Elsevier

Sleep Medicine Clinics

Volume 5, Issue 4, December 2010, Pages 513-528
Sleep Medicine Clinics

Neuropharmacology of Sleep and Wakefulness

https://doi.org/10.1016/j.jsmc.2010.08.003Get rights and content

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γ-aminobutyric acid

The major inhibitory neurotransmitter in the brain is γ-aminobutyric acid (GABA), and activation of GABAA receptors causes neuronal inhibition by increasing chloride ion conductance. Because of their powerful inhibitory effects, GABAA receptors are the targets of most sedative-hypnotic and general anesthetic drugs. GABAA receptors exist as multiple subtypes9 and these subtypes are differentially located throughout the brain.10 The differences in clinical effects caused by various benzodiazepine

Acetylcholine

Acetylcholine is distinguished as being the first identified neurotransmitter. Although the first neurochemical theory of sleep28 correctly posited that acetylcholine plays a primary role in generating the brain-activated states of wakefulness and REM sleep, cholinergic drugs are not part of the standard pharmacologic armamentarium of sleep disorders medicine. Nonetheless, understanding the mechanisms by which cholinergic neurotransmission generates and maintains REM sleep is crucial, because

Adenosine

Adenosine is a breakdown product of adenosine triphosphate (ATP). Increases in endogenous adenosine levels in a specific brain region during a period of prolonged wakefulness indicate that the region has been metabolically active. Direct biochemical measures show that ATP levels increase during sleep in areas of the brain that are most active during wakefulness.47 This finding provides direct support for the hypothesis that sleep serves a restorative function.48

Four subtypes of adenosine

Biogenic amines

The monoamines have long been known to promote wakefulness. Serotonin (5-hydroxytryptamine; 5HT)-containing neurons of the dorsal raphé nucleus (see Fig. 1), norepinephrine-containing neurons of the locus coeruleus (see Fig. 1), and histamine-containing neurons of the tuberomammillary nucleus (see Fig. 1) discharge at their fastest rates during wakefulness, slow their firing in NREM sleep, cease discharging before and during REM sleep, and resume firing before the onset of wakefulness.2

Glutamate

Glutamate is the main excitatory neurotransmitter in the brain and acts at α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate, and N-methyl-d-aspartate (NMDA) ionotropic receptors. Surprisingly, little is known about glutamatergic regulation of sleep and wakefulness. Sleep state-dependent changes in levels of endogenous glutamate change differentially across the brain.116 For example, glutamate levels in some areas of rat cortex show increases in concentration during

Peptides

Many peptides are known to modulate sleep.130 This article focuses on hypocretin (orexin), leptin, and ghrelin because of their relevance for sleep disorders medicine.

Opioids

Opioids are the major class of drugs used to treat acute and chronic pain, and one side effect of opioids is sleep disruption. Sleep disruption, in turn, exacerbates pain183, 184 and increases the dose of opioids required for successful pain management.69, 70 Clinically relevant doses of opioids given to otherwise healthy humans disrupt sleep.185 For example, a single intravenous infusion of morphine in healthy volunteers decreases stages 3 and 4 NREM sleep, decreases REM sleep, and increases

Future directions

This selective overview was completed during the summer of 2010, a date also marking the 20th anniversary of the human genome project. The stunning successes—and unmet hopes—of genomic approaches to medicine were highlighted in the June 12th and 14th issues of The New York Times.192, 193 These two articles offer a sobering reminder that taking a molecule from preclinical discovery to commercially available drug typically requires 15 or more years. This time interval is without any mandate to

Acknowledgments

We thank Mary A. Norat and Sarah L. Watson for critical comments on this article.

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    Disclosure Statement: This work supported by National Institutes of Health grants: HL40881, HL65272, HL57120, MH45361, and the Department of Anesthesiology. This work was not an industry-supported study and the authors have no financial conflicts of interest.

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