Neurochemical regulation of sleep

JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 41 (2007) 537–552

www.elsevier.com/locate/jpsychires

Neurochemical regulation of sleep Axel Steiger

*

Max Planck Institute of Psychiatry, Department of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany Received 16 January 2006; received in revised form 31 March 2006; accepted 6 April 2006

Abstract This review summarizes recent developments in the field of sleep regulation, particularly in the role of hormones, and of synthetic GABAA receptor agonists. Certain hormones play a specific role in sleep regulation. A reciprocal interaction of the neuropeptides growth hormone (GH)-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) plays a key role in sleep regulation. At least in males GHRH is a common stimulus of non-rapid-eye-movement sleep (NREMS) and GH and inhibits the hypothalamo-pituitary adrenocortical (HPA) hormones, whereas CRH exerts opposite effects. Furthermore CRH may enhance rapid-eye-movement sleep (REMS). Changes in the GHRH:CRH ratio in favor of CRH appear to contribute to sleep EEG and endocrine changes during depression and normal ageing. In women, however, CRH-like effects of GHRH were found. Besides CRH somatostatin impairs sleep, whereas ghrelin, galanin and neuropeptide Y promote sleep. Vasoactive intestinal polypeptide appears to be involved in the temporal organization of human sleep. Beside of peptides, steroids participate in sleep regulation. Cortisol appears to promote REMS. Various neuroactive steroids exert specific effects on sleep. The beneficial effect of estrogen replacement therapy in menopausal women suggests a role of estrogen in sleep regulation. The GABAA receptor or GABAergic neurons are involved in the action of many of these hormones. Recently synthetic GABAA agonists, particularly gaboxadol and the GABA reuptake inhibitor tiagabine were shown to differ distinctly in their action from allosteric modulators of the GABAA receptor like benzodiazepines as they promote slow-wave sleep, decrease wakefulness and do not affect REMS.  2006 Elsevier Ltd. All rights reserved. Keywords: Sleep; Sleep endocrinology; Neuropeptides; Steroids; GABA agonists; Gaboxadol; Depression; Ageing; Insomnia

1. Introduction This review gives an overview of recent developments in the neurochemical regulation of sleep, particularly in the role of hormones (neuropeptides and steroids) in sleep regulation and in the effects of synthetic c-aminobutyric acid (GABAA) agonists, which promise to represent a new class of hypnotics. Human sleep is characterized by the cyclic occurrence of periods of non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS). During the first NREMS period the major portion of slow wave sleep (SWS) and, as assessed by EEG spectral analysis (Borbe´ly et al., 1981) of slow wave activity (SWA) occur. *

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During the second half of the night REMS and sleep stage 2 preponderate. The sleep-related secretion of various hormones shows distinct patterns. During the first half of the night the growth hormone (GH) surge is found, whereas corticotropin (ACTH) and cortisol levels reach their nadir. Vice versa during the second half of the night ACTH and cortisol reach their acrophase, whereas GH release is low (Weitzman, 1976). This pattern suggests (i) a reciprocal interaction of the hypothalamo-pituitarysomatotrophic (HPS) and the hypothalamo-pituitary-adrenocortical (HPA) systems and (ii) the existence of common regulating factors of the sleep EEG and the nocturnal hormone secretion. It appears likely, that a reciprocal interaction of the key hormones of the HPS and HPA systems, GH-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) plays a major role in sleep regulation.

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Besides of GHRH and CRH various other peptides and steroids participate in sleep regulation. Many of them act via GABAergic mechanisms. There exist gender differences in sleep-endocrine activities. In normal young subjects cortisol secretion is higher in females than in males. Most men show a single GH peak near to sleep onset. In women however, a pre-sleep GH surge and one or more additional GH peaks are found frequently (Antonijevic et al., 1999b). Sleep EEG (Bliwise, 1993) and nocturnal hormone secretion (Van Coevorden et al., 1991) change during ageing. In females the menopause is a major turning point towards impaired sleep (Ehlers and Kupfer, 1997), whereas in men the sleep quality declines continuously. Already during the third decade of the life span distinct parallel decreases of SWS, SWA and GH secretion start. 2. Hypothalamo-pituitary-somatotrophic (HPS) system GH stimulates tissue growth and protein anabolism. The synthesis and the secretion of GH are stimulated by GHRH and ghrelin and are inhibited by somatostatin. All components of the HPS system participate in sleep regulation. The major amount of GH during 24 h is released near to sleep onset, in temporal association to the first period of SWS (Quabbe et al., 1966; Steiger et al., 1987). The GH surge appears to be widely sleep dependent and is suppressed during sleep deprivation (Sassin et al., 1969). However, GH release prior to sleep onset may occur in normal subjects (Steiger et al., 1987). Furthermore, in sleep deprived, but relaxed normal males who were 24 years old or younger unchanged nocturnal GH peak was reported. From the age of 25 years the GH peak was blunted (Mullington et al., 1996). Obviously the suppression of GH during sleep deprivation is age-dependent. On the other hand lying relaxed appears to be sufficient to trigger the nocturnal GH surge. In patients with isolated ˚ stro¨m and Lindholm, GH deficiency SWS and SWA (A ˚ stro¨m and 1990) are lower than in normal controls (A Jochumsen, 1989). 2.1. Growth hormone-releasing hormone (GHRH) GHRH is an important endogenous sleep-promoting substance. The GHRH receptor gene is found in the mouse in the region of chromosome 13 linked to SWA (Franken et al., 2001). Hypothalamic GHRH mRNA depends on a circadian rhythm. In rats it peaks at the onset of the light period when sleep propensity reaches its maximum in these night active animals (Bredow et al., 1996). Furthermore hypothalamic GHRH levels are low in the morning, increase in the afternoon and decrease at night (Gardi et al., 1999). Calcium levels in GABAergic neurons cultured from rat fetal hypothalamus increase when perfused with GHRH (De et al., 2002). Many hypothalamic GHRH responsive neurons appear to be GABAergic.

SWS increases after intracerebroventricular (icv) administration of GHRH in rats and rabbits (Ehlers et al., 1986; Oba´l et al., 1988), after its injection into the medial preoptic area of rats (Zhang et al., 1999) and after its i.v. administration to rats (Oba´l et al., 1996). Similarly after repetitive hourly i.v. injections of GHRH between 22:00 and 01:00 SWS and GH increase and cortisol decreases in young men (Steiger et al., 1992). Mimicking the pulsatile endogenous release appears to be crucial, since GHRH infusion does not affect sleep EEG (Marshall et al., 1999). Sleep promotion in males was confirmed after i.v. (Kerkhofs et al., 1993; Marshall et al., 1999) and intranasal (Perras et al., 1999a) GHRH. The influences of GHRH on human sleep were investigated in three states with a change of the GHRH/CRH ratio in favor of CRH – (i) the early morning in young normal men, (ii) in the elderly and (iii) in patients with depression. (i) Repetitive i.v. GHRH from 04:00 to 07:00 prompts no major changes of sleep EEG (Schier et al., 1997). (ii) The sleep-promoting effect of i.v. GHRH is only weak in elderly women and men (Guldner et al., 1997). In a pilot study the hypothesis was tested that after priming (e.g. i.v. GHRH every 2 days for 12 days) the sleep-promoting effect of GHRH would be restored in the elderly. The results in two subjects do not support this hypothesis (Murck et al., 1997b). (iii) In drugfree patients with depression of both sexes of a wide age range and in matched controls, a sexual dimorphism in the response to i.v. GHRH was found. In male patients and controls GHRH decreases ACTH and cortisol. In females however, these hormones are enhanced. Similarly NREMS increases and wakefulness decreases in male patients and controls. Opposite sleep-impairing effects are found in women. These data corroborate a reciprocal antagonism of GHRH and CRH in males (see below), whereas their synergism is suggested in females (Antonijevic et al., 2000b,c). In rats NREMS decreases after GHRH receptor antagonists (Oba´l et al., 1991) and antibodies to GHRH (Oba´l et al., 1992b). In the so-called super-mice, the giant transgenic mice, GH is elevated, and during the light period NREMS is higher and REMS is almost doubled compared to normal mice. Also after sleep deprivation the super-mice sleep more than control mice (Hajdu et al., 2002). In dwarf rats with deficits in the central GHRHergic transmission and reduced hypothalamic GHRH, NREMS is lower than in controls (Oba´l et al., 2001). Similarly in dwarf homozygous (lit/lit) mice with non-functional GHRH receptors NREMS and REMS are diminished. Obviously GHRH deficiency and decreases in NREMS are associated (Oba´l and Krueger, 2004). Sleep deprivation is the major stimulus for sleep (Borbe´ly et al., 1981). GHRH appears to mediate this effect. In rats GHRH antibodies (Oba´l et al., 1992b) and microinjections of a GHRH antagonist into the area preoptica inhibit sleep promotion after sleep deprivation (Zhang et al., 1999). Sleep deprivation prompts a depletion of hypothalamic GHRH and low hypothalamic GHRH contents (Gardi et al., 1999), whereas hypothalamic GHRH

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mRNA increases and hypothalamic somatostatin decreases after sleep deprivation in rats (Toppila et al., 1997; Zhang et al., 1998). During the recovery night after sleep deprivation the NREMS promoting effect of sleep deprivation was augmented by repetitive i.v. GHRH and CRH as well in normal subjects (Schu¨ssler et al., in press-b). Seifritz et al. (1996) investigated in young normal men correlations between SWA, REMS, GH and cortisol levels in nocturnal sleep and sleep displaced in the morning hours after 22 h of sleep deprivation. During morning sleep no rebound of SWS or SWA was found. The GH peak in the morning was lower than during night sleep, whereas cortisol showed opposite trends between conditions. The authors suggested, that according to the hypothesis submitted by Ehlers and Kupfer (1987) (see below) the differences in endocrine activity between the two conditions may explain the lack of an increase of SWA. Indeed, similar to the study by Schier et al. (1997) as mentioned before, the higher activity of endogenous CRH may have inhibited sleep promotion by GHRH in the morning condition, as reflected by the levels of cortisol and GH. In another study the same group of researchers (Seifritz et al., 1995) tested the effects of the benzodiazepine antagonist flumazenil on recovery sleep after sleep deprivation. After this substance SWS, SWA and GH decreased when compared to placebo. The authors suggested that EEG and GH effects of sleep deprivation are mediated in part through GABAergic mechanisms. This is in line with the finding that many GHRH responsive neurons are GABAergic (see before). In all GHRH promotes NREMS in various species including humans, at least in male subjects or animals. High activity of GHRH is associated with high amounts of NREMS, whereas reduced activity of GHRH (e.g. during ageing or in animal experiments with GHRH antagonists or antibodies) goes ahead with a decline in SWS or NREMS. GHRH participates in sleep promotion after sleep deprivation. Besides age, time of administration and gender modulate the effects of GHRH on sleep EEG. Animal experiments are lacking to further explore the mechanisms of the sexual dimorphism of the sleep-endocrine effects of GHRH. 2.2. Growth hormone, insulin-like growth factor-1 (IGF-1) Negative feedback inhibition of GHRH after administration of GH in humans (Mendelson et al., 1980), and animals (Oba´l and Krueger, 2004) or higher dosages of icv insulin-like growth factor-1 (IGF-1) (Oba´l et al., 1999) decrease NREMS. On the other hand GH antagonism impairs sleep (Oba´l et al., 1997a). The latter finding suggest that also GHRH promotes sleep. Sleep remains unchanged, however, after chronic GH substitution to patients with acquired GH deficiency (Schneider et al., 2005). 2.3. Somatostatin After icv somatostatin selective increases of REMS were observed in rats (Danguir, 1986). In contrast in rats sys-

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temic and icv administration of the somatostatin analogue octreotide decreases NREMS and GH (Beranek et al., 1999). Similarly SWS decreases and intermittent wakefulness increases in young normal men after subcutaneous octreotide (Ziegenbein et al., 2004). Octreotide is long acting and more potent than exogenous somatostatin. Accordingly i.v. somatostatin impairs sleep in the elderly (Frieboes et al., 1997), whereas it has no effect in young subjects (Steiger et al., 1992; Kupfer et al., 1992). The same dose of somatostatin which is ineffective in young men impairs sleep in the elderly probably due to a decline of endogenous GHRH during ageing. In cats and rats somatostatin inhibits GABAergic transmission in the sensory thalamus via presynaptic receptors (Leresche et al., 2000). It is thought that this mechanism contributes to the decrease of NREMS after somatostatin. All data suggest a reciprocal interaction of GHRH and somatostatin in sleep regulation similarly to their opposite effects on GH release. 2.4. Ghrelin and GH secretagogues Similar to the effects of GHRH repetitive i.v. ghrelin increases SWS and GH in young men (Weikel et al., 2003). In contrast to the decrease of cortisol after GHRH in young men (Steiger et al., 1992), ACTH and cortisol increase after ghrelin (Weikel et al., 2003). The first injection of ghrelin prompts the highest response of GH, whereas the increase of cortisol is relatively low. In contrast the last injection leads to the highest response of cortisol and the lowest of GH. This observation suggests that ghrelin acts as an interface between the HPA and the HPS systems. The pattern of hormone changes after ghrelin resembles the effects of i.v. administration of the synthetic GH secretagogues (GHSs) GH-releasing peptide-6 (GHRP-6) (Frieboes et al., 1995) and hexarelin (Frieboes et al., 2004). The sleep-EEG effects of GHRP-6 and hexarelin however differ from those of ghrelin. After GHRP-6 sleep stage 2 increases (Frieboes et al., 1995), whereas SWS and SWA decrease after hexarelin, probably due to a change of the GHRH/CRH ratio in favor of CRH. In mice ghrelin enhances NREMS (Oba´l et al., 2003). An intact GHRH receptor is the prerequisite for this effect, since in animals with non-functional GHRH receptors sleep is not changed. Oral administration of the GHS MK-677 for one week exerts a distinct sleep-promoting effect in young men, whereas it has only a weak effect in elderly controls (Copinschi et al., 1997). Several studies in humans investigated the relationship between sleep–wake-behaviour and ghrelin levels. Dzaja et al. (2004) examined interactions of sleep and ghrelin in young men who were semirecumbent during 24 h. When they are allowed to sleep a sharp increase of ghrelin occurs by sleep onset which is followed by a decline throughout the night. When the subjects are sleep-deprived, this nocturnal rise of ghrelin is blunted. In another study ghrelin levels were determined between 20:00 and 07:00 in normal

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female and male subjects who were active during daytime. Ghrelin concentrations differ during the interval between 20:00 and 23:00, before the subjects are allowed to sleep. In males there is a continuous rise of ghrelin until 23:00. In females however ghrelin levels are at 20:00 already in the same range as during the sleeping period. No relationship exists between ghrelin and sleep stages or the nocturnal secretion of GH, cortisol and ACTH (Schu¨ssler et al., 2005b). During the recovery night after sleep deprivation ghrelin secretion in normal subjects increases earlier than during the baseline night (Schu¨ssler et al., in press-a). The comparison between extended (12 h) and restricted (4 h) sleep time during 2 days each in normal controls shows at daytime increases in ghrelin levels, self-rated hunger and appetite and a decrease in leptin after sleep restriction (Spiegel et al., 2004). In a large sample of controls the interaction between sleep and ghrelin morning levels was investigated. Short sleep time was associated with higher ghrelin levels (Taheri et al., 2004). In a patient with night eating syndrome nocturnal ghrelin levels appeared to be elevated (Rosenhagen et al., 2005). 3. Hypothalamo-pituitary adrenocortical (HPA) system The HPA system mediates the reaction to acute physical and psychological stress. It starts with the release of CRH from the parvocellular neurons of the paraventricular nucleus of the hypothalamus. This results in the secretion of ACTH from the anterior pituitary and finally in the secretion of cortisol (in humans) or corticosterone (in rats) from the adrenocortex. In rats CRH gene transcription levels increase during the dark period, when the animals are active, and decrease in the morning and throughout the light period (Watts et al., 2004). In humans during the first few hours of the night the quiescent period of ACTH and cortisol is found. Between 02:00 and 03:00 the first pulse of cortisol occurs. It is followed by further pulses until awakening (Weitzman, 1976). Weitzman and colleagues (Weitzman, 1976) did pioneering work as they used manipulations as sleep deprivation and nocturnal awakenings in studying the interaction between sleep EEG and hormones. They showed that the pattern of cortisol secretion is widely dependent on a circadian rhythm, whereas manipulation of the sleep–wake pattern prompts subtle changes in HPA secretion. A novel statistical method, event history analysis helps to assess the effects of cortisol on the transition between sleep stages in normal human control subjects. The aim of this analysis is to examine the instantaneous probabilities of transitions between sleep stages, provided they are influenced by both various time dependent factors (e.g. hormone secretion) and the history of the process. High cortisol levels facilitate the transition intensity of (i) waking to sleeping around two hours after sleep onset, (ii) NREMS to REMS around 6 h later, (iii) sleep stage 1 or 2 to SWS around 2, 4 or 6 h later and (iv) SWS to sleep stage 1 or 2 about 2 h later. Furthermore, high cortisol concentrations at the beginning of REMS

periods favors the change to NREMS, whereas later the influence of cortisol on a change becomes weaker (Yassouridis et al., 1999). 3.1. Sleep in disorders with pathological changes of HPA activity In Addison’s disease the capacity of the adrenal glands to produce corticosteroids is severely reduced. No major disturbances of sleep in these patients were found (Gillin et al., 1974). Addison’s patients were compared under two conditions, either continuous hydrocortisone replacement or short term hydrocortisone withdrawal. After replacement REMS latency declines, and REMS time and intermittent wake time increase in comparison to withdrawal. Hence cortisol may be needed to initiate and maintain REMS (Garcia-Borreguero et al., 2000). Hypercortisolism and disturbed sleep are frequent symptoms in Cushing’s disease and in depression. Excessive cortisol levels are produced in Cushing’s disease, either of central or peripheral origin. In these patients, decreased SWS, disturbances of sleep continuity and REMS desinhibition were reported (Shipley et al., 1992). Similar symptoms are frequently observed in depression, whereas the dysregulation of the HPA system is more subtle. Characteristic sleep-EEG changes in patients with depression are disturbed sleep continuity (prolonged sleep latency, increased number of awakenings, early morning awakening), a decrease of NREMS (decreases of stage 2 sleep and SWS, in younger patients a shift of the major portion of SWS from the first to the second NREMS/ REMS cycle) and REMS desinhibition (shortened REMS latency, prolonged first REMS period, elevated REMS density, a measure for the amount of rapid-eye movements during REMS) (reviewed in: Kupfer, 1995). Most sleependocrine studies in depressed patients report elevated cortisol and ACTH throughout the night (Steiger et al., 1989; Antonijevic et al., 2000c) or throughout 24 h (Linkowski et al., 1987), respectively, in comparison to normal controls. GH was blunted in most (Steiger et al., 1989; Jarrett et al., 1990; Voderholzer et al., 1993), but not in all (Linkowski et al., 1987) studies. These findings point to a causal relationship between shallow sleep, low GH and HPA hyperactivity in depression. Furthermore there are similarities in the sleep-endocrine changes during depression and during normal ageing. Two studies compared sleep-endocrine activity longitudinally between acute depression and recovery in adult patients. One study showed a decrease of ACTH and cortisol during 24 h and a normalization of REMS after recovery (Linkowski et al., 1987). Since some of the patients received tricyclic antidepressants, which suppress REMS (Steiger et al., 1993c) at the examination during recovery it is difficult to differentiate between the effects of remission and of drugs. Intra-individual comparison of adult patients who were drug-free at least 14 days before each examination confirmed a decrease of cortisol after recovery. The

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sleep-EEG changes and low GH levels, however, persisted (Steiger et al., 1989). Both studies corroborate that HPA hypersecretion is a state marker of depression in adult patients. The persistence of most sleep-EEG (Kupfer et al., 1993) and GH changes (Jarrett et al., 1990) after recovery has been confirmed over a period of three years. Obviously cortisol normalizes independently from sleep. Hence hypercortisolism in depression is not secondary to shallow sleep. It appears likely that the metabolic disturbances during acute depression result in a biological scar as reflected by the persisting changes of sleep EEG and of GH in remitted patients. This hypothesis is further supported by a study on male patients who survived severe brain injury (Frieboes et al., 1999). Several months later their cortisol levels were in the range of normal controls. However their GH and sleep stage 2 time were reduced. Whereas cortisol levels were normal at the time of the examination in this study, it appears likely, that either HPA overactivity due to stress under the intensive care situation after brain injury, or treatment with glucocorticoids in some patients contributes to the changes of sleep EEG and of GH levels. Some (Rodenbeck et al., 2002; Vgontzas et al., 2001), but not all (Riemann et al., 2002) studies in primary insomnia report elevated HPA hormones. In obstructive sleep apnea syndrome during an episode of apnea upper airway constriction, progressive hypoxemia due to asphyxia, autonomic and sleep-EEG arousal occur. Buckley and Schatzberg (2005) suggested that obstructive sleep apnea causes activation of the HPA system through autonomic activation, awakening and arousal. This HPA activation may be a risk factor in the development of the metabolic syndrome in untreated obstructive sleep apnea. Furthermore the authors proposed that HPA hyperactivity may contribute to the pathophysiology of obstructive sleep apnea in hypertension. 3.2. Corticotropin-releasing hormone (CRH) In the Lewis rat the synthesis and the release of CRH is reduced due to a hypothalamic gene defect. Lewis rats spend less time awake and more time in SWS than intact strains (Opp, 1997). In contrast, spontaneous wakefulness of rats is reduced by a CRH antisense oligodeoxynucleotide (Chang and Opp, 2004). A role in the maintenance of wakefulness and sleep-disturbing effects of CRH is suggested by these studies. In homozygous mice overexpressing CRH in the CNS NREMS is reduced, whereas wakefulness and REMS are elevated in comparison to the wild type. After forced swimming and after sleep deprivation the NREMS rebound is reduced, whereas the REMS rebound increases in these transgenic mice when compared to controls (Mu¨ller-Preuss et al., 2005). After 72 h of sleep deprivation CRH levels in the striatum, limbic areas and pituitary increase, whereas hypothalamic CRH is reduced. CRH binding decreases in the striatum and in the pituitary (Fadda and Fratta, 1997).

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After icv CRH SWS decreases in rats (Ehlers et al., 1986) and rabbits (Opp et al., 1989). Even after 72 h of sleep deprivation CRH reduces SWS in rats. Furthermore, sleep latency and REMS increase (Marrosu et al., 1990). Repetitive hourly i.v. CRH (4 · 50 lg, 22:00– 01:00) in young normal men has a similar effect on NREMS as SWS decreases. Furthermore REMS decreases, the GH surge is blunted, and cortisol levels increase during the first half of the night (Holsboer et al., 1988). Similarly after i.v. CRH (100 lg) SWS decreases and light sleep increases in young males (Tsuchiyama et al., 1995). A dose of CRH which is not effective in young men impairs sleep in middle-aged men (Vgontzas et al., 2001). Hourly i.v. injections of 10 lg CRH (08:00–18:00) fail to induce sleep-EEG changes during the following night (Kellner et al., 1997), whereas melatonin levels decrease. After a single i.v. bolus of CRH in young males EEG activity in the sigma frequency range increases throughout the first three sleep cycles, both after administration during the first SWS period and during wakefulness (Antonijevic et al., 1999a). This finding is in line with the observation that EEG sigma activity increases throughout the night arbitrarily in parallel to the increase in HPA activity (Antonijevic et al., 1999b). After two different CRH antagonists, a-helical CRH and astressin given before the dark period, wakefulness decreases dose-dependently, whereas the time courses for these effects differ between the compounds (Chang and Opp, 1998). In contrast in another study (Gonzalez and Valatx, 1997) a-helical CRH was effective only in stressed animals. In these rats REMS is enhanced and decreases to values of the non-stressed condition after the substance. In sleep deprived rats a-helical CRH diminishes the REMS rebound but not the SWS rebound during recovery sleep. Stress acting via CRH is thought to be the major factor inducing the REMS rebound after sleep deprivation (Gonzalez and Valatx, 1998). In rats kindling of the amygdala at light onset decreases SWS and REMS and increases corticosterone. Icv CRH antagonists, astressin or a-helical CRH, antagonize the effects of kindling on SWS and corticosterone. Probably central increases of CRH mediate the changes after kindling (Yi et al., 2004). Some of this preclinical work (Gonzalez and Valatx, 1997, 1998; Marrosu et al., 1990; Mu¨ller-Preuss et al., 2005) suggests that CRH promotes REMS. From the study in normal humans the influence of endogenous CRH on REMS is uncertain, however, since CRH suppresses REMS (Holsboer et al., 1988). In normal male controls a-helical CRH prompts CRH-agonistic and CRH-antagonistic effects as well on sleep-endocrine activity (Held et al., 2005). Studies on the sleep-EEG effects of ACTH and cortisol help to differentiate the central and peripherally mediated sleep-EEG changes after CRH in humans (see below). The role of CRH in sleep regulation is further elucidated by a study on the effects of CRH receptor-1-antagonism in patients with depression (Held et al., 2004). After a four week trial with the substance

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R121919 the characteristic sleep-EEG changes in a sample of depressed patients are counteracted, as the number of awakenings and REMS density decrease and SWS increases. These results suggest that (i) CRH is involved in the pathophysiology of sleep-EEG changes during depression including REMS desinhibition and that (ii) CRH-1-receptor antagonism helps to treat besides other symptoms of depression (Zobel et al., 2000) impaired sleep. 3.3. Vasopressin The neuropeptide vasopressin is the major cofactor with CRH in the activation of the stress reaction. Icv vasopressin increases wakefulness in rats (Arnauld et al., 1989). Chronic intranasal vasopressin improves sleep in normal elderly subjects as total sleep time, SWS and REMS increase (Perras et al., 1999b). The authors suggested that this treatment may compensate for an age-related decrease in vasopressin content of the suprachiasmatic nucleus, or that vasopressin could act by stimulating the expression of central corticosteroid receptors. 3.4. ACTH Nocturnal infusions of ACTH suppress REMS in normal subjects (Fehm et al., 1993; Gillin et al., 1974), whereas cortisol and GH increase (Born et al., 1989). The synthetic ACTH (4–9) analogue ebiratide shares several behavioural effects of ACTH but does not influence peripheral hormone secretion. Accordingly after repetitive i.v. ebiratide, GH and cortisol remain unchanged in young male controls, sleep onset increases, and during the first third of the night awake time is elevated and SWS decreases (Steiger et al., 1991). This observation corroborates the view that the blood–brain interface is no obstacle for CNS effects of i.v. administered neuropeptides, as ebiratide induces sleep-EEG changes in the absence of effects on peripheral hormone secretion. 3.5. Cortisol, synthetic glucocorticoid and mineralocorticoid receptor ligands Continuous nocturnal (23:00–07:00) infusion of cortisol (Born et al., 1991) and pulsatile i.v. administration (hourly from 17:00 to 07:00) increase SWS (Friess et al., 1994) and SWA (Friess et al., 2004) and decrease REMS in young normal controls. In the latter study GH increases after cortisol. Similarly SWS, SWA and GH increase and REMS decreases in analogue protocols with i.v. cortisol in elderly men (Bohlhalter et al., 1997) and in patients with depression (Schmid et al., 2000). Since CRH (Holsboer et al., 1988) and cortisol exert opposite effects on SWS (Born et al., 1991; Friess et al., 1994) and GH (Bohlhalter et al., 1997; Friess et al., 1994) it appears unlikely that these effects are mediated by increased cortisol. In contrast these changes may be due to negative feed-

back inhibition of endogenous CRH. Because CRH (Holsboer et al., 1988), ACTH (Born et al., 1989) and cortisol (Born et al., 1991; Friess et al., 1995b, 1994) diminish REMS in contrast to ebiratide, REMS suppression may be mediated by cortisol after each of these hormones. This hypothesis is supported by the observation that the inhibition of cortisol synthesis by metyrapone reduces SWS and cortisol in normal controls, whereas REMS is not affected (Jahn et al., 2003). In this experiment endogenous CRH is probably enhanced, since ACTH is distinctly elevated. In contrast to the effects of acute cortisol administration subchronic treatment of female patients with multiple sclerosis with the glucocorticoid receptor (GR) agonist methylprednisolone results in shortened REMS latency, increased REMS density and a shift of the major portion of SWS from the first to the second NREMS period. These changes resemble the sleep-EEG disturbances in depression (Antonijevic and Steiger, 2003). In vivo microdialysis in rats shows a marked rise in free corticosterone levels in the brain during sleep deprivation (Penalva et al., 2003). In a single case study after oral administration of the mixed GR and progesterone receptor antagonist mifepristone, ACTH and cortisol levels increased in a young male subject. Sleep was disrupted distinctly (Wiedemann et al., 1992). This pilot study was extended in a set of experiments on the effects of GR and mineralocorticoid receptor (MR) antagonists (Wiedemann et al., 1994). Normal subjects participated in four protocols: (i) placebo only; in the other protocols prior to the examination nights dexamethasone was given orally, the following day at 14:00 either (ii) placebo or (iii) the MR antagonist spironolactone or (iv) mifepristone were administered orally. After pretreatment with dexamethasone sleep EEG remains unchanged. After the combination of dexamethasone with spironolactone REMS decreases. Dexamethasone followed by mifepristone results in decreases of SWS and REMS and an increased number of awakenings. Pretreatment with dexamethasone suppresses ACTH and cortisol secretion. Mifepristone, but not spironolactone counteracts this effect. Finally the effects of mifepristone, the progesterone receptor agonist megestrol acetate, and placebo were compared (Wiedemann et al., 1998). Mifepristone and megestrol exert opposite effects on hormone levels, but compound their impairing effects on sleep. HPA hormones increase and GH decreases after mifepristone, whereas megestrol exerts inverse effects. Again mifepristone disturbs sleep, and megestrol selectively suppresses REMS. The combination of these substances increases wakefulness and shallow sleep and decreases REMS. It is thought that these effects are mediated by an interaction of GR and progesterone receptors. The precise evaluation of the function of corticosteroid receptors becomes puzzling with the discovery that receptor complexes, composed of both MRs and GRs mediate genomic effects on CNS activity (for discussion, see Bohlhalter et al., 1997).

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4. Hypothalamo-pituitary-thyreoid (HPT) system Changes of vigilance are frequent symptoms of disorders of the thyroid gland as hyperthyroidism is linked with insomnia. In contrast, fatigue occurs in hypothyroidism. Therefore it is astonishing that there are only a few data on sleep EEG in these diseases. One study reported reduced SWS in patients with hypothyroidism in comparison to controls. These changes normalized after therapy (Kales et al., 1967). Pulsatile i.v. thyreotropin-releasing hormone (TRH) results in decreases sleep efficiency and advanced occurrence of the cortisol morning rise in young male controls (Hemmeter et al., 1998). 5. Prolactin, vasoactive intestinal polypeptide Prolactin is a circulating hormone and a neuroprotein as well. In humans prolactin rises after sleep onset and reaches its peak during the second or the last third of the night (Weitzman, 1976). In contrast to many other hormones prolactin is neither affected by normal ageing (Van Coevorden et al., 1991) nor by an episode of depression (Steiger and Holsboer, 1997b). During the recovery night after sleep deprivation prolactin increases in young and in elderly normal subjects as well (Murck et al., 1999). Systemic and intrahypothalamic prolactin promotes REMS in cats, rabbits and rats (Roky et al., 1994, 1993). In adult rats bearing juvenile rat anterior grafts under the capsule of the kidney, REMS and NREMS increase (Oba´l et al., 1992a). Vice versa systemic or intrahypothalamic injection of antiserum to prolactin decreases REMS in rats (Oba´l et al., 1997b; Roky et al., 1994). In patients with hyperprolactinoma SWS is increased whereas REMS is unchanged when compared to normal controls (Frieboes et al., 1998). Similar to prolactin icv vasoactive intestinal polypeptide (VIP) enhances REMS in laboratory animals (DruckerColin et al., 1984). When VIP is given to rats during the dark period NREMS and REMS increase (Oba´l et al., 1994; Riou et al., 1982). Similarly VIP microinjections into the pontine reticular tegmentum (Bourgin et al., 1997) and into the oral pontine tegmentum enhance REMS in rats (Bourgin et al., 1997). In rats the REMS-promoting effect of systemic VIP is inhibited by immunoneutralization of circulating prolactin. It appears likely that stimulation of prolactin is involved in the promotion of REMS after VIP (Oba´l et al., 1992a). Similarly central administration of VIP antibodies (Riou et al., 1982) or a VIP antagonist to rats (Mirmiran et al., 1988) diminish REMS. In young normal male subjects two doses of VIP exert different effects (Murck et al., 1996). After pulsatile i.v. administration of 4 · 10 lg VIP prolactin decreases, whereas sleep EEG remains unchanged. In contrast after the higher dose of 4 · 50 lg VIP prolactin increases. Furthermore the NREMS–REMS cycles are decelerated. Each of the NREMS and REMS periods is prolonged, the cortisol nadir appears advanced, and the GH surge is blunted

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(Murck et al., 1996). VIP appears to affect the circadian clock, resulting in prolonged sleep cycles and the advanced occurrence of the cortisol nadir. The blunted GH surge may be related to advanced increase of HPA activity. 6. Galanin The peptide galanin is widely located in the mammalian brain. It coexists in neurons with various peptides and classical neurotransmitters participating in sleep regulation. In the rat sleep remains unchanged after icv galanin, whereas REMS deprivation prompts galanin gene expression (Toppila et al., 1995). Repetitive i.v. galanin increases SWS and the duration of REMS periods but does not affect the secretion of GH and cortisol in young male controls (Murck et al., 1997a). A cluster of GABAergic and galaninergic neurons was identified in the ventrolateral preoptic area, which is thought to stimulate NREMS (Saper et al., 2001). Galanin or placebo was given i.v. to patients with depression during antidepressive therapy with trimipramine. After galanin REMS latency increases and the severity of depression as measured by the Hamilton Depression Scale decreases. These observations point to an acute antidepressive effect of galanin (Murck et al., 2004). 7. Orexins Nearly simultaneously two groups discovered a pair of neuropeptides synthesized in the lateral hypothalamus, named orexins (Sakurai et al., 1998) or hypocretins (de Lecea et al., 1998). In animal models it was shown that a lack of orexins or their receptor causes symptoms of narcolepsy. Narcolepsy is characterized by several abnormalities of the sleep–wake organization and of the sleep structure as cataplexy, excessive daytime sleepiness and, in the sleep EEG, sleep-onset REMS episodes, e.g. the occurrence of REMS during the first 10 min after sleep onset. In knockout mice which do not produce orexins a cataplexy-like behaviour was observed (Chemelli et al., 1999). In dogs a genetic form of narcolepsy was found to be related to mutation of the gene for the orexin-B receptor (Lin et al., 1999). Brains of patients with narcolepsy contain only few orexin neurons (Thannickal et al., 2000). Orexin A levels are low in these patients, whereas the plasma levels are in the normal range (Dalal et al., 2001). Saper et al. (2005) suggest that the role of the orexins is to stabilize the sleep– wake pattern by preventing unwanted transitions between sleep and wake stages. In narcolepsy a lack of orexin or orexin receptors led to numerous unintended transitions between vigilance states and to the intrusion of fragments of REMS into wakefulness. Siegel (2004) submitted the hypothesis that orexin fascilitates ‘‘motor activity tonically and physically in association with motivated behaviours and to coordinate their facilitation with the activation of attention and sensory systems’’. Orexin A administration reduces cataplexy and normalizes the sleep–wake pattern in dogs (Saper et al., 2001).

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8. Melatonin Melatonin release depends on the light-dark cycle. At night melatonin secretion peaks in light-active and in dark-active species as well. Probably it supports a ‘‘dark appropriate’’ behaviour (van den Heuvel et al., 2005). There is a controversy whether melatonin is helpful in sleep disorders (van den Heuvel et al., 2005; Zhdanova, 2005). 9. Neuropeptide Y (NPY) Opposite effects of CRH and neuropeptide Y (NPY) were found in animal models of anxiety (reviewed in Steiger and Holsboer, 1997a). Icv NPY changes EEG spectral activity similarly to benzodiazepines in rats (Ehlers et al., 1997a). The prolongation of sleep latency after CRH is antagonized dose-dependently by NPY in rats (Ehlers et al., 1997b). In young normal male subjects repetitive i.v. NPY decreases sleep latency, the first REMS period, cortisol and ACTH, and increases stage 2 sleep and sleep period time (Antonijevic et al., 2000a). In patients with depression of both sexes with a wide age range and in matched controls the sleep latency is shortened, and prolactin levels increase after NPY, whereas cortisol and ACTH and other sleep-EEG variables remain unchanged (Held et al., 2006). It is thought that NPY participates in sleep regulation, particularly as a signal for sleep onset as an antagonist of CRH acting via the GABAA receptor. 10. Gonadal hormones In a small group of adult women, no clear interaction between estradiol levels and sleep was observed (Alford et al., 1973). In males, testosterone rises constantly throughout the night (Weitzman, 1976). In women the menstrual cycle, pregnancy and the menopause reflect distinct changes in endocrine activity and have some impact on sleep regulation. Only few studies addressed these issues so far. Most studies on sleep regulation were performed selectively in men or in male animals. One of the reasons why females are not included in such studies is because of the variability of the menstrual cycle (Kimura, 2005). In normal women the percentage of REMS tends to be higher in the early follicular than in the late luteal phase, and the percentage of NREMS is higher in the luteal compared to the follicular phase. In NREMS EEG power density in the upper frequency range of the sleep spindles exhibits a large variety across the menstrual cycle, with maximum in the luteal phase (Driver et al., 1996). In women during the menopause EEG activity in the sigma frequency range shows a distinct decline, whereas in men these changes occur more gradually (Ehlers and Kupfer, 1997). After the menopause sleep-endocrine changes associated with depression are accentuated. This view is supported by a comparison of sleep-endocrine activity in pre- and postmenopausal women with depression and in matched controls. Cortisol is elevated in the

postmenopausal patients, whereas it is reduced in postmenopausal controls. A decrease in SWS and an increase of REMS density are prominent in post- but not in premenopausal patients. An inverse correlation is found between the decline in SWS and in sleep continuity and follicle stimulating hormone (FSH) secretion in the patients. A role of menopause for these sleep-EEG changes appears likely (Antonijevic et al., 2003). Administration of gonadal hormones to adult animals exerts only weak effects on sleep EEG (Manber and Armitage, 1999). High chronic dosages of estradiol in transsexual men who underwent cross-gender therapy increase stage 1 sleep (Ku¨nzel et al., 2000). Estrogen replacement therapy by skin patch in postmenopausal women enhances REMS and reduces intermittent wakefulness during the first two sleep cycles. The normal decrease in SWS and SWA from the first to the second cycle is restored (Antonijevic et al., 2000d). For the effects of progesterone replacement please see below. In all the effects of gonadal steroids on sleep EEG appear to be relatively weak in women before the menopause and in male subjects. The endocrine changes during the menopause contribute to sleep-EEG alterations. Replacement therapy appears to help to counteract these changes. 11. Neuroactive steroids Certain steroids, so-called neuroactive steroids, exert direct effects on neuronal membranes and thereby rapidly affect CNS excitability (Paul and Purdy, 1992). Their effect on neuronal excitability is mediated by the GABAA-receptor complex. Neuroactive steroids are involved in the regulation of anxiety, memory and sleep. Glial cells are capable to synthesize certain neuroactive steroids independently of peripheral steroid sources (Jung-Testas et al., 1989). Various neuroactive steroids exert specific effects on sleep EEG in humans and rats. After oral pregnenolone in young normal controls SWS increases, and EEG power in the spindle frequency range decreases (Steiger et al., 1993b). These changes resemble the effects of a partial inverse agonist at the GABAA receptor. Similarly in rats subcutaneous pregnenolone at the beginning of the light period increases SWA (Lancel et al., 1994). I.p. pregnenolone sulfate in rats, however, increases REMS (Darnaudery et al., 1999). A dose-dependent hypnotic effect of i.v. progesterone was reported as early as in 1954 (Merryman et al., 1954). In normal young men after oral progesterone, NREMS, particularly stage 2 sleep, increases, and SWA decreases (Friess et al., 1997). Furthermore EEG power in the higher frequency range (>15 Hz) tends to be elevated. There is a distinct interindividual variability in the bioavailability of progesterone and consequently in the time curse of the concentrations of its metabolite allopregnanolone. Two subgroups were identified, one with an early peak and one with a late peak of allopregnanolone. The time course of this peak is associated with the changes in the EEG power

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spectra. The initial increase in the EEG activity in the spindle and alpha range during the first few hours of sleep is found in the subjects with an early allopregnanolone peak, whereas the decrease of SWA is seen mainly in those subjects with a later peak of this metabolite. The sleep-EEG changes after progesterone in this study resemble those after benzodiazepines. They appear to be mediated in part via the conversion of progesterone into allopregnanolone. In women, progesterone declines after the menopause. Subchronic oral progesterone replacement increases REMS and decreases intermittent wakefulness in postmenopausal women (Schu¨ssler et al., 2005a). I.p. administration of three doses of progesterone at the onset of the dark period in rats prompts dose-dependent decreases of NREMS latency, wakefulness and REMS and increases of REMS latency and of pre-REMS, an intermediate state between NREMS and REMS. EEG activity decreases in the lower frequencies and increases in the higher frequencies. I.p. allopregnanolone reduces NREMS latency and increases pre-REMS in rats; in NREMS EEG activity decreases in the lower frequencies and increases in the higher frequencies (Lancel et al., 1997b). These data confirm benzodiazepine-like effects of allopregnanolone on sleep. The ring A reduced metabolite of deoxycorticosterone3-alpha, 21-dihydroxy-5-alpha-pregnan-20-one (THDOC) is a barbiturate like ligand of the GABA receptor complex. In the rat THDOC shortens sleep latency and increases NREMS (Mendelson et al., 1987). In young men the THDOC precursor DOC did not affect sleep EEG (Steiger et al., 1993a). Oral dehydroepiandrosterone (DHEA) increases selectively REMS in young normal men (Friess et al., 1995a). This finding is compatible with a mixed GABAA agonistic/antagonistic effect. After intraperitoneal DHEA sulfate (DHEAS), a dose-dependent effect on EEG power occurs in rats. 50 mg/kg DHEAS augments EEG power in the spindle-frequency range, whereas 100 mg/kg DHEAS exert opposite effects (Schiffelholz et al., 2000). It would be interesting to examine whether DHEA is capable to counteract an age-related decline of REMS in the elderly. 12. GABAA receptor agonists Nowadays the most widely used hypnotics are agonistic modulators of GABAAreceptors, benzodiazepines, zolpidem and zopiclone. These substances induce and maintain sleep, whereas they diminish REMS. Furthermore these drugs promote sleep spindles, which are characteristic for shallow sleep and suppress SWA (review: Lancel and Steiger, 1999). The GABAA agonists muscimol and gaboxadol (THIP) are structural analogues of GABA. These substances interact directly with the GABA-binding sites on the GABAA receptor complex and thereby increase the membrane conductance for chloride ions. GABAA agonists and benzodiazepines mimic and potentiate the action of endogenous GABA at the GABAA receptor. Also the novel

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compound indiplon shares this way of action (Iversen, 2004). Therefore one would expect that GABAA agonists exert effects similar to those of benzodiazepines on sleep EEG, and that their effects should be enhanced by benzodiazepines. Interestingly this is clearly not the case. The reason may be that gaboxadol acts at extrasynaptic GABAA receptors insensitive to benzodiazepines and containing a4b3d subunits (Krogsgaard-Larsen et al., 2004). Systemic administration of muscimol in rats during the light period increases NREMS, SWA and REMS (Lancel et al., 1996). This pattern of effects differs from the effects of the GABA analog pregabaline, acting at the a2d subunit, which enhances NREMS but decreases REMS in rats (Kubota et al., 2001) and humans (Hindmarch et al., 2005). NREMS and SWA increase also after i.p. administration of gaboxadol to rats at the beginning of the light period, whereas REMS remains unchanged (Lancel and Faulhaber, 1996). After repeated doses of gaboxadol for 5 days these effects are sustained during all treatment days. After drug withdrawal the sleep pattern of the animals receiving gaboxadol is identical to a control group receiving placebo. This observation suggests that gaboxadol does not produce tolerance. Drug withdrawal may not be associated with sleep disturbances (Lancel and Langebartels, 2000). Also in young normal men gaboxadol increases SWS and SWA and reduces EEG activity in the spinal frequency range whereas it does not affect REMS (Faulhaber et al., 1997). Gaboxadol was also shown to improve disturbed sleep, e.g. in healthy elderly subjects (Lancel et al., 2001; Mathias et al., 2005) and during post nap sleep in normal subjects (Mathias et al., 2001a). In these conditions gaboxadol decreases intermittent wakefulness, increases total sleep time, SWS and SWA. In healthy elderly subjects gaboxadol does not influence neither nocturnal hormone secretion (Lancel et al., 2001) nor next day attention and memory function (Mathias et al., 2005). When benzodiazepines and muscimol are coadministered to rats they do not augment each others’ effects on sleep EEG but even attenuate each others’ effects on EEG signals within NREMS (Lancel et al., 1997a). The effects of the GABA-uptake inhibitor tiagabine on sleep EEG resemble those of GABAAagonists. I.p. tiagabine dose-dependently elevates EEG power density in all frequency bands during NREMS, most prominent in the lower frequencies. It slightly suppresses REMS (Lancel et al., 1998). A single oral dose of tiagabine increases sleep efficiency, SWS and SWA and, by trend, decreases wakefulness in normal elderly subjects (Mathias et al., 2001b). The sleep-promoting effect of tiagabine was confirmed in another sample of elderly subjects (Walsh et al., 2005). Since the effects of tiagabine on sleep EEG are very similar to those after GABA agonists it appears likely that their influence on sleep may be due to tonic stimulation of GABAA receptors. The hypnotic properties of gaboxadol and tiagabine differ considerably from those of the agonistic modulators, benzodiazepines, zolpidem and zopiclone. In contrast to the latter substances these drugs mimic the

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Table 1 Effects of peptides and steroids on sleep Effects on Substance

Species, population

Gender

Wakefulness

NREMS

REMS

Rat, rabbit h, normal subjects, patients with depression h, normal subjects, patients with depression Cat Rat h, normal subjects h, acquired GH deficiency Rat h, young controls h, elderly subjects Mouse h, young controls

m m

– –/fl

› ›

–/› –/›

f

›

fl

–

f m m f/m m m f/m m m

– – – – – – › – –

fl fl/› fl – fl fl fl › ›

› › › – –/› – fl – (fl)

GR agonista

Rat h, young controls h, middle-aged controls Rat h, elderly subjects h, young controls h, young controls h, young and elderly controls, patients with depression h, patients with multiple sclerose

m m m m m m m m f/m f

› – › › – – (›) – – –

fl fl fl – › – (fl) › › –

–/› fl – – › fl – fl fl –

Other peptides TRH Prolactin Prolactin VIP VIP

h, young controls Cats, rats, rabbits h, patients with prolactinoma Rat h, normal controls

m m f/m m m

– – – – –

– –/› › –/› –

– › – › –

Galanin Galanin

Rat h, normal controls

m m

– –

– ›

– –

Galanin NPY

h, patients with depression Rat

f/m m

– –

– –

– –

NPY

h, young controls

m

–

›

–

NPY

h, middle-aged controls and patients with depression Mouse, dog, h

f/m

–

–

–

f/m

–

–

–

Gonadal hormones Estrogen h, postmenopausal

f

(›)

–

(›)

Neuroactive steroids Pregnenolone Rat Pregnenolone h, young controls Progesterone Rat Progesterone h, young controls Progesterone h, postmenopausal

m m m m f

– – fl – fl

› › – › –

–

THDOC DHEA

m m

– –

› –

– ›

HPS system GHRH GHRH GHRH GH GH GH GH SRIF SRIF SRIF Ghrelin Ghrelin HPA system CRH CRH CRH Vasopressin Vasopressin ACTH ACTH (4–9) Cortisol

Orexin

Rat h, young controls

Other

Remarks REMS› via GH› REMS› via GH›

Chronic administration

REMSfl via cortisol

Chronic administration

SWS shift to 2nd NREMS period REMS latency fl, REMS density ›

10 days administration

SEI fl

Decelaration of NREMS/ REMS cycles Decelaration of REMS periods › REMS latency fl Benzodiazepine-like changes of sleep EEG Sleep latency fl, 1st REMS period fl, SPT › Sleep latency fl Stabilization of vigilance states

fl – ›

Subchronic administration Sleep latency fl

–/› etc. means controversial reports; (›) means weak effect. Abbreviations. h, humans; SPT, sleep period time; SEI, sleep efficiency index; SRIF, somatostatin or octreoide, respectively. a Glucocorticoid receptor agonist methylprednisolone.

A. Steiger / Journal of Psychiatric Research 41 (2007) 537–552

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sleep-promoting effect of sleep deprivation. These substances appear to represent a new class of hypnotics. Currently clinical trials with gaboxadol are performed. 13. Conclusions Various hormones (particularly neuropeptides and steroids) exert specific effects on the sleep EEG (see Table 1). A model of peptidergic sleep regulation is proposed in Fig. 1. Some peptides (GHRH, ghrelin, galanin, NPY) promote sleep, at least in males, whereas others (CRH, somatostatin) impair NREMS. The reciprocal interaction of GHRH and CRH plays a keyrole in sleep regulation. GHRH promotes NREMS, at least in males, and stimulates GH, whereas CRH maintains wakefulness and enhances the HPA hormones. Some, but not all studies suggest that CRH promotes REMS. Changes in the CRH:GHRH ratio in favor of CRH contribute to the sleep-endocrine changes during depression and ageing. On the other hand GHRH participates in sleep promotion after sleep deprivation. In women however, GHRH exerts CRH-like effects. Similar to their reciprocal role in GH secretion, GHRH and somatostatin exert opposite effects on sleep EEG, at least in males. Somatostatin is another sleep-impairing peptide. Besides of GHRH galanin and ghrelin promote NREMS. Intact GHRH receptors are the prerequisite for the effect of ghrelin. In contrast to GHRH ghrelin stimulates HPA activity in males. Ghrelin may act as an interface between the HPA and HPS systems. Galanin is colocalized with GABA in the ventrolateral preoptic nucleus. Many hypothalamic GHRH responsive neurons are GABAergic. Galanin, ghrelin and GHRH may either act in a synergistic fashion or these peptides may be part of a cascade resulting in the promotion of NREMS. Probably GABAergic neurons mediate the effects of these peptides. Also the effects of NPY, which is a major signal for sleep onset, appear to be mediated via the GABAA receptor. Thalamic GABAergic transmission is thought to be involved in the sleep impairing effect of somatostatin. VIP appears to participate in the temporal organization of sleep. In young men after VIP the NREMS/REMS cycle is decelerated, probably by action at the suprachiasmatic nucleus. Beside of peptides steroids are involved in sleep regulation. Acute administration of cortisol promotes SWS, probably via feedback inhibition of CRH. Furthermore cortisol suppresses REMS in humans, whereas REMS decreases after short term withdrawal of hydrocortisone substitution in Addison’s patients. Hence cortisol may promote REMS. Similarly subchronic administration of a GR agonist in patients with multiple sclerosis prompts sleep-EEG changes similar to those in patients with depression including REMS desinhibition. Physiological cortisol levels appear to contribute to REMS maintenance; a synergism of elevated CRH activity and enhanced glucocorticoid levels appears to contribute to the changes of SWS and REMS during depression.

Fig. 1. Model of peptidergic regulation. CRH, corticotropin-releasing hormone; GHRH, growth hormone-releasing hormone; NPY, neuropeptide Y; SRIF, somatostatin. Characteristic hypnograms and patterns of cortisol and GH secretion are shown in a young and in an elderly normal subject and in a depressed patient. It is thought that GHRH is released during the first half of the night, whereas CRH preponderates during the second half of the night. GHRH stimulates GH and SWS around sleep onset, whereas CRH is related to cortisol release and REMS in the morning hours. NPY is a signal for sleep onset. Besides of GHRH, galanin and ghrelin promote sleep, whereas somatostatin impairs sleep. During depression (CRH overactivity) and during normal ageing, similar changes of sleep-endocrine activity are found. Changes in the GHRH/CRH balance in favor of CRH appear to play a key role in these aberrances. Nervenarzt (1995), 66: 15–27, Schlafendokrinologie, Axel Steiger, Fig. 2, Copyright Springer-Verlag 1995, with kind permission of Springer Science and Business Media.

GABAA steroids, of sleep effect of

receptors are also targets of various neuroactive which exert specific effects on sleep. The changes EEG after the menopause and the beneficial estrogen replacement therapy suggest a role of

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estrogen in sleep regulation. The effects of CRH-1 receptor antagonism in depression, of arginine vasopressin in the elderly and of estrogen and progesterone replacement therapy in the menopause are promising hints for a clinical application of sleep research. Furthermore galanin analogs may be useful to treat depression. GHRH or related drugs may help to counteract age-related changes of sleep-endocrine activity. It should be kept in mind however that it may be to late to start such a therapy during senescence. A threshold age should be identified, when such an intervention should begin. Finally orexins promise to be leads for the development of a novel therapy of narcolepsy. The GABAA agonist gaboxadol and the GABA reuptake inhibitor tiagabine represent a new class of hypnotics which promise to modulate sleep in patients with insomnia in a way better related to physiology as they mimick the effects of sleep deprivation on sleep EEG. Acknowledgment Research from the author’s laboratory was supported by the Deutsche Forschungsgemeinschaft (Ste 486/5-4). References Alford FP, Baker HW, Burger HG, De Kretser DM, Hudson B, Johns MW, et al. Temporal patterns of integrated plasma hormone levels during sleep and wakefulness. II. Follicle-stimulating hormone, luteinizing hormone, testosterone and estradiol. Journal of Clinical Endocrinology & Metabolism 1973;37:848–54. Antonijevic IA, Steiger A. Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis. Psychoneuroendocrinology 2003;28:780–95. Antonijevic IA, Murck H, Frieboes RM, Holsboer F, Steiger A. Hyporesponsiveness of the pituitary to CRH during slow wave sleep is not mimicked by systemic GHRH. Neuroendocrinology 1999a;69: 88–96. Antonijevic IA, Murck H, Frieboes RM, Holsboer F, Steiger A. On the gender differences in sleep-endocrine regulation in young normal humans. Neuroendocrinology 1999b;70:280–7. Antonijevic IA, Murck H, Bohlhalter S, Frieboes RM, Holsboer F, Steiger A. NPY promotes sleep and inhibits ACTH and cortisol release in young men. Neuropharmacology 2000a;39:1474–81. Antonijevic IA, Murck H, Frieboes RM, Barthelmes J, Steiger A. Sexually dimorphic effects of GHRH on sleep-endocrine activity in patients with depression and normal controls – part I: the sleep EEG. Sleep Research Online 2000b;3:5–13. Antonijevic IA, Murck H, Frieboes RM, Steiger A. Sexually dimorphic effects of GHRH on sleep-endocrine activity in patients with depression and normal controls – part II: hormone secretion. Sleep Research Online 2000c;3:15–21. Antonijevic IA, Stalla GK, Steiger A. Modulation of the sleep electroencephalogram by estrogen replacement in postmenopausal women. Journal of Obstetrics and Gynaecology 2000d;182: 277–82. Antonijevic IA, Murck H, Frieboes RM, Uhr M, Steiger A. On the role of menopause for sleep-endocrine alterations associated with major depression. Psychoneuroendocrinology 2003;28: 401–18. Arnauld E, Bibene V, Meynard J, Rodriguez F, Vincent JD. Effects of chronic i.c.v. infusion of vasopressin on sleep-waking cycle of rats. American Journal of Physiology 1989;256:R674–84.

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