Elsevier

Sleep Medicine Reviews

Volume 16, Issue 2, April 2012, Pages 187-197
Sleep Medicine Reviews

Physiological Review
Noradrenergic modulation of wakefulness/arousal

https://doi.org/10.1016/j.smrv.2011.12.003Get rights and content

Summary

The locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus noradrenergic neurons has long-suggested a role of this system in the induction of an alert waking state. Work over the past two decades provides unambiguous evidence that the locus coeruleus, and likely other noradrenergic nuclei, exert potent wake-promoting actions via an activation of noradrenergic β- and α1-receptors located within multiple subcortical structures, including the general regions of the medial septal area, the medial preoptic area and, most recently, the lateral hypothalamus. Conversely, global blockade of β- and α1-receptors or suppression of norepinephrine release results in profound sedation. The wake-promoting action of central noradrenergic neurotransmission has clinical implications for treatment of sleep/arousal disorders, such as insomnia and narcolepsy, and clinical conditions associated with excessive arousal, such as post-traumatic stress disorder.

Introduction

The regulation of sleep and waking serves a critical role in behavior and ultimately survival. Moreover, during waking, arousal levels fluctuate, ranging from sleepiness/sedation associated with a relative insensitivity to sensory stimuli to high-arousal stress or fear-related conditions associated with a hypersensitivity to sensory events (hyperalertness, hypervigilance). Fluctuations in sleep-wake/arousal state are accompanied by alterations in forebrain neuronal activity that are reflected in electroencephalographic (EEG) signals.1, 2 The formal examination of the neurobiology of arousal/waking dates back to the work of von Economo,3 Bremer4 and Moruzzi and Magoun,5 which identified a critical role of the brainstem in the induction and maintenance of arousal. Subsequent work has identified a large array of brainstem and basal forebrain neural systems that participate in the regulation of behavioral state. Included among these is the locus coeruleus (LC)-noradrenergic system.

The LC is a small pontine nucleus that provides the majority of brain norepinephrine (NE).6 NE acts at three major receptor families, α1, α2, and β, each comprised of multiple subtypes. α1- and β-receptors are thought to exist primarily postsynaptically whereas α2-receptors are present both pre- and postsynaptically. Early electrophysiological observations indicated that the LC-NE system may play a role in the regulation of behavioral state.6, 7 For example, LC neurons display higher discharge rates during waking than in sleep while within waking LC discharge rate is positively correlated with behavioral and EEG indices of arousal.8, *9, *10 Importantly, these alterations in LC discharge rate precede changes in behavioral state.8, *9, *10 Combined, these observations suggested a potentially causal role of the LC-noradrenergic system in the regulation of sleep-wake/arousal state. Results from studies conducted over the past two decades provide unambiguous evidence for a prominent wake/arousal-promoting role of the LC and other brain noradrenergic systems (e.g., A1, A2), as reviewed below.

Section snippets

Wake/arousal-promoting actions of the locus coeruleus

Early lesion and pharmacological studies attempted to address whether there exists a causal relationship between LC neuronal activity and behavioral and EEG indices of waking/arousal (for review11, 12). In general, lesions of noradrenergic systems have had an inconsistent impact on indices of arousal (for review12). There is now strong reason to believe this limited action of noradrenergic lesions on behavioral state likely reflects the occurrence of time-dependent lesion-induced compensation

Neurocircuitry and receptor mechanisms of noradrenergic dependent waking: wake-promoting actions of α1- and β-receptors in the medial septal and medial preoptic areas

Collectively the observations reviewed above provide strong evidence that the LC-NE system exerts wake-promoting actions. This raises the question of which LC terminal fields and which postsynaptic receptors participate in these actions. Subcortically, the general regions of the medial septal area (MSA), the medial preoptic area (MPOA), and the substantia innominata (SI) are known to modulate forebrain EEG activity state25, 26, 27 and each of these regions receives LC-noradrenergic input.28, 29

Additional regions involved in NE-dependent waking

In addition to the MSA and MPOA, the lateral hypothalamus (LH) has been implicated in the regulation of sleep-wake state and state-dependent processes.65, 66 In particular, the neuropeptide family, hypocretin (HCRT; orexin), exerts potent wake-promoting actions.67, 68 HCRT-synthesizing neurons are located solely in the perifornical region of the LH, an area that receives a moderately dense noradrenergic innervation most of which arises from outside the LC.69, 70 Recently completed studies

Synergistic actions of β- and α1-receptors in the maintenance of alert waking

Substantial evidence indicates that stimulation of either α1- or β-receptors within any one of a number of brain regions is sufficient to induce the alert waking state. This high degree of redundancy suggests that α1-/β-receptor action in any given region is unlikely to be necessary for the maintenance of alert waking, consistent with observations reviewed above regarding a lack of effect of β-antagonist infusions into the MSA on indices of arousal in unanesthetized animals. To initially

Potential sleep-promoting actions of α1-receptors within the MPOA

In contrast to the robust wake-promoting effects of NE agonists infused into the MPOA and MSA, 6-OHDA lesions of the ventral noradrenergic bundle (VNAB) have been reported to increase time spent awake.85 This has been interpreted as suggesting a potential sleep-promoting action of NE, particularly within the MPOA.86 However, as noted above, 6-OHDA lesion of the VNAB will not eliminate all VNAB noradrenergic input to the MPOA. Moreover there are multiple sources of the noradrenergic innervation

Behavioral state modulatory actions of norepinephrine occur in conjunction with other behavioral actions

Evidence reviewed above indicates potent arousal-promoting actions of the LC-NE and presumably other noradrenergic systems. However, this is not to say that the sole function of the central noradrenergic systems is the regulation of arousal. Indeed, NE-induced arousal occurs in tandem with a large variety of modulatory actions of NE on physiological and behavioral processes, including endocrine regulation, perception, motor function, attention and memory, and decision and action (for review12).

Clinical relevance

The wake and arousal-promoting actions of central noradrenergic neurotransmission may have clinical relevance in a number of conditions associated with the dysregulation of sleep and waking and/or arousal. For example, the data reviewed above demonstrate that under normal conditions, acute activation of LC-noradrenergic signaling is incompatible with the state of sleep. Thus, inappropriate excitatory drive on this system, which can arise from upstream regions including the prefrontal cortex and

Conclusion

The regulation of arousal is a critical aspect of normal behavior. A substantial body of work demonstrates a prominent role of the LC and other noradrenergic systems in the regulation of waking and arousal. NE-dependent waking/arousal involves additive/synergistic actions of α1- and β-receptors located within multiple subcortical regions. Combined, the available evidence indicates that under normal physiological conditions even moderate activity of the LC-NE system is incompatible with the

Acknowledgments

This work was supported by PHS grants MH62359, DA10681, DA00389 and the University of Wisconsin Graduate School.

References (99)

  • R. Vetrivelan et al.

    Tonic activity of alpha1 adrenergic receptors of the medial preoptic area contributes towards increased sleep in rats

    Neuroscience

    (2006)
  • R. Szymusiak et al.

    Hypothalamic control of sleep

    Sleep Med

    (2007)
  • T. Osaka et al.

    Noradrenaline inhibits preoptic sleep-active neurons through alpha 2-receptors in the rat

    Neurosci Res

    (1995)
  • M. Modirrousta et al.

    Gabaergic neurons with alpha2-adrenergic receptors in basal forebrain and preoptic area express c-Fos during sleep

    Neuroscience

    (2004)
  • E.A. Stone et al.

    Regulation of alpha and beta components of noradrenergic cyclic AMP response in cortical slices

    Eur J Pharmacol

    (1987)
  • D.J. Stewart et al.

    Topographical projection of cholinergic neurons in the basal forebrain to the cingulate cortex in the rat

    Brain Res

    (1985)
  • R.C. Meibach et al.

    Efferent connections of the septal area in the rat: an analysis utilizing retrograde and anterograde transport methods

    Brain Res

    (1977)
  • T. Ino et al.

    Direct projections of non-pyramidal neurons of Ammon’s horn to the supramammillary region in the cat

    Brain Res

    (1988)
  • C.W. Berridge et al.

    Contrasting effects of noradrenergic beta-receptor blockade within the medial septal area on forebrain electroencephalographic and behavioral activity state in anesthetized and unanesthetized rat

    Neuroscience

    (2000)
  • S.E. Loughlin et al.

    Efferent projections of nucleus locus coeruleus: topographic organization of cells of origin demonstrated by three-dimensional reconstruction

    Neuroscience

    (1986)
  • M. Sarter et al.

    Abnormal regulation of corticopetal cholinergic neurons and impaired information processing in neuropsychiatric disorders

    Trends Neurosci

    (1999)
  • G.G. Berntson et al.

    Blockade of epinephrine priming of the cerebral auditory evoked response by cortical cholinergic deafferentation

    Neuroscience

    (2003)
  • R.A. España et al.

    Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action

    Neuroscience

    (2001)
  • A. Yamanaka et al.

    Regulation of orexin neurons by the monoaminergic and cholinergic systems

    Biochem Biophys Res Commun

    (2003)
  • L. Bayer et al.

    Opposite effects of noradrenaline and acetylcholine upon hypocretin/orexin versus melanin concentrating hormone neurons in rat hypothalamic slices

    Neuroscience

    (2005)
  • M.M. Thakkar

    Histamine in the regulation of wakefulness

    Sleep Med Rev

    (2011)
  • D.R. Stevens et al.

    Nicotinic depolarizations of rat medial pontine reticular formation neurons studied in vitro

    Neuroscience

    (1993)
  • C.W. Berridge et al.

    Synergistic sedative effects of noradrenergic alpha(1)- and beta- receptor blockade on forebrain electroencephalographic and behavioral indices

    Neuroscience

    (2000)
  • V.M. Kumar et al.

    Sleep-inducing function of noradrenergic fibers in the medial preoptic area

    Brain Res Bull

    (1993)
  • V.M. Kumar et al.

    Noradrenergic afferents and receptors in the medial preoptic area: neuroanatomical and neurochemical links between the regulation of sleep and body temperature

    Neurochem Int

    (2007)
  • E. Mogilnicka

    Increase in beta- and alpha 1-adrenoceptor binding sites in the rat brain and in the alpha 1-adrenoceptor functional sensitivity after the DSP-4-induced noradrenergic denervation

    Pharmacol Biochem Behav

    (1986)
  • R. Vetrivelan et al.

    Sleep induction and temperature lowering by medial preoptic alpha(1) adrenergic receptors

    Physiol Behav

    (2006)
  • B.A. Reyes et al.

    Amygdalar peptidergic circuits regulating noradrenergic locus coeruleus neurons: linking limbic and arousal centers

    Exp Neurol

    (2011)
  • M.A. Raskind et al.

    A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder

    Biol Psychiatry

    (2007)
  • M.C. Bushnell et al.

    Behavioral enhancement of visual responses in monkey cerebral cortex. I. modulation in posterior parietal cortex related to selective visual attention

    J Neurophysiol

    (1981)
  • E.V. Evarts

    Effects of sleep and waking on spontaneous and evoked discharge of single units in visual cortex

    Fed Proc

    (1960)
  • C. Von Economo

    Sleep as a problem of localization

    J Nerv Ment Dis

    (1930)
  • F. Bremer

    Cerebral activity during sleep and narcosis: contribution to the study of the mechanisms of sleep

    Bull Acad Royale Med Belgique

    (1937)
  • S.L. Foote et al.

    Nucleus locus ceruleus: new evidence of anatomical and physiological specificity

    Physiol Rev

    (1983)
  • S.L. Foote et al.

    Extrathalamic modulation of cortical function

    Annu Rev Neurosci

    (1987)
  • G. Aston-Jones et al.

    Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle

    J Neurosci.

    (1981)
  • S.L. Foote et al.

    Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal

    Proc Natl Acad Sci USA 1980

    (1980)
  • J.A. Hobson et al.

    Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups

    Science

    (1975)
  • C.H. Vanderwolf et al.

    Reticulo-cortical activity and behavior: a critique of the arousal theory and a new synthesis

    Behav Brain Sci

    (1981)
  • E.D. Abercrombie et al.

    Partial injury to central noradrenergic neurons: reduction of tissue norepinephrine content is greater than reduction of extracellular norepinephrine measured by microdialysis

    J.Neurosci

    (1989)
  • E. Castaneda et al.

    Changes in striatal dopamine neurotransmission assessed with microdialysis following recovery from a bilateral 6-OHDA lesion: variation as a function of lesion size

    J Neurosci

    (1990)
  • T.E. Robinson et al.

    Time course of recovery of extracellular dopamine following partial damage to the nigrostriatal dopamine system

    J Neurosci

    (1994)
  • P. Lidbrink et al.

    Effects of intracerebral injections of 6-hydroxydopamine on sleep and waking in the rat

    J Pharm Pharmacol

    (1973)
  • P.J. Gatti et al.

    Central nervous system site of action for the hypotensive effect of clonidine in the cat

    J Pharmacol Exp Ther

    (1988)
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