Elsevier

Sleep Medicine Reviews

Volume 11, Issue 2, April 2007, Pages 113-133
Sleep Medicine Reviews

Physiological Review
The involvement of dopamine in the modulation of sleep and waking

https://doi.org/10.1016/j.smrv.2006.08.003Get rights and content

Summary

Dopamine (DA)-containing neurons involved in the regulation of sleep and waking (W) arise in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc). The VTA and SNc cells have efferent and afferent connections with the dorsal raphe nucleus (DRN), the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT), the locus coeruleus (LC), the lateral and posterior hypothalamus (LH), the basal forebrain (BFB), and the thalamus. Molecular cloning techniques have enabled the characterization of two distinct groups of DA receptors, D1-like and D2-like receptors. The D1 subfamily includes the D1 and D5 receptors, whereas the D2 subfamily comprises the D2, D3, and D4 receptors. Systemic administration of a selective D1 receptor agonist induces behavioral arousal, together with an increase of W and a reduction of slow wave sleep (SWS) and REM sleep (REMS). Systemic injection of a DA D2 receptor agonist induces biphasic effects, such that low doses reduce W and increase SWS and REMS (predominant activation of the D2 autoreceptor), whereas large doses induce the opposite effect (predominant facilitation of the D2 postsynaptic receptor). Compounds with DA D1 or D2 receptor blocking properties augment non-REMS and reduce W. Preliminary findings tend to indicate that the administration of a DA D3-preferring agonist induces somnolence and sleep in laboratory animals and man. DA neurons in the VTA and the SNc do not change their mean firing rate across the sleep-wake cycle. It has been proposed that DA cells in the midbrain show a change in temporal pattern rather than firing rate during the sleep-wake cycle. The available evidence tends to indicate that during W there occurs an increase of burst firing activity of DA neurons, and an enhanced release of DA in the VTA, the nucleus accumbens (NAc), and a number of forebrain structures. A series of structures relevant for the regulation of the behavioral state, including the DRN, LDT/PPT, LC, and LH, could be partly responsible for the changes in the temporal pattern of activity of DA neurons.

Introduction

Dopamine (DA) was recognized as an independent neurotransmitter in the late 1950s. Soon after, it was proposed that DA reduction at striatal sites could be related to the symptoms of Parkinson′s disease, and that DA could also be implicated in the mechanism of action of neuroleptic drugs.1 Although much of the attention since then has been given to DA in locomotor activity, sensorimotor integration, and motivation,2 attempts have also been made to elucidate the role of DA in the regulation of sleep and waking (W).3, 4, 5 However, as compared with investigations of the role of other neurotransmitters, progress has been slow and laborious. This has been related to some extent to the proposal by Jones et al.6 that DA neurons of the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) are involved only in the maintenance of behavioral arousal, and to the finding by Trulson et al.7, 8 that these cells do not change their mean firing rate across the sleep-wake cycle.

Section snippets

Dopamine synthesis and metabolism

Labeled DA does not cross the blood-brain barrier, which indicates that the central nervous system (CNS) depends upon local neuronal biosynthesis. Dopamine in the brain is formed from l-tyrosine, which must be transported across the blood-brain barrier into the DA cell. The rate-limiting step in the synthesis of DA is the conversion of l-tyrosine to l-dihydroxyphenylalanine (l-Dopa), catalyzed by the enzyme tyrosine hydroxylase, which is localized in the cytosol of catecholamine-containing

Dopaminergic nuclei and pathways

The dopamine neuron systems relevant to sleep and waking are located in the upper mesencephalon and have been termed the long-length systems.12 One group of DA neurons arises mainly in the SNc and terminates in the dorsal striatum. A second group of DA neurons arises in the VTA and projects to: (a) the septal area, olfactory tubercle, nucleus accumbens, amygdaloid complex, and piriform cortex (mesolimbic projection), and (b) the medial prefrontal, cingulate, and entorhinal areas (mesocortical

Dorsal raphe nucleus

Pasquier et al.14 and Wirtshafter et al.15 characterized a direct projection from the DRN to the SNc of the rat by means of a retrograde axonal transport method. The majority of these neurons have been found to project also to the caudate-putamen.16, 17

The serotonergic innervation of the rat VTA has been examined using light and electron microscopic radioautography.18 [3H]5-HT labeled axons have been detected throughout the ventral portion of the VTA, where they form synapses, both with

Operational characteristics of DA receptors

Molecular cloning techniques have enabled the characterization of two distinct groups of DA receptors, D1-like and D2-like receptors. The D1 subfamily includes the D1 and D5 receptors, whereas the D2 subfamily comprises the D2–D4 receptors. The D1 and D2 receptors have a wider distribution and predominate in the CNS as compared with the D3–D5 receptors.

The D1 receptor is a postsynaptic receptor. It is coupled to adenylate cyclase and its stimulation facilitates the activity of the enzyme. Rat

Firing pattern of DA-containing neurons in the midbrain

Grace and Bunney67, 68 originally proposed that DA-containing neurons in the midbrain fire in one of two patterns: (a) slow, irregular spontaneous action potentials or (b) bursts of spikes that show a progressive decrease in amplitude and increase in duration. The average intraburst frequency is higher in the conscious animal as compared with the anesthetized one.69 Both the spontaneous spike firing and the burst firing are modulated by afferent inputs from a number of cortical and subcortical

Glutamatergic and cholinergic afferents

The glutamatergic innervation of the VTA and the SNc arises predominantly from three neuroanatomical structures: the medial prefrontal cortex (mPFC), the subthalamic nucleus (STN), and the PPT/LDT nuclei.76, 86, 87, 88 Dopamine cells of the VTA and the SNc also receive cholinergic afferents from the PPT/LDT.

The excitatory projection from the rat mPFC to the VTA and the SNc originates from pyramidal neurons of cortical layer V, and its stimulation induces the release of GLU at postsynaptic sites.

Role of dopamine in the regulation of behavioral arousal

Several approaches have been followed to characterize the role of DA in the regulation of behavioral arousal. They include (1) identification of the effect of lesions of DA-containing cells of the SNc and the VTA; (2) characterization of the changes occuring in DA D1−5-receptor deficient mice, and in animals injected with a D2 or D3 antisense vector; and (3) determination of the changes that follow the administration of DA-receptor agonists and antagonists. This last aspect will be dealt with

Role of dopamine in the regulation of EEG arousal

The data pertinent to the role of DA in the regulation of sleep and W have been obtained mainly from (1) DAT knockout mice; (2) animals with neurotoxin-provoked cell loss in the SNc and the VTA; and (3) pharmacologic studies in which selective and relatively selective DA receptor agonists and antagonists have been administered to laboratory animals and man.

Clinical context and perspective

Nocturnal sleep is frequently disrupted in patients with Parkinson′s disease (PD). Several factors compromise sleep in these patients, including bradykinesia, rigidity, obstructive sleep apnea, and periodic leg movements. Levodopa, dopamine agonists, anticholinergic medications, and other drugs used in PD may indirectly improve or worsen sleep by changing motor symptoms or promoting W.186, 187

Excessive daytime sleepiness (EDS) is also a common problem in PD; it limits the symptomatic treatment

Conclusions

Although many questions remain about the role of DA in regulating sleep and W, recent genetic, electrophysiological, and neuropharmacological studies have revealed much detailed information about this process. Attempts to characterize the role of DA receptors on sleep variables have been limited to investigations of the D1–D3 receptors. Most studies have examined the effect of systemic administration of selective and relatively selective agonists and antagonists on sleep and W in the rat. More

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