Heather A. Mitchella and David Weinshenker , a,
a Department of Human Genetics, Emory University, Atlanta, GA 30322, United States
Received 1 September 2009;
accepted 2 October 2009.
Available online 13 October 2009.
Sleep is a crucial biological process that is regulated through complex interactions betweenmultiple brain regions and neuromodulators. As sleep disorders can have deleterious impacts on health and quality of life, a wide variety of pharmacotherapies have been developed to treat conditions of excessive wakefulness and excessive sleepiness. The neurotransmitter norepinephrine (NE), through its involvement in the ascending arousal system, impacts the efficacy of many wake- andsleep-promoting medications. Wake-promoting drugs such as amphetamine and modafinil increase extracellular levels of NE, enhancing transmission along the wake-promoting pathway. GABAergic sleep-promoting medications like benzodiazepines and benzodiazepine-like drugs that act more specifically on benzodiazepine receptors increase the activity of GABA, which inhibits NE transmission and the wake-promotingpathway. Melatonin and related compounds increase sleep by suppressing the activity of the neurons in the brain's circadian clock, and NE influences the synthesis of melatonin. Antihistamines block the wake-promoting effects of histamine, which shares reciprocal signaling with NE. Many antidepressants that affect the signaling of NE are also used for treatment of insomnia. Finally, adrenergic receptorantagonists that are used to treat cardiovascular disorders have considerable sedative effects. Therefore, NE, long known for its role in maintaining general arousal, is also a crucial player in sleep pharmacology. The purpose of this review is to consider the role of NE in the actions of wake- and sleep-promoting drugs within the framework of the brain arousal systems.
Graphical abstractKeywords: Norepinephrine; Locus coeruleus; Sleep; Wake; Arousal
Abbreviations: 5-HT, serotonin; AMP, adenosine monophosphate; AR, adrenergic receptor; BDNF, brain-derived neurotrophic factor; DA, dopamine; DAT, dopamine transporter; Dbh, dopamine beta hydroxylase; DMH, dorsal medial hypothalamus; DRN, dorsal raphe nucleus; EEG, electroencephalogram; GABA, gamma-aminobutyric acid; GPCR, Gprotein-coupled receptor; H, histamine (receptor); KO, knockout; LC, locus coeruleus; MAOI, monoamine oxidase inhibitor; MPOA, medial preoptic area; MSA, medial septal area; MT, melatonin (receptor); NE, norepinephrine; NET, norepinephrine transporter; PFC, prefrontal cortex; PKA, protein kinase A; REM, rapid eye movement; SCN, suprachiasmatic nucleus; SERT, serotonin transporter; SSRI, selective serotoninreuptake inhibitor; TCA, tricyclic antidepressant; TMN, tuberomammillary nucleus; TrkB, tyrosine kinase receptor B; VLPO, ventrolateral preoptic area; vPAG, ventral periaqueductal grey; z-drug, drug that acts specifically on the α1 subunit of the benzodiazepine receptor
1.2. Sleep disorders
1.3. Regulation of arousal states
1.4. NE and sleepregulation
2. Wake-promoting medications
3. Sleep-promoting medications
3.2. Benzodiazepine-related compounds
3.3. Melatonin and melatonin receptor agonists
3.6. Sedative effects of adrenergic drugs
Sleep is one ofthe most universal biological processes in existence. It is highly conserved, and creatures from Drosophila melanogaster and Caenorhabditis elegans to humans experience at least some form of it. Depriving an organism of sleep altogether can be extremely detrimental, and may even lead to death . Sleep is therefore considered necessary for life, but why this is so remains unclear. Sleep is...