Neuropharmacology of Sleep and Wakefulness
Section snippets
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.
References (196)
- et al.
Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence
Neurosci Biobehav Rev
(2007) Neurobiology of REM and NREM sleep
Sleep Med
(2007)- et al.
Forebrain and midbrain distribution of major benzodiazepine-sensitive GABAA receptor subunits in the adult C57 mouse as assessed with in situ hybridization
Neuroscience
(2007) - et al.
GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain
Neuroscience
(2000) - et al.
Microinjections of muscimol and bicuculline into the pontine reticular formation modify the sleep-waking cycle in the rat
Neurosci Lett
(1991) - et al.
Blockade of GABA, type A, receptors in the rat pontine reticular formation induces rapid eye movement sleep that is dependent upon the cholinergic system
Neuroscience
(2008) - et al.
GABAergic processes in the mesencephalic tegmentum modulate the occurrence of active (rapid eye movement) sleep in guinea pigs
Neuroscience
(2007) - et al.
Chronic low-amplitude electrical stimulation of the laterodorsal tegmental nucleus of freely moving cats increases REM sleep
Brain Res
(1996) - et al.
Enhancement of acetylcholine release during paradoxical sleep in the dorsal tegmental field of the cat brain stem
Neurosci Lett
(1990) - et al.
Microdialysis measurement of cortical and hippocampal acetylcholine release during sleep-wake cycle in freely moving cats
Brain Res
(1995)
Inhibition of synaptically evoked cortical acetylcholine release by adenosine: an in vivo microdialysis study in the rat
Neuroscience
Restoration of brain energy metabolism as the function of sleep
Prog Neurobiol
Caffeine reduces low-frequency delta activity in the human sleep EEG
Neuropsychopharmacology
Caffeine intake (200 mg) in the morning affects human and EEG power spectra at night
Brain Res
Adenosine and sleep-wake regulation
Prog Neurobiol
Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state
Behav Brain Res
Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study
Neuroscience
Sleep deprivation increases A1 adenosine receptor density in the rat brain
Brain Res
Adenosine inhibits basal forebrain cholinergic and noncholinergic neurons in vitro
Neuroscience
Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus
Neuroscience
Enhancement of rapid eye movement sleep in the rat by actions at A1 and A2a aednosine receptor subtypes with a differential sensitivity to atropine
Neuroscience
On-line detection of extracellular levels of serotonin in dorsal raphé nucleus and frontal cortex over the sleep/wake cycle in the freely moving rat
Neuroscience
Extracellular serotonin variations during vigilance states in the preoptic area of rats: a microdialysis study
Brain Res
Effects induced by the electrical stimulation of the nucleus raphé dorsalis upon hypothalamic release of 5-hydroxyindole compounds and sleep parameters in the rat
Brain Res
The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking
Prog Brain Res
Effects of activation and blockade of 5-HT2A/2C receptors in the dorsal raphé nucleus on sleep and waking in the rat
Prog Neuropsychopharmacol Biol Psychiatry
Effects of the serotonin 5-HT2A/2C receptor agonist DOI and of the selective 5-HT2A or 5-HT2C receptor antagonists EMD 281014 and SB-243213, respectively, on sleep and waking in the rat
Eur J Pharmacol
The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes
Brain Res Rev
Role of medial preoptic area beta adrenoceptors in the regulation of sleep-wakefulness
Pharmacol Biochem Behav
Relationship between locus coeruleus discharge rates and rates of norepinephrine release within the neocortex as assessed by in vivo microdialysis
Neuroscience
Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus
Brain Res
Role of noradrenergic and GABA-ergic inputs in pedunculopontine tegmentum for regulation of rapid eye movement sleep in rats
Neuropharmacology
Evidence for histaminergic arousal mechanisms in the hypothalamus of cats
Neuropharmacology
Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats
J Pharmacol Sci
A neurochemical perspective on states of consciousness
Neuroanatomy and neurochemistry of sleep
Cell Mol Life Sci
Hypothalamic regulation of sleep and arousal
Ann N Y Acad Sci
International union of pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update
Pharmacol Rev
Role of GABAA receptors in the physiology and pharmacology of sleep
Eur J Neurosci
GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits
J Comp Neurol
Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors
Nat Rev Neurosci
Extrasynaptic GABAA receptors are critical targets for sedative-hypnotic drugs
J Clin Sleep Med
The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia
Sleep
GABAA receptors in the pontine reticular formation of C57BL/6J mouse modulate neurochemical, electrographic, and behavioral phenotypes of wakefulness
J Neurosci
Evidence that wakefulness and REM sleep are controlled by a GABAergic pontine mechanism
J Neurophysiol
Pontine reticular formation (PnO) administration of hypocretin-1 increases PnO GABA levels and wakefulness
Sleep
γ-aminobutyric acid-mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia
Anesthesiology
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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.