly globus pallidus neurons. Altogether, 24 of 89 (27%) narcoleptics exhibited pattern A or B or C. None of the patterns were exclusive for narcolepsy but were also detected in the OSRD group at significantly lower numbers. Also, some healthy controls exhibited these patterns. The antigen of pattern A autoantibodies was identified as the common C-terminal epitope of neuropeptide glutamic acidisoleucine/α-melanocyte-stimulating hormone (NEI/αMSH) peptides. Passive transfer experiments on rat showed significant effects of pattern A human IgGs on rapid eye movement and slow-wave sleep time parameters in the inactive phase and EEG θ-power in the active phase. We suggest that NEI/αMSH autoantibodies may interfere with the fine regulation of sleep, contributing to the complex pathogenesis of narcolepsy and OSRDs. Also, patterns B and C are potentially interesting, because recent data suggest a relevance of those brain regions/neuron populations in the regulation of sleep/arousal.arcolepsy is a chronic neurological disease characterized by irresistible daytime sleepiness (hypersomnia) and disturbed nocturnal sleep. Narcolepsy can be divided into two types: narcolepsy with cataplexy (NC) and narcolepsy without cataplexy. A typical feature of NC is sudden loss of muscle tone triggered by emotions (cataplexy). Other symptoms of narcolepsy are, for example, hypnagogic or hypnopompic hallucinations and sleep paralyses (1). The age of onset is usually around 12-16 y of age, but the disease is often diagnosed several years later (1). It affects ∼25-50 per 100,000 individuals, and the yearly incidence rate has been estimated to be around 1 per 100,000 person-y (2). Narcolepsy has a major negative impact on the quality of life, afflicting both physical and mental parameters (3). A major hallmark of narcolepsy (mostly NC) is the loss of hypocretin-1/ orexin-A (Hcrt/Orx), a neuropeptide hormone initially discovered independently by two groups (4, 5), by either a destruction of the orexinergic neurons or a selective down-regulation of Hcrt/Orx expression (6, 7). Consequently, a typical feature of NC is low levels (<110 pg/mL) of Hcrt/Orx peptide in the cerebrospinal fluid (CSF) (1).The causes of the loss of Hcrt/Orx and narcolep...
Although the 5-HT(5) receptor subfamily was discovered more than 15 years ago, it is unambiguously the least known 5-HT receptor subtype. The G(i)/G(0)-mediated signal transduction and its intensive presence in raphe and other brainstem and pons nuclei suggest mechanisms similar to those of 5-HT(1) receptors, the ligands of which are already applied in the treatment of e.g. anxiety and migraine. In addition, a unique coupling and inhibition of adenosine diphosphate-ribosyl cyclase have also been described. High concentrations of 5-HT(5) receptor in other key regions including, e.g. locus coeruleus, nucleus of the solitary tract, arcuate and suprachiasmatic nuclei of the hypothalamus indicate a wide range of physiological effects, thus its ligands are potential drug candidates in various areas, e.g. anxiety, sleep, incontinence, food intake, learning and memory, pain or chemoreception pathways. These findings have motivated several institutes and pharmaceutical companies to participate in the research of this field. Despite extensive research, no selective agonist and only two selective antagonists have been identified until now. Beyond these compounds, the present review provides a complete overview on all other published 5-HT(5A) receptor ligands as well as on the structure, function, distribution, genetics and possible therapeutic applications of this receptor.
The effects of the widely used selective serotonin reuptake inhibitor (SSRI) antidepressants on sleep have been intensively investigated. However, only a few animal studies examined the effect of escitalopram, the more potent S-enantiomer of citalopram, and conclusions of these studies on sleep architecture are limited due to the experimental design. Here, we investigate the acute (2 and 10 mg/kg, i.p. injected at the beginning of the passive phase) or chronic (10 mg/kg/day for 21 days, by osmotic minipumps) effects of escitalopram on the sleep and quantitative electroencephalogram (EEG) of Wistar rats. The first 3 h of EEG recording was analyzed at the beginning of passive phase, immediately after injections. The acutely injected 2 and 10 mg/kg and the chronically administered 10 mg/kg/day escitalopram caused an approximately three, six and twofold increases in rapid eye movement sleep (REMS) latency, respectively. Acute 2-mg/kg escitalopram reduced REMS, but increased intermediate stage of sleep (IS) while the 10 mg/kg reduced both. We also observed some increase in light slow wave sleep and passive wake parallel with a decrease in deep slow wave sleep and theta power in both active wake and REMS after acute dosing. Following chronic treatment, only the increase in REMS latency remained significant compared to control animals. In conclusion, adaptive changes in the effects of escitalopram, which occur after 3 weeks of treatment, suggest desensitization in the function of 5-HT(1A) and 5-HT(1B) receptors.
Serotonin 2C receptors (5-HT 2C Rs) are implicated in the pathomechanism and treatment of anxiety and depression. Recently, as a new biomarker of depression, alterations in the gamma power of the electroencephalogram (EEG) have been suggested. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram has been shown to cause sleep-wake stage-dependent alterations in gamma power. However, despite the antidepressant potency of 5-HT 2C R-antagonists, there is no data available regarding the effects of selective 5-HT 2C R-antagonists on gamma activity. Therefore, we investigate the acute effect of the 5-HT 2C R-antagonist SB-242084 on gamma power in different vigilance stages when given in monotherapy, or in combination with chronic escitalopram treatment. We administered SB-242084 (1 mg/kg, intraperitoneally) or vehicle to EEG-equipped rats after a 21-day-long pretreatment with escitalopram (10 mg/kg/day, via osmotic minipumps) or vehicle. Frontoparietal EEG, electromyogram, and motor activity were recorded during the first 3 h of passive phase, after the administration of SB-242084. Quantitative EEG analysis revealed that acute SB-242084 increased gamma power (30-60 Hz) in light and deep slow-wave sleep, and passive wakefulness. However, in active wakefulness, rapid eye movement sleep, and intermediate stage, no change was observed in gamma power. The profile of the effect of SB-242084 on gamma power was similar to that produced by chronic escitalopram. Moreover, SB-242084 did not alter chronic escitalopram-induced effects on gamma. In conclusion, the similarity in the effect of the 5-HT 2C R-antagonist and chronic SSRI on gamma power provides further evidence for the therapeutic potential of 5-HT 2C Rantagonists in the treatment of depression and/or anxiety.
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