Physiological ReviewSerotonin control of sleep-wake behavior
Introduction
Within the central nervous system serotonin (5-HT) participates in a great number of functions including sleep-wake behavior, cognition, affect, sexual function, thermoregulation and food intake. It has been established, in addition, that increases or decreases of 5-HT at central sites correlate with improved or worsened depression. In this respect, most of the drugs used to treat mood disorders including the selective serotonin reuptake inhibitors (SSRIs), the tricyclic antidepressants and the monoamine oxidase inhibitors increase synaptic levels of 5-HT. The SSRIs are also the first line drugs for the treatment of anxiety disorders such as generalized anxiety disorder, panic disorder and obsessive compulsive disorder1.
Although many questions remain about the complicated role of 5-HT and its receptors in regulating sleep and wakefulness (W), recent studies have revealed much detailed information about this process. It should be mentioned that in the 1970s, based on lesion studies and neuropharmacological analysis, 5-HT was hypothesized to be responsible for the initiation and maintenance of slow wave sleep (SWS).2 However, a series of findings from several laboratories seriously challenged the serotonergic hypothesis of sleep. Thus, the firing rate of 5-HT-containing dorsal raphe nucleus (DRN) neurons decreases during SWS relative to W3; reduction of brain 5-HT by p-chlorophenylalanine (PCPA) fails to disrupt sleep in humans, and in some studies, also in the rat4, 5; 5,7-dihydroxytryptamine, which produces a more selective and extensive depletion of brain 5-HT than the raphe lesions, does not significantly affect SWS6; and there is no significant difference between tryptophan-deficient and -replete rats in time spent in SWS.7 Concerning those studies showing that PCPA increases W in the rat,8, 9 it should be taken into consideration that this 5-HT synthesis inhibitor also induces increased responsiveness to noxious or neutral environmental stimuli and enhances motor activity, aggressivity, and sexual activity.10, 11, 12, 13 Therefore, insomnia after PCPA in the rat and the cat could be related to a general hyper-responsiveness to stimuli rather than to impairment of sleep regulation itself. Even in the studies in which insomnia followed PCPA administration, the effect was a transitory one, and SWS returned while 5-HT levels remained depleted.14 Moreover, in rats subjected to combined treatment with PCPA and sleep deprivation, delta activity reached the same high levels as after deprivation alone, which tends to indicate that SWS-regulating mechanisms are not disrupted in PCPA-treated rats.15 With regard to an alternative hypothesis,16 there is no firm evidence to support the proposal that 5-HT released during W might act as a neurohormone and induce the synthesis and/or release of hypnogenic factors secondarily responsible for SWS and REM (rapid eye movement) sleep (REMS) occurrence.
More recently it has been posed that 5-HT should not be considered either wake-promoting or SWS-promoting, and that the effect of 5-HT on sleep-wake behavior would depend upon the degree to which the serotonergic system is activated (systemic administration of low vs. high doses of the 5-HT precursor 5-hydroxytryptophan), and the time at which the activation occurs (light vs. dark period of the light-dark cycle).17, 18, 19 It has been hypothesized that the 5-hydroxytryptophan-related increase of SWS during the dark period depends upon the synthesis or release of as yet to be identified sleep-promoting factors.17 Alternatively, sleep occurrence might be associated with a 5-HT1A receptor-mediated reduction in the activity of cholinergic waking-promoting neurons in the basal forebrain (BFB).20, 21
On the basis of results obtained from genetic, neurochemical, electrophysiological and neuropharmacological studies conducted over the past three decades it is proposed that 5-HT functions predominantly to promote W and to inhibit REMS. Notwithstanding this, under certain circumstances the indolamine seems to contribute to the increase in sleep propensity. The evidence that 5-HT is involved in the regulation of the behavioral state and its relationship to other sleep-wake regulatory neurotransmitters is the focus of this review.
The brain regions and neurotransmitter systems involved in the regulation of the behavioral state will be described next.
The brain regions involved in the promotion of the waking state are located in the brain stem, hypothalamus and BFB. The nuclei found in the brain stem include serotonin [5-HT: dorsal raphe nucleus (DRN), median raphe nucleus (MRN)]; norepinephrine [NE: locus coeruleus (LC)]; dopamine [DA: ventral tegmental area (VTA), substantia nigra pars compacta (SNc), ventral periaqueductal grey matter (VPGM)]; acetylcholine [ACh: laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT); BFB]; and glutamate [GLU: medial pontine reticular formation (mPRF); BFB]-containing neurons. The structures located in the hypothalamus include histamine [HA: tuberomammillary nucleus (TM)]; and orexin [OX: posterior lateral hypothalamus (LH) around the fornix ]-containing cells. The cholinergic and glutamatergic neurons of the BFB involved in the regulation of the behavioral state are located predominantly in the medial septum and the diagonal band of Broca.22, *23
The neural structures that participate in the regulation of W give rise to mainly ascending projections. In this respect, a) 5-HT-, NE-, and HA-containing neurons send long ascending projections to the thalamus, cerebral cortex, and BFB; b) DA-containing cells project into the basal ganglia (caudate and putamen, external and internal globus pallidus, subthalamic nucleus) and the frontal cortex; c) cholinergic neurons from the midbrain tegmentum (LDT/PPT) project to the thalamus (ventromedial, intralaminar, and midline nuclei) and the BFB, and cholinergic BFB neurons have widespread rostral projections to the cerebral cortex and the hippocampus; d) orexin-containing neurons from the LH project to the entire forebrain and brain stem arousal systems; and e) glutamatergic neurons make up the projection neurons of the mPRF and thalamus.*23, *24 All these ascending projections into the forebrain follow a dorsal and a ventral route.23 The dorsal route terminates in nonspecific thalamic nuclei, which in turn project to the cerebral cortex. The ventral route passes through the hypothalamus and continues into the BFB, where cells in turn project to the cerebral cortex and the hippocampus. In addition, a number of neural structures send descending projections to the spinal cord that modulate muscle tone.
Neurons of the preoptic area, anterior hypothalamus, and adjacent BFB constitute the sleep-inducing system.25 Sleep active neurons of the preoptic area are mainly located in the ventrolateral preoptic area (VLPO). A majority of these neurons contain γ-aminobutyric acid (GABA) and galanin, and project to the BFB and to brain stem and hypothalamic areas involved in the promotion of W including the DRN, LC, LDT/PPT and LH neurons. During SWS, the neurons of the VLPO inhibit the W-producing structures. A similar role has been proposed for the melanin-concentrating hormone (MCH). Accordingly, MCH-containing neurons located in the zona incerta, perifornical nucleus and lateral hypothalamic area facilitate sleep occurrence by inhibiting 5-HT, NE, ACh and OX neurons involved in the promotion of W.26 Of note, interleukin-1 (IL-1) increases SWS in several animal species, and the serotonergic system participates in the response. In this respect, the DRN contains IL-1 receptors; IL-1β inhibits the firing rates of DRN 5-HT neurons in a slice preparation; and microinjection of IL-1β into the DRN of freely behaving rats increases SWS.27 It has been determined, in addition, that IL-1β inhibits DRN 5-HT cells by potentiating GABAergic inhibitory effects.28
On the grounds of studies in which the cholinergic agonist carbachol was microinjected into rostral pontine structures of the cat, it has been proposed that the critical areas for REMS generation could be one or more of the following: a) the most ventral and rostral part of the pontine reticular nucleus; b) the perilocus coeruleus alpha nucleus (peri-LCα) of the mediodorsal pontine tegmentum; c) the rostral part of the rostral pontine tegmentum; d) the medial pontine reticular formation which encloses the rostral and caudal part of the pontine reticular nucleus and dorsally reaches the locus coeruleus alpha (LCα), or e) the ventral part of the pontine reticular nucleus.29, 30, 31 The reciprocal interaction hypothesis of REMS generation identifies cholinergic neurons of the LDT/PPT as promoting REMS and posits the inhibition of these neurons by, among others, serotonergic afferents from the DRN.32 The REMS induction region of the mPRF, one of the neuroanatomical structures proposed to be responsible for REMS generation, includes predominantly glutamatergic neurons, which are in turn activated by efferent connections of the LDT/PPT. The DRN provides the principal source of 5-HT innervation to the LDT/PPT and the REMS induction zone of the mPRF.33 Accordingly, serotonergic terminals have been characterized that make synaptic contacts with the soma and the proximal dendrites of cholinergic tegmental neurons, and with non-cholinergic, presumptively glutamatergic, neurons of the REMS induction zone of the mPRF.34 The DRN also sends ascending non-serotonergic projections to the LDT/PPT.35, 36
Section snippets
The structure and efferent and afferent connections of the dorsal raphe nucleus
Serotonergic neurons of raphe regions of the brain stem are regarded as forming caudal and rostral cell groups. The most caudal nuclei project mainly to the medulla and the spinal cord, whereas the most rostral cell aggregates innervate the telencephalon, diencephalon, mesencephalon, and rhombencephalon.37, 38 In this respect, most of the serotonergic innervation of the cerebral cortex, amygdala, BFB, thalamus, preoptic and hypothalamic areas, raphe nuclei, LC and pontine reticular formation
Serotonin receptors
Understanding the mode of action and effects of 5-HT receptors is fundamental to appreciating the physiological role of 5-HT on the behavioral state.
The 5-HT receptors can be classified into at least seven classes, designated 5-HT1–7. The 5-HT1, 5-HT2, 5-HT3 and 5-HT5 classes consist of five (5-HT1A–B–D–E–F), three (5-HT2A–B–C) and two (5-HT3A–B and 5-HT5A–B) subtypes, respectively, whereas the 5-HT4, 5-HT6 and 5-HT7 classes have at present one subtype each.45 Except for the 5-HT3 receptor, all
Firing pattern of serotonergic neurons of the DRN
Spontaneously active immunohistochemically identified 5-HT cells recorded in a slice preparation of the rat DRN are characterized by slow, rhythmic activity, a broad action potential, a large after hyperpolarization potential, and a decrease of their firing rate in response to the stimulation of the 5-HT1A somatodendritic receptor.65 Allers and Sharp66 characterized a group of neurons of the DRN immunoreactive for 5-HT or both 5-HT and tryptophan hydroxylase in urethane-anesthetized rats. The
The role of 5-HT in regulating wakefulness and REMS
Strategies aimed at determining the role of 5-HT receptors in the regulation of W and REMS have included: 1. genetic (knock-out) technology of several of the molecularly defined receptor subtypes; 2. local brain delivery of 5-HT receptor agonists and antagonists; 3. systemic and intracerebroventricular (i.c.v.) administration of 5-HT receptor ligands.
Clinical context and perspective
Ritanserin has been administered to poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder (GAD) or a mood disorder. Ritanserin 5 mg taken by poor sleepers for 20 days caused a large and significant increase in SWS during the early and the late drug period compared to baseline placebo nights. Concomitantly with the increase in SWS, there was a reduction in stage 2 sleep and in the frequencies of awakenings.134 The administration of
Conclusions
Attempts to characterize the role of serotonin receptors on sleep variables have been limited to the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6 and 5-HT7 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. Recently, results from several studies have quantified the spontaneous sleep/waking cycles in serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C or 5-HT7 receptor knock-out mice.
Limitations of the approaches used to study the role of 5-HT in the regulation of W and REMS
The selectivity of the knock-out technology has been emphasized on the grounds of a more specific impairment of 5-HT receptors than the neuropharmacological approach.149 However, the proposal would apply almost exclusively to mutant mice that do not express 5-HT1A or 5-HT1B receptor. Accordingly, opposite to animals treated sistemically with selective 5-HT1A or 5-HT1B receptor agonists where REMS is suppressed, knock-out mice show an increase of the behavioral state. On the other hand, data
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