Antagonism of serotonergic 5-HT2A/2C receptors: mutual ... - CiteSeerX

European Journal of Neuroscience

European Journal of Neuroscience, Vol. 29, pp. 1795–1809, 2009

doi:10.1111/j.1460-9568.2009.06718.x

REVIEW

Antagonism of serotonergic 5-HT2A ⁄ 2C receptors: mutual improvement of sleep, cognition and mood? H.-P. Landolt1,2 and R. Wehrle1 1 2

Institute of Pharmacology and Toxicology, University of Zu¨rich, Winterthurerstrasse 190, 8057 Zu¨rich, Switzerland Zu¨rich Center for Integrative Human Physiology (ZIHP), University of Zu¨rich, Zu¨rich, Switzerland

Keywords: APD125, daytime functions, eplivanserin, insomnia, pharmacogenetics, serotonin receptors, slow wave sleep

Abstract Serotonin [5-hydroxytryptamine (5-HT)] and 5-HT receptors are involved in sleep and in waking functions such as cognition and mood. Animal and human studies support a particular role for the 5-HT2A receptor in sleep, which has led to renewed interest in this receptor subtype as a target for the development of novel pharmacological agents to treat insomnia. Focusing primarily on findings in healthy human volunteers, a review of the available data suggests that antagonistic interaction with 5-HT2A receptors (and possibly also 5-HT2C receptors) prolongs the duration of slow wave sleep and enhances low-frequency (< 7 Hz) activity in the sleep electroencephalogram (EEG), a widely accepted marker of sleep intensity. Despite certain differences, the changes in sleep and the sleep EEG appear to be remarkably similar to those of physiologically more intense sleep after sleep deprivation. It is currently unclear whether these changes in sleep are associated with improved vigilance, cognition and mood during wakefulness. While drug-induced interaction with sleep must be interpreted cautiously, too few studies are available to provide a clear answer to this question. Moreover, functional relationships between sleep and waking functions may differ between healthy controls and patients with sleep disorders. A multimodal approach investigating subjective and objective aspects of sleep and wakefulness provides a promising research avenue for shedding light on the complex relationships among 5-HT2A ⁄ 2C receptormediated effects on sleep, the sleep EEG, cognition and mood in health and various diseases associated with disturbed sleep and waking functions.

Introduction The neurotransmitter and neuromodulator serotonin (5-hydroxytryptamine, 5-HT) plays fundamental roles in the mechanisms regulating a variety of brain functions including distinct aspects of sleep, cognition, affect and many others (Adrien, 2002; Ursin, 2002; Cools et al., 2008). Disturbances of sleep such as acute and chronic insomnia are highly prevalent in all societies around the world (Ohayon, 2002). The symptoms of insomnia include difficulties in initiating or maintaining sleep, nonrestorative or poor quality of sleep, and impaired daytime functioning including cognitive and emotional impairments associated with inadequate sleep (ICSD-2 2005; see also Riemann & Kloepfer, 2009; this issue of EJN). Nonpharmacological options such as cognitive behavioral therapy and ⁄or hypnotics acting as allosteric agonistic modulators of c-amino-butyric-acid type A (GABAA) receptors currently provide the strategies most often used to treat insomnia symptoms (Smith et al., 2002; Morin et al., 2007; Wafford & Ebert, 2008; see also Winsky-Sommerer, 2009; this issue of EJN). In addition, off-label prescription of sedating antidepressants that often interfere with serotonergic neurotransmission is highly common in patients with sleep problems. The serotonergic system and in particular the serotonin-2 (5-HT2) receptor subtypes have recently

Correspondence: H.-P. Landolt, 1Institute of Pharmacology and Toxicology, as above. E-mail: [email protected] Received 16 November 2008, revised 7 January 2009, accepted 14 January 2009

emerged as among the most promising targets in the search for effective and well-tolerated novel medications for treating primary and secondary sleep disorders (Teegarden et al., 2008; Wafford & Ebert, 2008). The aims of the present overview are to outline and summarize the current knowledge of mechanisms involving 5-HT and the 5-HT2 receptors for the regulation of sleep, and possible functional relationships among sleep, cognition and mood. Specifically, we address the question of whether pharmacological interaction with 5-HT2A ⁄ 2C receptors (or a distinct 5-HT2 receptor subtype when selectivity has been shown) may promote physiological sleep and improve cognitive and affective functions, which are typically impaired as a consequence of inadequate sleep. To this end we review, after a brief general introduction to the significance of 5-HT and 5-HT receptors in the central nervous system (CNS), primarily (pharmaco)genetic, imaging and behavioural data obtained in healthy humans, but also include selected findings from clinical, animal and in vitro studies.

Serotonin in the central nervous system Sixty years ago, a then-unidentified serum factor capable of inducing vasoconstriction was named serotonin to indicate its origin from blood serum and its effect on vascular muscle tone (Rapport et al., 1948). Subsequent chemical analyses revealed that the molecule was 5-HT and was closely related to the essential amino acid tryptophan, which is the dietary precursor of 5-HT. Soon it was discovered that 5-HT is

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd

1796 H.-P. Landolt and R. Wehrle also present in the brain, especially in the limbic system and hypothalamus (Twarog & Page, 1953; Amin et al., 1954). It is believed today that 90% of 5-HT in the human body exists in the mucous membranes of the gastrointestinal system, 8–10% in blood platelets and 1–2% in the CNS (Feldman et al., 1997). The potential significance of 5-HT in the CNS became evident when the potent hallucinogen lysergic acid diethylamide (LSD) was shown to antagonize the contractile action of 5-HT in smooth muscle preparations (Gaddum, 1953; Woolley & Shaw, 1954). Moreover, it has been reported that the antipsychotic drug reserpine reduces the intestinal 5-HT concentration (Pletscher et al., 1955) and that the antidepressants imipramine and iproniazide alter 5-HT levels in platelets (Marshall et al., 1960). Dahlstrom & Fuxe (1964) described nine morphologically different 5-HT-containing cell groups in the CNS, the majority of which originate in the raphe nuclei and the reticular region of the lower brainstem. The axons of these cell clusters project caudally to the spinal cord and rostrally to numerous parts of diencephalon, mesencephalon, basal ganglia, limbic structures and all regions of the neocortex. It was found that 80% of the brain serotonergic terminals originate in the dorsal raphe nuclei (DRN) and median raphe nuclei, which can be considered the major source of brain serotonergic innervation (Fig. 1; also Holmes, 2008; Vertes & Linley, 2008). The serotonin precursor l-tryptophan competes with other large, neutral and branched-chain amino acids for a carrier protein to be actively transported into the brain. The serotonergic neurons contain all proteins needed to synthesize 5-HT (Sanders-Bush & Mayer, 2006). Newly formed 5-HT is accumulated in synaptic vesicles, where it is protected from the metabolizing enzyme monoamine oxidase (MAO). Released 5-HT is efficiently removed from the synapse by high-affinity, Na+-dependent, presynaptic 5-HT transporters (5-HTT; aka SERT). In nonserotonergic neurons and glia cells, 5-HT is rapidly metabolized by the MAO isoform MAO-A to 5-hydroxy-indolacetic acid. Consistent with the notion that 5-HT acts not only as a neurotransmitter but also as a neuromodulator, 5-HT is also released

Fig. 1. Schematic illustration of the serotonergic system and 5-HT2A receptor density in humans. Originating in the dorsal raphe nucleus in the pons, serotonergic neurons innervate the cortex and the limbic system but also subcortical structures such as thalamus, basal ganglia and cerebellum (arrows). Areas with high 5-HT2A receptor density are highlighted in red. Highest receptor density is found in prefrontal and orbitofrontal cortex, (subgenual) anterior cingulate cortex, occipital and parietal cortex (van Dyck et al., 2000; Adams et al., 2004; Hinz et al., 2007).

from axonal varicosities without distinct synaptic contacts (Descarries et al., 1990; Sanders-Bush & Mayer, 2006).

Multiple serotonin receptors More than a dozen 5-HT receptor subtypes mediate the wide range of physiological effects of 5-HT. The existence of more than one 5-HT binding site was first suggested in the isolated guinea pig ileum (Gaddum & Picarelli, 1957). Later, Peroutka and Snyder reported that radio-labeled ligand binding at 5-HT receptors in rat frontal cortex was ligand-dependent and displaced with different potencies by 5-HT, LSD and spiperone. These authors concluded that distinct 5-HT receptor subtypes also exist in the brain and proposed that 3H-5-HT and 3 H-spiperone labeled different receptor populations, which they referred to as 5-HT1 and 5-HT2 receptors, respectively (Peroutka & Snyder, 1979). In the meantime, seven 5-HT receptor families (5-HT1–7) comprising 14 distinct receptor subtypes have been identified in mammals. The characteristics and potential psychopharmacological significance of 5-HT receptor subtypes have been comprehensively covered in recent reviews (Aghajanian & Sanders-Bush, 2002; Geyer & Vollenweider, 2008; Hannon & Hoyer, 2008; Holmes, 2008) and can not be discussed in detail. Briefly, convergent findings from studies using research techniques derived from molecular biology, biochemistry, pharmacology and (electro)physiology have demonstrated that all currently known 5-HT receptor subtypes are encoded by separate

Fig. 2. (A) Schematic representation of the 5-HT2A receptor. Each 5-HT2A receptor consists of seven transmembrane domains. The third cytoplasmatic loop and the carboxy terminal are thought to be important for G-protein coupling. Upon activation, the G-protein induces an intracellular cascade involving phospholipase C, Ca2+ release from intracellular storage sites and MAP kinase pathways. (B) The 5-HT2A receptors are located on apical dendrites of pyramidal cells (cortical layer V), inducing neuronal excitation, and (C) are also found on GABA-ergic interneurons exerting inhibitory effects.

ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 29, 1795–1809

5-HT2A ⁄ 2C receptors, sleep, cognition and mood 1797 genes and have distinct patterns of distribution in the CNS. They are located on postsynaptic membranes and modulate ion flux to primarily mediate an excitatory, depolarizating (5-HT2, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptors) or inhibitory, hyperpolarizing (5-HT1 and possibly 5-HT5 receptors) neuronal response. Certain subtypes such as the 5-HT1A and 5-HT1B receptors are also located presynaptically at somas, dendrites or nerve terminals, where they serve as 5-HT autoreceptors, depressing neuronal firing and inhibiting 5-HT release upon activation. Except for the 5-HT3 receptor (a ligand-gated ion channel), all other 5-HT recognition sites belong to the superfamily of G-protein-coupled receptors (GPCRs) and activate intracellular responses via distinct signal transduction pathways. Like other GPCRs they consist of seven transmembrane domains, which are connected by intra- and extracellular loops with multiple sites for potential glycolysation, phosphorylation and palmitoylation (Hartig, 1989; Saltzman et al., 1991; Glennon et al., 2000; Aghajanian & Sanders-Bush, 2002; also Fig. 2).

The 5-HT2 receptor subtypes There are three known subtypes of 5-HT2 receptors: 5-HT2A, 5-HT2B and 5-HT2C receptors. The 5-HT2A receptor now refers to the classical ‘D receptor’ initially described by Gaddum & Picarelli (1957), and later defined as the 5-HT2 receptor by Peroutka & Snyder (1979), the 5-HT receptor with low affinity for 3H-5-HT and high affinity for 3 H-spiperone. Early on, many central and peripheral actions of serotonergic agents were attributed to a 5-HT2A as opposed to a 5-HT1 mechanism. This was due to the availability of what was then considered a selective 5-HT2A (vs. 5-HT1) receptor antagonist, ketanserin. The 5-HT2B and 5-HT2C receptors were previously thought to belong to the ‘5-HT1-like’ family (Hannon & Hoyer, 2008). However, they exhibit considerable sequence homology with the 5-HT2A binding site and are coupled to the same second messenger system, i.e., the phosphoinositol signaling pathway (Fig. 2). The 5-HT2A receptors are located on apical dendrites on pyramidal cells and, particularly in subcortical regions, on local (GABA-ergic) interneurons (Jakab & Goldman-Rakic, 1998; Barnes & Sharp, 1999; Aghajanian & Sanders-Bush, 2002; also Fig. 2). Stimulation of 5-HT2A receptors on glutamatergic dendrites increases the release of glutamate through a presynaptic mechanism, and has a direct postsynaptic excitatory effect by activating phospholipase C and mobilizing intracellular Ca2+ via G-protein coupling (Aghajanian & Sanders-Bush, 2002). When the receptors are expressed in Xenopus oocytes, the increase in intracellular Ca2+ concentration induces a rapid Cl) ion current through a Ca2+-dependent Cl) channel. 5-HT2A receptor activation also induces the closing of a K+ channel, leading to depolarization of the cell. Discovery of 5-HT2C receptors, the demonstration of limited selectivity of ketanserin for the 5-HT2A receptor subtype and evidence suggesting that 5-HT2A receptors exhibit different states of affinity have weakened earlier conclusions about the distinct roles for the 5-HT2A receptors in physiological brain mechanisms (Glennon et al., 2004). In contrast to most other GPCRs, chronic blockade of 5-HT2A ⁄ 2C receptors appears to lead to a (paradoxical) down-regulation rather than an (expected) up-regulation of receptors (Van Oekelen et al., 2003).

Distribution of 5-HT2 receptors in the brain The 5-HT-induced increase in excitatory postsynaptic currents is most pronounced in rat brain slices obtained from frontal cortical areas

(Aghajanian & Marek, 1997). This finding reflects the regional distribution of 5-HT2A receptors, which is higher in that region of the rat brain than in more posterior regions. High levels of 5-HT2A binding sites, 5-HT2A receptor mRNA and 5-HT2A receptor-like immunoreactivity are also found in many cortical areas (neocortex, entorhinal and pyriform cortex and claustrum), caudate nucleus, nucleus accumbens, olfactory tubercule and hippocampus (Pompeiano et al., 1994; Barnes & Sharp, 1999; Lopez-Gimenez et al., 2001). The regional distribution of 5-HT2A receptors within the brain has major impact on their differential functionality, ranging from inhibition via location on GABA-ergic cells such as in locus coeruleus, hippocampus, piriform cortex and basolataral amygdala, to excitatory effects on glutamatergic neurons in medial prefrontal cortex and in inferior olivary nucleus within medulla oblongata, which is functionally linked to the cerebellum. Not all functional interactions of regionspecific 5-HT2A receptors are yet established. Their distributions and functions in the human brain were first studied post mortem (Pazos et al., 1987). Today, they can be investigated in living human subjects using positron emission tomography (PET) with increasingly selective 5-HT2A receptor radioligands such as 3H-ketanserin, 18F-setoperone, 18 F-spiperone, 18F-altanserin and 11C-volinanserin (M[DL] 100907) (Wong et al., 1987; Sadzot et al., 1995; Meltzer et al., 1998; van Dyck et al., 2000; Hall et al., 2000; Moresco et al., 2002; Adams et al., 2004; Hinz et al., 2007; Palomero-Gallagher et al., 2008). In good agreement with the data obtained in rats and primates, the majority of findings suggest highest 5-HT2A receptor density in frontal (including prefrontal, frontomedial and orbitofrontal cortex), (subgenual) anterior cingulate, occipital and parietal cortex (Fig. 1 and Table 1). Accordingly, the preferential 5-HT2A receptor agonist psilocybin increases glucose metabolic rates most markedly in frontomedial, frontolateral and anterior cingulate cortex (Vollenweider et al., 1997). Lower receptor density is found in limbic areas such as insula, amygdala and hippocampus, and in basal ganglia. Lowest to no ligand uptake is reported for cerebellum and pons. It should be kept in mind, however, that a minority of these ligands show true 5-HT2A receptor subtype selectivity. Normative data in healthy volunteers suggest that the specific binding of 18F-altanserine declines with age (Sheline et al., 2002; Adams et al., 2004). In frontal and temporal areas, it also correlates with the body-mass index (Adams et al., 2004). Specific radio tracers for 5-HT2B and 5-HT2C receptors are scarce or not available. In humans, mRNA encoding the 5-HT2B receptor is abundantly expressed in liver and kidney, whereas lower expression levels are found in cerebral cortex and whole-brain preparations (Bonhaus et al., 1995). The 5-HT2C receptor is present in the choroid plexus, hypothalalmus, basal ganglia and parts of the limbic system (Hietala et al., 2001; Anderson et al., 2002).

Human genetics of 5-HT2A ⁄ 2C receptors The 5-HT2C receptor was among the first 5-HT receptors to be cloned. Given its similar characteristics to the 5-HT2A receptor with respect to pharmacology and signal transduction, the DNA sequence of the latter was established based on homology cloning (Hannon & Hoyer, 2008). Nevertheless, activation of 5-HT2A and 5-HT2C receptors may elicit distinct behavioral effects, for example in relation to premature impulsive responses (Winstanley et al., 2004). The gene encoding the human 5-HT2A receptor (HTR2A) is located on chromosome 13q14–q21 (Barnes & Sharp, 1999). It consists of three exons separated by two introns and spans > 63 kb (Serretti et al., 2007). A total of 299 single-nucleotide polymorphisms (SNP) of


1798 H.-P. Landolt and R. Wehrle Table 1. Pharmacology of 5-HT2 receptors Examples of

Agonists 5-HT2A subtype DOB, DOI, LSD, psilocybin, a-methyl-5-HT, TFPP, TGBA01AD

5-HT2B subtype a-Methyl-5-HT, m-CPP, DOI, (LSD)

5-HT2C subtype a-Methyl-5-HT, m-CPP, DOI, LSD, TFPP

Inverse agonists

APD125, pimavanserin (ACP-103)

Physiological role and clinical significance

Antagonists

Receptor density in CNS

Ketanserin, spiperone, trazodone, altanserin, ritanserin, seganserin, clozapine, olanzapine, quetiapine, seganserin, risperidone, mianserin, (es)mirtazapine (ORG 50081), eplivanserin (SR 46349), volinanserin (M 100907), pruvanserin (EMD 281014), LY-53857, HY 10275 (LY2624803), TGWOOAD ⁄ AA, doxepin, AVE8488

High receptor density in: prefrontal ⁄ orbitofrontal cortex, anterior cingulate gyrus, occipital cortex, parietal cortex, superior temporal cortex, sensorimotor cortex. Intermediate receptor density in: insula, putamen ⁄ pallidum, caudate nucleus, amygdala ⁄ hippocampus

Psychosis, anxiety, depression,sleep, eating behavior

LY-53857, SB-204 741, RS 127445, agomelatine, LY-156735 (TIK-301)

Low receptor density in: cerebellum, lateral septum, dorsal hypothalamus, medial amygdala*

Eating behaviour, brain development

Mesulergine, ritanserin, clozapine, olanzapine, seganserin, RS-102221, SB-242 084, SP 243213, (es)mirtazapine (ORG 50081), agomelatine,doxepin, LY-53857, LY156735 (TIK-301)

Intermediate receptor density in: choroid plexus, anterior cingulate gyrus, hippocampus ⁄ amygdala, basal ganglia, hypothalamus

Migraine, eating behaviour, sleep, depression, anxiety, nociception, epilepsy treatment

Substances that show high affinity for the respective 5-HT2 receptor, and ⁄ or are currently evaluated for sleep or affective disorders are reported [cf. http:// www.clinicaltrials.com and http://www.neurotransmitter.net (last accessed on 1.10.2008)]. DOB, 1-(2,5-dimethoxy-4-bromophenyl)-2-amino-propane; DOI, 1-(2,5dimethoxy-4-iodophenyl)-2-amino-propane; m-CPP, 1-(3-chloro-phenyl)piperazine; LSD, d-lysergic acid diethylamide; TFPP, trifluoromethylphenylpiperazine. *based on animal data. Relative affinities: a-methyl-5-HT, high affinity for 5-HT2A receptor, intermediate affinity for 5-HT2C receptor; LY-53857, higher affinity for 5-HT2A receptor, lower affinity for 5-HT2C receptor; doxepin, also acting as selective norepinephrine re-uptake inhibitor (SNRI) and antagonist at a1, histamine H1 and muscarinic acetyl-choline receptor antagonist; agomelatine, 5-HT2B ⁄ 2C antagonist and melatonin MT1 receptor agonist; LY-156735, also acting as melatonin (MT) receptor agonist.

HTR2A have been identified to date and have been investigated as functional candidates in various neuropsychiatric disorders (see Serretti et al., 2007 for a recent overview). The most widely investigated SNPs of HTR2A are 102 T ⁄ C (rs6313), )1438 A ⁄ G (rs6311) and His452Tyr (= 1354 C ⁄ T, rs6314). It appears that the first two polymorphisms could be considered together because they are in complete linkage disequilibrium. The 102 T ⁄ C polymorphism does not result in any change in the amino acid sequence of the 5-HT2A receptor, yet may change the secondary structure of the transcript and its stability and translational activity. The )1438 A ⁄ G variation is close to the promoter region and could influence gene expression, similar to the His452Tyr polymorphism, which is located in the C-terminal region, another putatively functional area of HTR2A (Serretti et al., 2007). Taken together, the C allele of the 102 T ⁄ C polymorphism, the G allele of the )1438 A ⁄ G polymorphism and the 452Tyr variant of the His452Tyr polymorphism are supposed to reduce 5-HT2A receptor density or functional availability in the brain. The most consistent findings related to 5-HT2A receptor polymorphisms revealed links to psychotic disorders (Serretti et al., 2007) and suicide attempts (Li et al., 2006). Apart from reducing serotonergic neurotransmission, existing evidence suggest that 5-HT2A receptor alterations lead to unfavourable interaction with or reduction of dopaminergic mechanisms, especially in prefrontal cortex (Di Pietro & Seamans, 2007; Serretti et al., 2007).

Serotonin and sleep–wake regulation Defined changes in electroencephalogram (EEG), electromyogram and electro-oculogram serve in mammals and birds to discriminate three basic states of vigilance, i.e., wakefulness, non-rapid-eye-movement (nonREM) sleep and rapid-eye-movement (REM) sleep. In humans, visually-scored stages 3 and 4 of nonREM sleep are referred to as slow wave sleep (SWS), which is characterized by the preponderance of EEG slow waves (< 2 Hz) with high amplitude. Computer-aided quantification of prevalence and amplitude of waves with distinct frequencies strongly suggest that predictable changes in delta (0.5– 4 Hz), theta (5–9 Hz) and sigma (11–15 Hz) frequencies reliably reflect the physiological processes underlying sleep–wake regulation. More specifically, EEG delta, theta and sigma activity in nonREM sleep depend on the prior history of waking and sleep, and are widely accepted markers of nonREM sleep intensity (Fig. 3).

The serotonergic system and wakefulness A typical serotonergic neuron of the DRN exhibits the highest discharge rate in waking, shows diminished activity in nonREM sleep and is virtually silent shortly before and during REM sleep (McGinty & Harper, 1976; Trulson & Jacobs, 1979; Ogasahara et al., 1980; yet also see Sakai & Crochet, 2001). This firing pattern is mimicked by changes in the extracellular 5-HT concentration across sleep–wake


5-HT2A ⁄ 2C receptors, sleep, cognition and mood 1799 of initial arousal followed by increased synchronized brain activity (Koella & Czicman, 1966). For example, the biosynthetic precursor of 5-HT, l-tryptophan, and the irreversible MAO inhibitor phenelzine induce drowsiness and increase theta power ( 5–8 Hz) in the waking EEG in animals and humans (Ursin, 1976; Landolt & Gillin, 2002). Whether this effect is mediated by a direct action of 5-HT and ⁄ or increased plasma levels of the 5-HT derivative melatonin has not been resolved yet.

The serotonergic system and sleep

Fig. 3. The 5-HT2A receptor antagonist eplivanserin increases low-frequency activity (0.25–6 Hz) and reduces spindle frequency activity (11–14 Hz) in nonREM sleep similar to sleep deprivation. Relative EEG power density values after prolonged wakefulness (40 h) and administration of eplivanserin and gaboxadol are expressed as a percentage of the corresponding values after normal wake duration (16 h) and administration of placebo (100%, dashed horizontal lines). Values are plotted in the middle of the frequency bins. Error bars are ± SEM. (Upper panel) Effect of sleep deprivation (n = 21). Data from Re´tey et al. (2006). (Lower panel) Effect of 1 mg eplivanserin administered 3 h before bedtime (n = 10). Data from Landolt et al., 1999. The effect of the selective extrasynaptic GABA receptor agonist gaboxadol (15 mg) administered 30 min before bedtime (n = 77) is illustrated for comparison. Values were replotted from published data (Walsh et al., 2007). Triangles above abscissae denote frequency bins for which power differed from placebo (P < 0.05, twotailed, paired t-test).

alternations in rats and cats (Portas & McCarley, 1994; Portas et al., 1998; Python et al., 2001; Penalva et al., 2003) and elevated 5-HT levels in several rat brain areas including the hippocampus during sleep deprivation (Asikainen et al., 1997; Penalva et al., 2003). These and other data are consistent with the notion that serotonergic neurotransmission stimulates wakefulness and is partially (in nonREM sleep) or almost completely (in REM sleep) turned off during sleep. Several studies indicate that serotonergic influences during wakefulness could prepare the brain and organism for sleep (Jones, 2005). Electrical stimulation of the raphe nuclei in cats does not produce sleep, yet elicits behavioral inhibition (‘drowsiness’). This effect could reflect attenuation of other systems that normally stimulate cortical activation and arousal. Indeed, 5-HT inhibits cholinergic cells in laterodorsal–pedunculopontine tegmentum and basal forebrain in vitro and in vivo (Luebke et al., 1992; Sanford et al., 1994). Furthermore, microinjections of 5-HT into the basal forebrain decrease highfrequency EEG activity, further indicating that serotonergic influences attenuate cortical activation and induce quiet waking or prepare the onset of sleep (Cape & Jones, 1998). Consistent with the electrophysiological data, pharmacological stimulation of the serotonergic system may induce a biphasic response

Based on early pharmacological, anatomical, physiological and biochemical data a direct role for 5-HT in promoting sleep was proposed (Jouvet, 1972). Subsequent experiments, however, investigating the effects of manipulating the brain 5-HT concentration in different species questioned the general validity of the ‘serotonin hypothesis’ of sleep (see Borbe´ly, 1983 for discussion). Although unit recordings and microdialysis studies supported the view that the brain 5-HT levels are intimately associated with the sleep–wake cycle, the accumulating data warranted modified interpretations. Jouvet (1999) proposed that 5-HT release in the hypothalamus participates in the wake-dependent accumulation of sleep propensity. In vitro electrophysiological studies show that 5-HT either inhibits or excites distinct neurons in the hypothalamic ventrolateral preoptic (VLPO) area (Gallopin et al., 2000, 2005). The galanin ⁄ GABAcontaining cells of the VLPO are thought to play an important role in initiation and maintenance of sleep, and reciprocal projections to the DRN are well established (Sherin et al., 1998; Gervasoni et al., 2000). Serotonergic cells of the DRN may be part of the inhibitory input to the VLPO during wakefulness (Chou et al., 2002), whereas the VLPO may modulate DRN firing in nonREM and REM sleep (Sherin et al., 1998). On the other hand, 5-HT excites a distinct subpopulation of sleep-active VLPO neurons, referred to as Type-2 cells, which appear to increase firing before the actual onset of sleep (Gallopin et al., 2005). These data support a dual role for 5-HT in the VLPO. Nevertheless, the underlying mechanisms and structures mediating the serotonergic modulation of wakefulness and sleep are far from being established. Preclinical and clinical studies have long shown that serotonergic drugs developed as antidepressants or antipsychotics affect sleep (Adrien, 2002; Cohrs, 2008). The first pharmacological agents to treat major depressive disorder were irreversible MAO inhibitors such as phenelzine. It was later discovered that these compounds eliminate REM sleep in healthy subjects and patients treated for depression and narcolepsy (Wyatt et al., 1969; Akindele et al., 1970). To further explore the consequences of MAO inhibitor-induced elimination of REM sleep, the effects of therapeutic phenelzine treatment on sleep and sleep EEG topography were studied in detail. It was found that REM sleep can be pharmacologically eliminated without disrupting the natural dynamics of the physiological process underlying nonREM sleep (Landolt et al., 2001; Landolt & Gillin, 2002). Increased serotonergic neurotransmission following inhibition of 5-HT reuptake by the 5-HTT is among the most important principles of action of currently used antidepressant medications. A functional variable-number tandem-repeat polymorphism in the 5¢-promoter region of the 5-HTT gene (SLC6A4) is consistently associated with psychiatric diagnoses and individual differences in the efficacy of antidepressant treatments. In vitro studies show that basal transcriptional activity of the long variant (L) allele is more than doubled when compared to the short (S) variant allele (Lesch et al., 1996). This difference may affect serotonergic tone and 5-HT receptor-mediated


1800 H.-P. Landolt and R. Wehrle neurotransmission (David et al., 2005). Clinical data indicate that the presence of the S allele is associated in healthy individuals undergoing a chronic stress situation with reduced subjective sleep quality as measured with the Pittsburgh Sleep Quality Index (Brummett et al., 2007). In depressed patients, carriers of the S allele were reported to show higher risk for new or worsening insomnia symptoms during treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Perlis et al., 2003), and less favourable response to therapeutic sleep deprivation (Benedetti et al., 1999). Administration of a tryptophan-free drink, a mixture of large amino acids all competing for active transport across the blood–brain barrier, reduces plasma tryptophan and provides an experimental approach in humans to transient reduction of brain 5-HT synthesis and decrease in cerebral 5-HT receptor binding (Nishizawa et al., 1997; Yatham et al., 2001; for review, see Moore et al., 2000). Double-blind administration of a tryptophan-free drink disinhibits REM sleep in remitted depressed patients despite continued MAO inhibitor administration (Landolt et al., 2003). By contrast, total sleep time, sleep efficiency and the sleep EEG are not affected. Thus, the pharmacological modulation of serotonergic neurotransmission provides the first nondisruptive, double-blind method for studying human subjects overnight with and without REM sleep. This method provides a novel strategy for investigating the functions of REM sleep, and the roles of 5-HT and REM sleep in regulating, for example, nonREM sleep, cognition and mood.

Serotonin receptor subtypes and sleep One major difficulty in reconciling earlier findings about the effects of 5-HT on sleep is related to the large number of 5-HT receptors and their distinct local expression within the CNS. The available literature suggests that, among all 5-HT receptors subtypes studied to date, primarily 5-HT1 and 5-HT2 receptors are involved in quantitative and qualitative aspects of wakefulness, nonREM sleep and REM sleep. Their possible roles, in particular those of 5-HT2A ⁄ 2C receptors, will be covered in the second part of this overview. In addition, recent pharmacological studies in rats indicate that a 5-HT6 receptor antagonist promotes nonREM sleep (Morairty et al., 2008) and that local injection into the DRN of 5-HT7 or 5-HT3 receptor agonists or antagonists, respectively, transiently reduces the expression of REM sleep (Monti & Jantos, 2008; Monti et al., 2008).

(Gillin et al., 1996; Seifritz et al., 1997). Studies in knock-out mice support a role for 5-HT1A receptors in the regulation of REM sleep and also suggest that 5-HT1B receptors are also involved (Boutrel et al., 1999, 2002).

5-HT2 receptors and sleep Pharmacological interaction with 5-HT2A ⁄ 2C receptors has no consistent effects on REM sleep (Idzikowski et al., 1986; Sanford et al., 1998). By contrast, studies in rats and humans have long shown that non-subtype-specific 5-HT2A ⁄ 2C receptor agonists increase wakefulness and inhibit SWS, whereas antagonists such as ritanserin, seganserin, eplivanserin (SR 46349[B]) and volinanserin enhance the duration of SWS and EEG low-frequency activity (LFA) in nonREM sleep (Idzikowski et al., 1986; Borbe´ly et al., 1988; Dijk et al., 1989; Dugovic et al., 1989; Katsuda et al., 1993; Sharpley et al., 1994; Landolt et al., 1999; Viola et al., 2002; Morairty et al., 2008). In both healthy volunteers and poor sleepers, the enhancement of SWS is robust and substantial (50–80%; Sharpley et al., 1994; Landolt et al., 1999; Viola et al., 2002), and the changes in the EEG power spectrum are remarkably similar to those induced by physiological intensification of nonREM sleep such as after sleep deprivation (Fig. 3). Eplivanserin is currently in late phase III clinical development for sleep disorders. It is considered to be a selective 5-HT2A receptor antagonist, at least in rodents (Rinaldi-Carmona et al., 1992; Van Oekelen et al., 2003). To further characterize the role for 5-HT2A receptors in sleep–wake regulation in humans, and to address the question whether the eplivanserin-induced sleep changes reflect physiological sleep mechanisms, the effects of a 1-mg dose on the sleep EEG were compared with those of prolonged wakefulness. In enhancing EEG LFA (0.5–7 Hz) and reducing spindle-frequency activity (11–14 Hz) in nonREM sleep, this compound mimicked the effect of sleep deprivation (Fig. 3). Nevertheless, some aspects of the drug-induced changes in the EEG power spectrum differed from those of prolonged wakefulness (Landolt et al., 1999). The results of the study indicate that altering the balance between 5-HT2A and 5-HT1A receptor activity is necessary, although maybe not sufficient, for inducing the physiological changes in the sleep EEG which are typically seen in response to sleep deprivation.

5-HT1 receptors and sleep

Mechanism underlying 5-HT2A ⁄ 2C receptor antagonist-induced promotion of nonREM sleep?

The 5-HT1A receptor appears to contribute substantially to the promotion of wakefulness and the inhibition of REM sleep (Boutrel et al., 2002; for review, see Adrien et al., 2004). Consistent with that notion, it has long been established that many antidepressants that increase overall serotonergic tone inhibit REM sleep (Adrien, 2002). Converging observations from preclinical and clinical studies support a key role for the 5-HT1A receptor in the inhibition of REM sleep. First, high levels of 5-HT1A receptor mRNA and binding sites are located on cholinergic cells of the rat laterodorsal–pedunculopontine tegmentum (Pompeiano et al., 1992), a major brain stem region thought to promote REM sleep (McCarley et al., 1995). Second, the laterodorsal–pedunculopontine tegmentum nuclei receive serotonergic projections from the DRN (Honda & Semba, 1994). Third, 5-HT and 5-HT1A receptor agonists such as 5-CT (carboxyamidotryptamine maleate) and 8-OH-DPAT inhibit cholinergic cells in vitro and in vivo (see above). Fourth, agonists of postsynaptic 5-HT1A receptors and an antagonist of presynaptic 5-HT1A autoreceptors inhibit REM sleep

The exact mechanisms underlying the 5-HT2A ⁄ 2C receptor antagonistinduced sleep changes are currently unknown. Interestingly, various studies suggest that the increase in SWS and LFA may be very similar to the effects of compounds which tonically activate GABAA receptors in the brain (also see Winsky-Sommerer, 2009; this issue of EJN). In healthy humans, single doses of the 5-HT2A ⁄ 2C receptor antagonists seganserin and eplivanserin (Dijk et al., 1989; Landolt et al., 1999), the 5-HT1A receptor agonist ipsapirone (Seifritz et al., 1996), the selective extrasynaptic GABA receptor agonist gaboxadol (or THIP; Faulhaber et al., 1997; Walsh et al., 2007) and the GABA uptake inhibitor tiagabine (Mathias et al., 2001) similarly enhance the pattern of LFA in nonREM sleep (Fig. 3). It may be speculated that these different pharmacological manipulations promote a ‘common final pathway’ underlying the generation or synchronization of slow waves in nonREM sleep. In this context, it may be important to note that the serotonergic neurons of the DRN are innervated by GABAergic cells originating in multiple areas in the basal forebrain and


5-HT2A ⁄ 2C receptors, sleep, cognition and mood 1801 brainstem, as well as by GABA-ergic interneurons (Gervasoni et al., 2000). In conclusion, 5-HT2A ⁄ 2C receptor antagonists and compounds promoting GABA-ergic neurotransmission may promote SWS via reduction of inhibitory input to the sleep-active cells of the VLPO. Ongoing controversy exists as to whether the 5-HT2A ⁄ 2C receptor antagonist-induced promotion of SWS is mediated via 5-HT2A and ⁄ or 5-HT2C receptors. Recent studies with more subtype-selective 5-HT2A and 5-HT2C receptor ligands (antagonists and inverse agonists), as well as experiments in knock-out mice, support a role for both of these 5-HT2 receptor subtypes in promoting SWS (Sharpley et al., 1994, 2001; Landolt et al., 1999; Frank et al., 2002; Popa et al., 2005; Morairty et al., 2008; Rosenberg et al., 2008). Further studies are needed to resolve this question. Accumulating evidence suggests that 5-HT2A ⁄ 2C receptors are involved in distinct forms of synaptic plasticity (Sodhi & SandersBush, 2004). Apart from general neuronal excitation (see above), 5-HT2A ⁄ 2C receptor stimulation facilitates synaptic plasticity via NMDA receptor-mediated mechanisms by increasing expression of several transcription factors including the gene encoding for brainderived neurotrophic factor (BDNF; Aghajanian & Sanders-Bush, 2002; Chen et al., 2003; Sodhi & Sanders-Bush, 2004; Rios et al., 2006; Juric et al., 2006). It may be speculated that 5-HT2A ⁄ 2C receptor antagonists prevent these events and, according to a recent hypothesis, contribute to synaptic downscaling and the promotion of synchronized LFA in nonREM sleep (Tononi & Cirelli, 2006). To critically evaluate such a possibility, it may be important to keep in mind that chronic administration of these compounds can induce up-regulation, but does seem to be followed by down-regulation, of 5-HT2A ⁄ 2C receptors (Van Oekelen et al., 2003), whereas acute administration invariably increases SWS. Novel medications for the treatment of insomnia should not only be devoid of impairment of next-day functions, but rather improve waking functioning along with better sleep (Wafford & Ebert, 2008). Apart from a role in the promotion of SWS, 5-HT and its receptors, including the 5-HT2A ⁄ 2C receptors, have been implicated in functional endophenotypes in basic cognitive domains such as learning and memory (e.g., spatial or aversive learning), attention and executive functions (e.g., response inhibition), as well as affective processes (Buhot, 1997; Schmitt et al., 2006; Cools et al., 2008; Geyer & Vollenweider, 2008). It has to be kept in mind that drug-induced changes may not necessarily be receptor-specific and reflect physiological mechanisms. Nevertheless, the question of whether pharmacological inhibition of 5-HT2A ⁄ 2C receptors may not only promote SWS but also improve cognition and mood is addressed in the final paragraphs of this article.

5-HT2A ⁄ 2C receptors, sleep and cognitive processes An important role for 5-HT2A ⁄ 2C receptors has emerged in view of distinct memory processes. Because of the high serotonergic innervation in the dorsolateral prefrontal cortex and the role of this area in working memory, Goldman-Rakic and colleagues studied in rhesus monkeys the effects of local application of 5-HT2A receptor agonists and antagonists to prefrontal neurons during a delayed-response task (Williams et al., 2002). Stimulation of 5-HT2A receptors increased activity in prefrontal pyramidal cells involved in spatial working memory, whereas blockade of these receptors attenuated cellular responses (Williams et al., 2002; Harvey, 2003; Boulougouris et al., 2008). Specific roles for 5-HT2A and 5-HT2B ⁄ 2C receptor-mediated modulation of dopamine release induced by amphetamine and morphine were shown in rat nucleus accumbens and striatum (Porras

et al., 2002). Moreover, systemic and local application of the selective 5-HT2A and 5-HT2C receptor antagonists volinanserin and SB 242084, respectively, decreased and increased impulsive behavior in a choice serial reaction time task in rats and mice (Fletcher et al., 2007; Robinson et al., 2008). In general, 5-HT2A receptor antagonists may improve behavioral responses such as avoidance of novel situations, spatial discrimination and performance on delayed matching tasks (Naghdi & Harooni, 2005; Terry et al., 2005; Celada et al., 2008). In humans, the His452Tyr polymorphism of HTR2A was recently associated with individual differences in verbal memory performance among 349 individuals 24 h after learning semantically unrelated nouns (de Quervain et al., 2003). More specifically, heterozygous carriers of the Tyr allele (allele frequency 8–9% of the population), which may lead to reduced 5-HT2A receptor function (Ozaki et al., 1997), showed 20% reduced recall performance when compared to homozygous His ⁄ His allele carriers. Fine-mapping of HTR2A revealed at least two additional SNPs to be associated with differences in memory performance (Sigmund et al., 2008). Given the possibility that consolidation of declarative memories is favored by SWS (Gais & Born, 2004), it could be hypothesized that the differences in delayedrecall performance could be hypothesized to be related to geneticallydetermined different amounts of SWS. The fact that recall 5 min after learning already differed between 452His and 452Tyr genotypes argues against such a hypothesis. The His452Tyr polymorphism did not affect episodic memory performance in a healthy older population, possibly related to the age-related decreased 5-HT2A receptor availability (Papassotiropoulos et al., 2005). The effects of functional polymorphisms of HTR2A on sleep and the sleep EEG are unknown. Psychotomimetic drugs (‘hallucinogens’) including LSD, psilocybin and mescaline stimulate 5-HT2A receptors, particularly those expressed on neocortical pyramidal cells (Nichols, 2004), although they typically show poor 5-HT2A receptor selectivity. Acute administration of these substances impairs working memory and sensory perception with reduced mismatch negativity, and in higher doses creates perceptual hypersensitivity, illusions and hallucinations, up to altered experience of time, space and self (for recent review, see Geyer & Vollenweider, 2008). These effects may be similar to the hallucinatory experience of vivid dreams. Subchronic (7 days) evening administration of the 5-HT2A ⁄ 2C receptor antagonist ritanserin (5 mg) potently prolonged SWS and improved a subjective measure of alertness during daytime in healthy volunteers (van Laar et al., 2001). By contrast, driving performance and objectively measured daytime sleepiness (multiple sleep latency test) were not affected. The increase in SWS did not relate to any changes in daytime performance (van Laar et al., 2001). Similar to the findings with ritanserin, the noradrenergic, specific serotonergic drug mirtazapine also promotes subjective (Ridout et al., 2003) and objective measures of sleep such as the duration of SWS (Aslan et al., 2002), possibly via a 5-HT2A receptor-mediated mechanism. One study reported that selfrated sleep duration in the first night following evening intake of 30 mg mirtazapine increased by 58 min (Wingen et al., 2005). Despite this positive effect on sleep, subjective alertness and contentedness were reduced in the morning following drug intake, and driving performance and divided attention were impaired. Studies with the 5-HT2A ⁄ 2C receptor antagonist ketanserin (50 mg) administered together with the SSRI escitalopram (20 mg) support an acute negative effect of blocking these receptors on sustained attention, motor impulse control and spatial working memory (Wingen et al., 2007a,b). Interestingly, a pharmaco-fMRI study revealed that mirtazapine slowed response times in an inhibition task but enhanced blood oxygenation level-dependent (BOLD) activation in right orbitofrontal


1802 H.-P. Landolt and R. Wehrle and parietal cortex in a task-specific manner (Vo¨llm et al., 2006). PET studies indicate a negative relationship between right frontal and left parietal 5-HT2A receptor density as quantified with 18F-spiperone and harm-avoidance tendencies (Moresco et al., 2002). Acute tryptophan depletion deteriorates memory consolidation, reaction times and recognition capacities, most pronounced in S-allele carriers of SLC6A4 (Marsh et al., 2006; Roiser et al., 2006). By contrast, reinforcement learning from punishment is most pronounced in L-allele homozygotes (Finger et al., 2007; Blair et al., 2008). Increased serotonergic tone following acute or chronic administration of SSRI induces inconsistent effects. Sensitization and desensitization of 5-HT receptors, different influences on cortical and subcortical structures, or an underlying U-shaped relationship for increased serotonergic neurotransmission with reduced performance at very high and very low 5-HT levels (similar to the dopaminergic system) are possible explanations for the inconsistent findings (Cools et al., 2008). Taken together, 5-HT2A ⁄ 2C receptor antagonists consistently promote SWS in humans, yet their effects on daytime cognitive functions appear variable and not directly related to the drug-induced changes in sleep.

5-HT2A ⁄ 2C receptors, sleep and affective processes The regulation of sleep and mood are tightly associated, and various affective disorders are characterized by subjective and ⁄ or objective disturbances of sleep. Moreover, the 5-HT2A and 5-HT2C receptors play prominent roles in affective functions including mood, aggression and impulsivity (Schmitt et al., 2006; Cools et al., 2008). Various psychiatric conditions appear to be associated with disturbance of serotonergic neurotransmission in general and region-specific alterations in 5-HT2A ⁄ 2C receptor function in particular. Such conditions include major depressive disorder (Biver et al., 1997; Yatham et al., 2000; Messa et al., 2003; Neumeister, 2003; Mintun et al., 2004; Sheline et al., 2004; Levinson, 2006), anxiety disorders including obsessive–compulsive disorder (Graeff et al., 1996; Bailer et al., 2004; Meira-Lima et al., 2004; Norton & Owen, 2005; Maron & Shlik, 2006; Unschuld et al., 2007), schizophrenia (Kaye et al., 2001; Meltzer et al., 2003; Stefanis et al., 2007; Geyer & Vollenweider, 2008) and eating disorders (Kaye et al., 2001). Even in healthy subjects, a relationship between increased frontolimbic 5-HT2A receptor binding and neuroticism, i.e., vulnerability to stress and anxiety, could be established (Frokjaer et al., 2008). The demonstration alike that prefrontal 5-HT2A receptor availability is reduced in subjects with increased risk of developing schizophrenia (Hurlemann et al., 2008), such data are important because they link serotonergic function as a biomarker to personality risk factors for affective disorders, allowing functional insights into emerging pathophysiology without confounding interaction with drugs (Fig. 4). Given the role for 5-HT in mood regulation, various genetic polymorphisms in genes involved in 5-HT synthesis, re-uptake and signal transduction were studied as possible modulators of individual vulnerability to develop psychiatric disorders and their symptoms. For example, a specific, centrally-acting isoform of tryptophan hydroxylase, TPH2 (as opposed to the peripherally-acting TPH1), which regulates 5-HT biosynthesis, has been linked to affective disorders (Harvey et al., 2004). Genetic association studies have also revealed that the functional variable-number tandem-repeat polymorphism in the 5¢-promoter region of SLC6A4 can influence both the morphology of limbic structures and the functionality of these circuits in emotional processing (Pezawas et al., 2005). The effects of this polymorphism are modified according to a gene–gene interaction by a functional

polymorphism of the BDNF gene (Pezawas et al., 2008). Preliminary genetic data in humans (Linn et al., 2007), as well as pharmacological data in rats (Faraguna et al., 2008), suggest that both the 5-HTT and the cortical expression of BDNF modify the duration of SWS. Further possibilities for 5-HT to simultaneously affect sleep and mood are via the hypothalamus–pituitary–adrenal axis (de Kloet et al., 2005; Leonard, 2005) and via modulation of other neurotransmitter and receptor systems such as dopamine and norepinephrine (Di Pietro & Seamans, 2007; Serretti et al., 2007). In depressed patients, however, no causal relationship was found between changes in sleep and the sleep EEG and the improvement in mood (Landolt et al., 2001; Landolt & Gillin, 2002). Numerous studies in the lasts years investigated putative links between psychiatric disorders and genetic polymorphisms of HTR2A (for a concise review please refer to Serretti et al., 2007). With the possible exceptions that the C-allele of the 102 T ⁄ C polymorphism and the 452Tyr variant modulate the risk for psychosis and antipsychotic response, these studies report rather conflicting and in general negative results (Serretti et al., 2007). It has to be kept in mind that methodological issues such as ethnic background, sample size, diagnostic heterogeneity or the genetic variant studied are of major importance in genetic association studies. Better stratification methods and information related to endophenotypes including predisposing traits and symptom severity is strongly warranted (Norton & Owen, 2005; Ni et al., 2006; Serretti et al., 2007; Unschuld et al., 2007). Despite the finding that the )1438 A ⁄ G polymorphism of HTR2A does not affect the clinical response to mirtazapine in patients with major depressive disorder, this medication appears to improve subjective sleep quality as assessed with the Hamilton Rating Scale of Depression in an HTR2A genotype-dependent manner (Kang et al., 2007). Moreover, bipolar depressed inpatients homozygous for the T-variant of the 102 T ⁄ C polymorphism showed better subjective and objective antidepressant response to repeated total sleep deprivation than carriers of the C-allele (Benedetti et al., 2008). No study has as yet investigated the possible effects of functional HTR2A gene variants on sleep and the sleep EEG in psychiatric patients. Some stimulants such as 3,4-methylene-dioxy-methamphetamine (MDMA or ecstasy) show agonistic properties at the 5-HT2A receptor and increase energetic drive, well-being and elation. These effects can be blocked by the 5-HT2A ⁄ 2C receptor antagonist ketanserin (Parrott & Stuart, 1997; Liechti et al., 2000), suggesting that they are mediated via 5-HT2A ⁄ 2C receptors. It has been assumed that phasic increases in prefrontal glutamatergic spillover underlie this action (Lambe & Aghajanian, 2006). Moreover, ritanserin prolonged subjective anxiety induced in healthy volunteers by a simulated public-speaking paradigm (Guimaraes et al., 1997). On the other hand, several antidepressants and atypical antipsychotics such as nefazodone, mirtazapine and mianserin block 5-HT2A ⁄ 2C receptors and improve sleep, as well as mood, in patients with neuropsychiatric disorders (Adrien, 2002; Wilson & Argyropoulos, 2005; Schmid et al., 2006; Cohrs, 2008). Combined blockade of 5-HT reuptake and 5-HT2A ⁄ 2C receptors may enhance efficacy in treating psychiatric symptoms including disturbed sleep (Marek et al., 2003, 2005). The novel antidepressant agomelatine acts as a melatonin MT1 ⁄ MT2 receptor agonist and 5-HT2B ⁄ 2C receptor antagonist. The possible beneficial effects of this compound on subjective and objective measures of sleep quality may differ between healthy subjects and depressed patients (Cajochen et al., 1997; Leproult et al., 2005; Quera Salva et al., 2007), and need to be investigated in more detail. In conclusion, genetic variation in HTR2A may influence changes in subjective sleep quality during antidepressant treatment and response to sleep deprivation in depressive patients. Whereas 5-HT2A ⁄ 2C


5-HT2A ⁄ 2C receptors, sleep, cognition and mood 1803

Fig. 4. Decreased 5-HT2A receptor availability in early and late prodromal phase of schizophrenia. Averaged 5-HT2A binding potentials as quantified with 18 F-altanserin in healthy controls (CTRL) and in subjects with ultra-high risk of schizophrenia in suspected early (EPS) and late (LPS) prodromal state. Binding potentials (BP1¢) decrease with increasing risk levels, especially in frontotemporal and insular areas (from Hurlemann et al. (2008), p. 584, reprinted with kind permission of Springer Science and Business Media).

receptor antagonists improve sleep and affect in psychiatric patients, they may acutely deteriorate distinct aspects of mood in healthy volunteers.

Future perspectives and limitations Various compounds acting as antagonists or inverse agonists at 5-HT2A receptors, and a few that more specifically target the 5-HT2C receptor (see Table 1), are currently in development as new sleeppromoting agents (Teegarden et al., 2008; Wafford & Ebert, 2008). The available literature suggests that these compounds promote SWS and LFA and improve sleep maintenance and sleep efficiency, in healthy volunteers as well as in patients with disturbed sleep. They do not typically shorten the latency to fall asleep and have variable effects on more superficial nonREM sleep (e.g., stage 2) and REM sleep. Future studies will have to conclusively demonstrate whether or not the sleep effects of these substances reflect physiologically intensified sleep. Only if physiological sleep is promoted such as after prolonged wakefulness can a role for the 5-HT2A ⁄ 2C receptors in (homeostatic)

sleep–wake regulation and potentially associated daytime functions be inferred. Highly relevant for the clinical usefulness of the novel medications are outcome variables related to subjective sleep quality and lack of detrimental effects, or rather positive influence, on daytime functions. Some data indicate that pharmacological enhancement of SWS is paralleled by improved subjective sleep quality in older subjects (Mathias et al., 2001). On the other hand, eplivanserin prolonged SWS and LFA in healthy young good sleepers without changing subjective sleep quality (Landolt et al., 1999). This finding is consistent with studies showing that experimental manipulations that objectively increase (e.g., body heating; Horne & Shackell, 1987) or decrease (e.g., administration of zolpidem; Brunner et al., 1991) SWS and ⁄ or LFA do not necessarily change subjective sleep quality in healthy individuals. Conversely, other studies found that polysomnographically derived sleep measures such as SWS, total sleep time and sleep continuity can predict perceived sleep quality (Sewitch, 1984; Akerstedt et al., 1997). Particularly in patients with sleep disorders, electrophysiologically measured sleep may be (mis)perceived as wakefulness (Sewitch, 1984; Vanable et al., 2000; Mercer et al.,


1804 H.-P. Landolt and R. Wehrle 2002; Weigand et al., 2007). It appears that patients suffering primarily from sleep maintenance problems such as those associated with major depression, schizophrenia, post-traumatic stress disorder and narcolepsy report improved subjective sleep quality following treatment with 5-HT2A ⁄ 2C receptor antagonists (Saletu-Zyhlarz et al., 2002; Mayer, 2003; van Liempt et al., 2006; Cohrs, 2008). The available data on the effects of SWS enhancement on next day performance are also controversial (van Laar et al., 2001; Mathias et al., 2005; Walsh et al., 2006, 2007; Go¨der et al., 2008). It is possible that potential benefits of enhanced SWS and LFA may be offset or masked by the relative suppression of other sleep features such as sleep spindles and ⁄ or changes in REM sleep characteristics (e.g., REM density). The plasma half-life of eplivanserin and volinanserin is 6–8 h, whereas receptor occupancy lasts considerably longer and hangover effects such as daytime sedation cannot be excluded (Gru¨nder et al., 1997; Teegarden et al., 2008). Mirtazepine (the elimination half-life ranging from 20 to 40 h) initially decreased subjective alertness and contentedness, and spontaneously reported adverse events during a 2-week trial in healthy subjects included fatigue, somnolence and dizziness (Wingen et al., 2005). These effects were restricted to acute treatment and were no longer observed during dose increase (day 9) and steady state (day 16). Potential further side-effects may include weight gain, cardiac disorders and sleep-related disturbances such as respiratory dysfunction (Mendelson, 2005; Wilson & Argyropoulos, 2005; Freudenmann et al., 2008). The long-term efficacy, safety and lack of abuse potential of 5-HT2A ⁄ 2C receptor antagonists in the treatment of insomnia have yet to be demonstrated in controlled clinical studies. Most studies performed to date have focused only on single aspects of 5-HT2A ⁄ 2C receptor-mediated actions, related to either sleep or daytime functions. Some studies, however, attempted to bridge the gap between sleep and wakefulness and different aspects of sleep and ⁄ or waking functions. Such attempts include investigation of pharmacological effects on sleep and daytime variables (van Laar et al., 2001; Mayer, 2003; Go¨der et al., 2008) and combinations of brain imaging with performance and subjective assessments (Moresco et al., 2002; Vo¨llm et al., 2006), as well as a pharmacological challenge with electrophysiological recordings in animals (Williams et al., 2002; Celada et al., 2008). A more extensive use of techniques that allow study of receptor functions in humans, such as in vivo PET imaging of receptor occupancy, is increasingly established in drug development (Offord et al., 1999). Such approaches, in combination with subjective and clinical assessments, are promising to shed light on the relationships among 5-HT2A ⁄ 2C receptor-mediated effects on sleep, cognition and mood in health and various diseases affecting sleep and waking functions.

Conclusions Several lines of evidence show that the 5-HT2A ⁄ 2C receptor system is a key player involved in sleep, sensory processing and learning, affective functioning and the pathophysiology of several neuropsychiatric disorders. Thus, pharmacological interaction with 5-HT2A ⁄ 2C receptor activity alters sleep, cognition and affective state. The 5-HT2A ⁄ 2C receptor antagonists potently modify sleep architecture and the sleep EEG yet have variable effects on cognitive performance and mood, and may even impair daytime functioning in certain (healthy) individuals. Various substances such as mirtazapine, eplivanserin and volinanserin previously used in or developed for cognitive and ⁄ or affective neuropsychiatric symptoms are currently being investigated

in clinical trials for the indication ‘sleep disorders’. The predominant frontal distribution of 5-HT2A receptors as revealed with different imaging techniques may provide a functional link between usedependent aspects of sleep need and daytime functions such as working memory and inhibitory control. The effects of functional variation in the genetic coding of 5-HT2A receptors point towards a role for this receptor in the response to antidepressant treatment, including the acute effects of sleep deprivation, and also in certain character traits such as impulsiveness. The possible functional relationships between distinct characteristics of sleep, especially LFA and spindle-frequency activity, and cognitive functions, in particular distinct forms of learning and memory, are currently a hot topic in sleep research. At first sight, the observation that the activity of serotonergic cells is low in nonREM sleep and almost absent in REM sleep may render a mutual involvement of 5-HT and 5-HT2A ⁄ 2C receptors in sleep and daytime functions rather unlikely. Nevertheless, the renewed interest in the roles for 5-HT2A ⁄ 2C receptors in sleep and their more recently discovered involvement in distinct cognitive and affective processes may inspire new approaches to investigation of their roles in the relationships between sleep and daytime functioning.

Acknowledgements We thank Josephine Hegewald for her help in preparing parts of this review. The authors’ research is supported by the Swiss National Science Foundation (Grant # 310000-120377), the Zu¨rich Center for Integrative Human Physiology (ZIHP) and a grant from the European Union (MCRT-CT-2004-512362).

Abbreviations 5-HT, 5-hydroxytryptamine or serotonin; 5-HTT, 5-hydroxytryptamine (serotonin) transporter, also known as SERT; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; DRN, dorsal raphe nucleus; EEG, electroencephalogram; GABA, c-amino-butyric-acid; LFA, low-frequency activity; LSD, lysergic acid diethylamide; MAO, monoamine oxidase; MDMA, 3,4-methylene-dioxy-methamphetamine or ecstasy; NonREM, non-rapid-eyemovement; PET, positron emission tomography; REM, rapid-eye-movement; SSRI, selective serotonin reuptake inhibitor; SWS, slow wave sleep; VLPO, ventrolateral preoptic area.

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