Sleep-wake mechanisms

Are the various sleep and wake mechanisms constitutionally fixed to produce a given, fixed, optimal, daily sleep output This is unlikely given the apparent compensations for destroyed components of sleep-wake mechanisms and the apparently homeostatic compensations for lost sleep. 

Figure 13.2 Schematic representation of the molecular mechanisms of sleep wake regulation by PGD2, PGE2, adenosine, histamine, and orexin.

Hayaishi, O. (2005). Molecular mechanisms of sleep-wake regulation. In Sleep Circuits and Functions, ed. P.-H. Luppi, Boca Raton, FL CRC Press, pp. 65-82. 

Some CNS stimulants have an effect on the same systems that are involved in wakefulness, including glutamate-, NE-, DA-, 5-HT-, histamine-, hypocretin- and ACh-containing neurons. This group includes molecules such as cocaine, amphetamine, and nicotine. The sleep-promoting systems are concentrated in the medial part of the brainstem, dorsal reticular substance of the medulla, anterior hypothalamus, and basal forebrain (Jones 2005). Other stimulants, such as caffeine and theophylline, block some sleep-inducing mechanisms. Modafinil is also a CNS stimulant with an unknown mechanism of action. 

Ramelteon (Rozerem). Recently approved by the FDA for treatment of insomnia in the US, ramelteon acts via a completely novel mechanism of action, that is, stimulating so-called melatonin Ti and T2 receptors in the brain s suprachiasmatic nucleus (SCN). The SCN is regarded as the body s master clock that regulates the sleep-wake cycle and other circadian rhythms. The effects of ramelteon in some respects mimic those of melatonin. Ramelteon, in clinical trials, administered at bedtime doses of 8 mg, outperformed placebo with respect to several indices of sleep disturbance (see Table 9.4). 

Koella has reviewed the evidence implicating the involvement of serotonin in the sleep-wake cycle but the involvement of specific serotonin receptor subtypes in sleep mechanisms is unclear. Experimental evidence suggests that 5-HTia agonists delay the onset of REM sleep while 5-HT2 antagonists suppress REM and have variable effects on non-REM sleep. 

Edgar DM. In search of neurobiological mechanisms regulating sleep-wakefulness an empirical and historical account of two opponent processes. Sleep Res Soc Bull 1995 1 22-27. 

Hayaishi O. Molecular mechanisms of sleep-wake regulation roles of prostaglandins D2 and E2. FASEB J 1991 5 2575-2581. 

Lesion, stimulation, and neuronal activation studies have implicated a plethora of structures and substances in the control of sleep and wakefulness. References to the examples cited below can be found in Barbara Jones superb review on Basic Mechanisms of Sleep-Wake States (1). 

This seemingly variable mixture of several different sleep and wake mechanisms seems at odds with the relative stability of total sleep amounts. (This report focuses entirely on total sleep rather than specific sleep stages like REM and slow-wave sleep, which depend on more specific mechanisms and appear to be more reactive to presleep experience.)... 

Does a yet-unidentifled master controller, e.g., a specific brain center, balance the outputs of the various sleep and wake mechanisms to produce a stable total output If such a center does exist, one would guess that given the many experimental lesions made throughout the brain, it would have been discovered. 

The compensations for lost sleep suggest that the master control of total sleep may not reside in specific, localizable sleep effectors or neuromodulators, but in a stimulus generated by the need for sleep. Presumably, this need-stimulus activates several sleep centers and substances and deactivates wake centers and substances, which then contribute to the production of sleep to the extent that they are affected. (Conceivably, a need for wakefulness might conversely activate wake mechanisms and deactivate sleep mechanisms.) If one sleep or wake effector were destroyed or blocked by experimental or natural intervention, the need-generated stimulus would opportunistically recruit whatever systems were available to answer the need. When the need was satisfied, the effector systems would remain inactive no matter how prepared they were to function. 

Jones, BE. Basic mechanisms of sleep-wake states. In Rryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia Saunders, 2000 134-54. 

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