Neuromodulator sleep

Baghdoyan, H. A. Lydic, R. (2002). Neurotransmitters and neuromodulators regulating sleep. In Sleep and Epilepsy The Clinical Spectrum, ed. C. W. Bazil, pp. 17 44. New York, NY Elsevier Science. 

Sakai, K. (1985). Neurons responsible for paradoxical sleep. In Sleep Neurotransmitters and Neuromodulators, ed. A. Wauquier and Janssen Research Foundation. 

Pace-Schott, E. F. Hobson, J. A (2002). Basic mechanisms of sleep New evidence on the neuroanatomy and neuromodulation of the NREM-REM cycle. In Neuropharmacology - The Fifth Generation of Progress, ed. D. Charney and C. Nemeroff, pp. 1859-77. Philadelphia, PA Lippincott Williams and Wilkins. 

The inhibitory neuromodulator, adenosine, is considered to be a major candidate for a sleep-inducing factor. Systemic or intracerebroventricular injec-... 

As with Thorazine, this discovery was both serendipitous and perspicacious. And, as with Thorazine, LSD s mechanism of action turned out to be related to the neuromodulators. In this case it was serotonin that was blocked, but dopamine transmission was also affected. The prominent effect on dopamine was activation. Recent work on serotonin-dopamine interaction suggests that serotonin may inhibit dopamine function such that a decrease in serotonin efficacy leads indirectly to dopamine enhancement. This combination of serotonin blockade and dopaminergic enhancement is interesting because it mimics the chemistry of REM sleep in which normal dreaming occurs. 

The first observation was the more unexpected because we were under the mistaken impression that the locus coeruleus should turn on, not off, in REM. But once we realized that we had the role of norepinephrine backwards, it was not difficult to find other REM-off cells—not only in the locus coeruleus, but also in the raphe nuclei—and to see that both of the pontine aminergic neuromodulators supported waking just as any extension of Hess s principles would suggest. Even the central sympathetic system works toward ergotrophic ends. Eor sleep to occur, this system must first be deactivated to allow NREM sleep to develop, and then actively suppressed, to allow REM to develop. 

With respect to the possible contribution of differential neuromodulation to the cognitive differences between sleeping and waking, we unfortunately have as yet very little direct evidence in humans. The indirect evidence constitutes the balance of this book. The psychopharmacological data from both medical and recreational drug sources generally supports the hypothesis, but there are many important exceptions that constitute problems for this aspect of the model. Two complementary facts at this chemical level of analysis strengthen the model ... 

We don t know the basis of this loss of temperature control, but we do know that REM sleep is itself associated with failure of the central thermostat, and we know that REM sleep deprivation also causes a loss of temperature. A unifying hypothesis is that any condition that potentiates REM sleep physiology may also compromise the central regulation of body temperature. Relevant to this hypothesis is the fact that the two brain stem aminergic neuromodulators that are inactivated in REM sleep are active in responding to thermal stress. 

How can enhancement and blockade of the same system result in such dissimilar alterations in consciousness In the case of acetylcholine, we find the answer not only in spatial differentiation, but also in the fact that acetylcholine activates the cortex in both waking and REM sleep but has quite different effects on consciousness because of the other neuromodulators serotonin and norepinephrine that are (in waking) or are not (in REM sleep) co-released. 

So far we have treated activation and modulation as separate processes. We will want to preserve that distinction even now as we explore their close interaction. In mania, whether it be driven by stimulants or by high levels of endogenous aminergic neuromodulator, the activation level is raised and the tendency to sleep is lowered. In depression, whether it comes in response to amine depletion by drugs like reserpine or to low levels of endogenous neuromodulators, the activation level is always low and the tendency to sleep may be high. There are notable exceptions to these rules, especially in depression, which is sometimes associated with extreme motor agitation and severe insomnia. 

In the discussion that follows we will focus mainly on norepinephrine, serotonin, and acetylcholine, the three neuromodulators most carefully studied by depression and sleep scientists. The dissociations that may occur among those three systems and other important neuromodulators like dopamine limit the value of the generalizations we can make today, but they nonetheless provide a solid grounding for the future work that will help us understand exceptions to the rules we can now lay down. 

Depression. Depression results from decreased efficacy of aminergic neuromodulation and reciprocal enhancement of the cholinergic system. Thus the set-point level of M declines. When subjects go to sleep they spend less time in stage IV and pass more rapidly to REM (seen as a decreased REM latency) and they spend a longer time in a more intense first REM period. When antidepressant medication raises M back up to normal levels, these sleep abnormalities disappear. 

In discussing schizophrenia, we have restricted our attention to the rule of neuromodulation. A second general rule concerns the excitability of the brain with special reference to phasic activity of the sort that drives the REM sleep process (on the one hand), and clinical seizures (on the other). In chapter 9, I pointed out some of the phenomenological and physiological processes that REM sleep and epilepsy share, and emphasized the importance to both of temporal lobe activation. 

Monti JM, Pellejero T, Jantos H and Pazos S (1985) In Sleep Neurotransmitters and Neuromodulators. Wauguier A, Gaillard JM, Monti JM, Radulovacki M(eds), Raven Press, New York, 197-209. 

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. 

None of this explains why memory is pre-empted. Nor does it explain how PGO waves arise in REM sleep. To unlock those puzzles, we needed the key provided by the discovery of control by neurons, i.e. neuromodulation, a special kind of chemical neurotransmission by which the brain is able to change its state... 

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