Sleep modulation disorders

Rye D. (2003). Modulation of normal and pathologic motoneuron activity during sleep. In Chokroverty S., Hening W., Walters A., editors. Sleep and Movement Disorders. Philadelphia, PA Butterworth-Heinemann pp. 94-119. 

Subsequent to the extensive medicinal chemistry exploration of Orexin antagonism, its utility in the treatment of sleep disorders in man has been reported recently. This important milestone for the therapeutic validation of the target results from the 0X1 /OX2 receptor antagonist ACT-078573 (20) [57], SB-649868 has also been announced to be in phase II clinical development, but neither the structural formula nor the results have been reported to date [58,59]. Moreover, insomnia treatments based on orexin modulation may be addressed by not only receptor antagonism but by inhibition of pathways related to the genesis of the bioactive peptides Orexin A or B, e.g. inhibition of Orexin-converting enzyme [60]. 

Bruxism mainly occurs in stage 2 sleep and REM sleep (Bader et ah, 1977). A relationship to stress and anxiety has been suggested, but the disorder can be chronic without apparent association with stress (Faulkner, 1990 Pierce et ah, 1995). It has been suggested that the central dopaminergic system may be involved in the modulation of sleep bruxism (Lobbezoo et al., 1997). Case reports indicate that bruxism can be induced by the SSRI paroxetine (Romanelli et al., 1996). The mechanism remains unclear possibilities include sleep disturbance, serotonergic-mediated inhibition of dopamine manifesting as akathisia, and SSRI-induced anxiety. SSRI-induced bruxism may respond to therapy with buspirone (Ellison et al., 1993). 

Nicholson AN, Pascoe PA Monoaminergic transmission and sleep in man, in Serotonin, Sleep and Mental Disorder. Edited by Idzikowski C, Cowen PJ. Petersfield, England, Wrightson Biomedical Publishing, 1991, pp 215-226 Nicholson AN, Pascoe PA, Stone BM Modulation of catecholamine transmission and sleep in man. Neuropharmacology 25 271-274, 1986 Nicholson AN, Pascoe PA, Turner C Modulation of sleep by trimipramine in man. Eur J Pharmacol 37 145-150, 1989a... 

Another approach considers the effects of various ligands on their receptors located in the diencephalic and mesiotemporal areas. Cell clusters in the hypothalamus coordinate the normal regulation of the vegetative functions of sleep, appetite, and sexual drive, which are typically disrupted in severe depression. In addition, the limbic area modulates many aspects of behavior and mood that are characteristically disturbed in affective disorders. 

Sleep loss is therefore common in and contributes powerfully to the development of psychosis. In the case of schizophrenia (now thought to be a disorder of excessive dopamine release and/or heightened effectiveness of dopamine), we can hypothesize an indirect but positive interaction with the other modulators of the awake state, noradrenaline and serotonin, and a direct negative interaction with acetylcholine. Significantly for my dreaming-as-delirium thesis, no distinctive changes in sleep are seen in chronic schizophrenia. 

In various brain areas neuronal histamine release and synthesis is regulated presynaptically by histamine H3 receptors [1]. Recent studies revestl that H3 receptors not only act as autoreceptors to regulate the release euid synthesis of histamine [2, 3], but also modulate the release of other neurotransmitters, like acetylcholine [4], serotonin [5], dopamine [6] and noradrenaline [7]. In view of these widespread modulatory activities of the histamine H3 receptors, important roles for this receptor subtype in the various mammalian brain functions have been indicated [8, 9]. Consequently, selective ligands for the H3 receptor have been suggested to be benificial in the treatment of e.g. epilepsia, Alzheimer disease, sleeping and attention-deficit disorders [10, 11,12, 13, 14, 15,16],... 

Alterations in 5-hydroxytryptamine (5-HT) neurotransmission have been implicated in a number of human disorders such as migraine, depression and anxiety as well as in normal human functions such as sleep, sexual activity and appetite. Unfortunately, the scientific association between 5-HT and these disorders has been largely suggestive rather than definitive. Nonetheless, recent advances in the understanding of 5-HT receptor subtypes have strengthened the ability to document specific links between modulation of 5-HT neurotransmission and human disease states. This brief chapter will present an overview of the current status of 5-HT receptor subtypes. 

Raiiy, R. V Heffeman, M. Pharmaceutical compositions comprising an agent with serotonin receptor modulating activity for sleep disorders. PCX Int. Appl. WO 2006069030, 2006 Chem. Abstr. 2006, 145, 110313. 

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