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CNS Neurol Disord Drug Targets
2009;8(4):235-244
  
Scholarpedia
Sleep-inducing factors
 
García-García F, Acosta-Peña E
Venebra-Muñoz A, Murillo-Rodríguez E.
 
Laboratorio de Biología de Sueño, Departamento de Biomedicina, Instituto de Ciencias de la Salud, Universidad Veracruzana, México.

Chat-logomini

 
Abstract
 
Kuniomi Ishimori and Henri Piéron were the first researchers to introduce the concept and experimental evidence for a chemical factor that would presumably accumulate in the brain during waking and eventually induce sleep. This substance was named hypnotoxin. Currently, the variety of substances which have been shown to alter sleep includes peptides, cytokines, neurotransmitters and some substances of lipidic nature, many of which are well known for their involvement in other biological activities. In this chapter, we describe the sleep-inducing properties of the vasoactive intestinal peptide, prolactin, adenosine and anandamide.
 
 
Intoduction
 
Henri Piéron was the first researcher to introduce the concept and experimental evidence for a chemical factor that would presumably accumulate in the brain during waking and eventually induce sleep. This concept lay dormant for many years, in absence of adequate techniques and knowledge to pursue the identification of such a hypnogenic factor. With the development of biochemical techniques and the description of various neurotransmitters with specific anatomical localizations, it was suggested that a subset of these endogenous chemicals could be involved in the generation of sleep. In the 1960s, Michel Jouvet championed the concept that sleep and waking could be respectively generated by specific chemical neurotransmitters contained in specific neuronal systems.
 
Recently, peptides and hormones have been identified as substances capable of modulating the sleep-wake cycle. Thus, chemicals of different molecular sizes were suggested to function as neurotransmitters, neuromodulators or neurohormones, providing the possibility for short-to-long acting molecules that could participate collectively in the generation and maintenance of the sleep-wake cycle. The variety of substances which have been shown to alter sleep includes peptides, cytokines, neurotransmitters and some lipid-containing substances, many of which are well known for their involvement in other biological activities. These substances, referred to as sleep-inducing factors (SIFs), have been classified with criteria by some authors in order to be considered as SIFs. In this section, we describe the evidence accumulated to date on several SIFs and the changes that they produce on sleep patterns.
 
The Origin of Sleep Inducing Factors
 
First investigators to propose the existence of a substance capable of inducing sleep were René Legendre and Henri Piéron (1913 in France and Kuniomi Ishimori in Japan (1909).
 
Kubota K. Kuniomi Ishimori and the first discovery of sleep-inducing substances in the brain. Neurosci Res. 1989;6(6):497-518.
 
In the first classic experiment, Piéron removed cerebrospinal fluid (CSF) from sleep-deprived dogs (for periods varying from 30 to 505 hours, but in no case beyond the point where they showed extreme sleepiness) and transferred it to normal dogs. The recipient animals were then observed to sleep longer than usual. Sleep-deprived dogs showed significant reductions of the muscle tone observed as a visible decrease of the postural tone for the head and flexion of the legs. Sleep-deprived dogs demonstrated no significant changes in the composition of the blood, blood pressure, heart beat frequency, breathing frequency or corporal temperature. Nevertheless, sleepdeprived dogs had the following changes in the cytology of the deep layers of the prefrontal cortex; displacement of the neuronal nuclei, vacuolization of the cytoplasm and disappearance of Nissl grains [4]. The damage in the cerebral cortex was proportional to the sleep deprivation time. Interestingly, if sleep-deprived dogs were allowed recovery sleep, the cellular damage was not observed. These results suggested that the accumulation of sleep-promoting substances in CSF during prolonged wake periods, collectively termed "hypnotoxin", was sufficient to induce sleep in normal animals. The hypnotic effects of hypnotoxin disappeared when CSF was warmed to 65°C in 5 minutes, suggesting the protein-like nature of the substance. Nevertheless, it was not possible to isolate that substance due to the technical limitations of the epoch. On the other hand, Ishimori performed experiments similar to those of Piéron, but Ishimori named the accumulated substance in the CSF of sleep-deprived dogs a "hypnogenic" substance. The works of Henri Piéron together with Ishimori marked the beginning of the study of humoral regulation of sleep.
 
Vasoactive Intestinal Peptide (VIP)
 
VIP was originally isolated from the small intestine and the lung as a peptide with potent vasodilator effects and has recently been suggested to play a major regulatory role in a large number of acute and chronic diseases. The primary structure of VIP is closely related to pituitary adenylate cyclase activating polypeptide. VIP contains 20 amino acids with a molecular weight of 3329 Da. The amino acid sequence of VIP in the rat, human and other mammalians species is identical. VIP receptors are widely distributed in the cerebral cortex, amygdaloid nuclei, hippocampus, olfactory lobes, thalamus, and suprachiasmatic nucleus.
 
Several studies have suggested a role for VIP as a SIF. In the decade of 1980's Riou and co-workers demonstrated that intracerebroventricular (i.c.v.) administration of 100 ng of VIP promotes rapid-eye movement (REM) sleep in rats. Subsequent studies indicated that i.c.v. injection of VIP also promotes REM sleep in other species such as cats and rabbits.
 
In 1986, Prospero-García and co-workers reported that both the cerebral CSF from cats sleep-deprived for 24 hours, as well as VIP, were each capable of restoring REM sleep in cats pretreated with para-chlorophenylalanine (PCPA), a specific inhibitor of serotonin synthesis which reduces sleep time. These results suggested that the CSF of sleep-deprived cats contains a VIP-like sleep factor possibly involved in triggering REM sleep. Subsequent studies demonstrated that i.c.v. administration of CSF in cats incubated with VIP antibodies blocked its REM sleepinducing effects [18], and that VIP also induces REM sleep recovery in insomniac forebrain-lesioned cats.
 
Subsequently, it has been observed that VIPimmunoreactivity in various areas of the rat brain after 24 and 48 hours of REM sleep deprivation did not change in any analyzed brain structure, suggesting that the increase in VIP peptide levels does not correlate with the REM sleep homeostatic process. However, other studies have shown that in both the suprachiasmatic nucleus and periventricular nucleus the concentration of VIPimmunoreactivity increases during the dark period, when rodents are mostly awake, and decreases during the subsequent light period, when most of the time is spent in sleep. VIP-immunoreactivity exhibits daily variations in the locus coeruleus nucleus, the periaqueductal gray matter and the paraventricular nucleus. These daily variations suggest that VIP may act as an endogenous hypnogenic factor which progressively accumulates during the waking period, until it reaches a critical level at which it could trigger REM sleep. Additionally, it has been demonstrated that the density of VIP receptors increases after 72 hours of REM sleep deprivation. The increase of VIP receptors occurred mainly in the laterodorsal tegmental nucleus and posterodorsal tegmental nucleus, brainstem areas involved in the generation and maintenance of REM sleep.
 
PRL and Sleep Regulation
In 1986, Michel Jouvet demonstrated that the systemic administration of PRL enhances the total time of REM sleep in cats. Studies in hypo-prolactinemic rats showed that REM sleep duration decreased, the circadian rhythm of REM sleep disappeared, while that of non-rapid eye movement (NREM) sleep remains unchanged. These studies were the first to provide evidence of PRL-involvement in sleep regulation. Further studies have shown that the administration of exogenous PRL in additional animal species including rabbits and rats induced REM sleep.
 
Additionally, the systemic administration of anti-PRL antibodies and anti-serum in rats reduced REM sleep. Likewise, it has been observed that the effect of PRL on REM sleep is photoperiod-dependent, because the amount of REM sleep decreased or increased when PRL was administered during the dark or light period, respectively. Furthermore, it has been reported that prolactinreleasing peptide (PrRP) also promotes REM sleep when it is administered to rats. These results suggest that PRL stimulated by i.c.v. injection of PrRP could contribute to the induction of REM sleep.
 
The firing frequency of mesopontine tegmental neurons, an area involved in REM sleep generation, increases after PRL injection. This result suggests that PRL is capable of inducing REM sleep and modulating cholinergic activity, but the mechanisms remain unclear. Additionally, there are other studies that show that PRL injection into the central nucleus of the amygdala, an area containing high concentrations of PRL immunoreactive fibers and receptors, decreased NREM sleep. However, microinjections of cholinergic agonist in the same nucleus induced REM sleep.
 
PRL administered locally into the rat dorsolateral hypothalamus, an area that contains PRL immunoreactive neurons, either increases REM sleep when it is given diurnally or decreases REM sleep when given nocturnally. Also, it has been demonstrated that in hypoprolactinemic rats under light-dark conditions, the circadian rhythms of NREM sleep and REM sleep display an alteration of their phase relation. This result suggests that the promoting effect of REM sleep by PRL could be regulated by circadian factors.
 
In addition, it has been shown that relatively higher levels of PRL secretion occurs during NREM sleep and that PRL secretion was coupled to delta waves in humans, in contrast alpha and beta bands frequencies were inversely proportional to PRL secretion. It is well established that plasma PRL concentrations exhibit a sleep-dependent pattern, with high levels occurring during sleep and low levels during waking. Thus, it has been suggested that endogenous PRL accumulation during NREM sleep contributes to subsequent REM sleep.
 
[....]
 
Adénosine AD, the Sleep-Inducing Purine
 
As discussed in the introduction, several molecules modulate the steps leading to the initiation of sleep. In addition to neurotransmitters, such as gamma-aminobutyric acid and peptide factors, including VIP and PRL, there are endogenous compounds with sleep-inducing properties. AD is a product of natural cellular metabolism and has been suggested to be an important homeostatic sleep factor acting in neurons in basal forebrain and preoptic areas through A1 and A2A receptors. In this section we will review the role of AD on sleep modulation.
 
Feldberg and Sherwood were the first to show that AD induced sleep-like behavior in the cat. Further research in rodents described that systemic administration of AD, its analogs or inhibitors of its metabolism increase NREM sleep.
 
To date, several AD receptors have been described. These receptors are G-protein-coupled, and compromise the following members: A1, A2A, A2B and A3. A1 (and A3) inhibit adenylyl cyclase, while A2 displays opposite properties. A1 are postsynaptic, leading to a stimulation of K+ channels, as well as a hyperpolarization and inhibition of neural activity.
 
The case for AD as a sleep factor has been suggested from multiple findings. Microdialysis studies have confirmed that cholinergic cells in the basal forebrain are presumably responsible for the accumulation of this purine during natural waking and during sleep deprivation. Additionally, infusions of AD into the basal forebrain of cats increase sleep, whereas the extracellular levels of this purine have been described to be about 20% higher during wakefulness (W) compared with sleep [80]. Importantly, when the period of prolonged W was increased to 6 h using sleep deprivation, a significant and robust increase of AD (200%) was found, and this value decreased during the recovery sleep period.
 
[....]
 
The sleep-inducing mechanism suggests that AD acts on an AD1 autoreceptor placed in cholinergic neurons in the basal forebrain. The activation of the AD1 decreases the activity of the cholinergic neurons blocking the inhibition of gamma-aminobutyric acid-ergic neurons in the ventrolateral preoptic area leading to a sleep induction. It is widely accepted that the drive to sleep is determined by the activity of the basal forebrain cholinergic neurons, which in turn release AD. It has been suggested that the increase in the endogenous levels of AD are due to the enhancement of the metabolic activity associated with the neuronal discharge activity during W. Thus, accumulating AD inhibits these neurons so that sleep-active neurons can become active. Importantly, this current hypothesis has been strengthened with experimental evidence showing that systemic or central administrations of AD induce sleep and its extracellular levels are increased during prolonged waking. Recently, it was demonstrated that the basal forebrain cholinergic neurons are central to the AD regulation of sleep drive. In rats in which at least 95% these neurons are successfully lesioned via injections of the neurotoxin 192-IgG-saporin, the extracellular levels of AD levels did not increase with 6 h of prolonged waking. However, the lesioned rats had intact sleep drive after 6 and 12 h of prolonged waking. These results suggested that AD accumulation in the basal forebrain is not necessary for sleep drive. Additionally, it was demonstrated that the basal forebrain cholinergic neurons were not essential to sleep induction as administration of the selective AD A1 receptor agonist N6-cyclohexyladenosine into basal forebrain of rats continued to induce sleep. Thus, results suggest that neither the activity of the cholinergic neurons placed in the basal forebrain nor the accumulation of AD in this brain area during wake is necessary for sleep drive.
 
Anandamide (ANA)
 
During the 1960s several experiments were carried out in order to evaluate the effects of the cannabinoids on sleep. The main conclusion of those experiments was that cannabinoids modulate sleep by increasing NREM and REM sleep.
 
Subsequently, transmembrane proteins in the central nervous system (CNS) that recognize the principal compound of marijuana, the delta-9-tetrahydrocannabinol were described. The receptors were classified as central or peripheral, CB1 and CB2, respectively. The presence of the CB1 receptor has been shown in specific areas of the CNS such as cortex, hippocampus, striatum, limbic system, cerebellum, and brainstem. This protein possesses 7 transmembrane domains and inhibits cAMP formation through Gi alpha subunit protein.
 
Once described as the receptors for the exogenous cannabinoids, the search for endogenous compounds for these cannabinoid receptors started. To date, the family of endogenous cannabinoids or endocannabinoids comprises arachidonoylethanolamine, 2-araquidonylglycerol (2AG), virodhamine, noladin-ether and N-arachidonyldopamine. Cannabimimetic effects, including disruptions in functions such as learning and memory, feeding, pain perception and sleep have been reported after systemic or central administrations of these compounds.
 
ANA was the very first endocannabinoid described, and it has been the most studied so far. Pharmacological studies have shown that injections of this lipid induce several intracellular and behavioural changes including sleep generation.
 
The distribution of ANA in the CNS includes regions such as cortex, hippocampus, striatum, cerebellum, and brainstem. Histological studies suggest that ANA and 2-AG are well-positioned to act upon CB1 in the CNS. Biochemically, the release of ANA follows a different mechanism from classical, synaptic vesicle-stored neurotransmitters. It has been hypothesized that ANA is released "on demand". This suggests that there is a biological mechanism that involves the activity of membrane phospholipids that are the precursors of those compounds. In this model, the biosynthesis of ANA is followed by its immediate release. The mechanism of ANA degradation involves two different pathways. In the first, the compounds are transported to the interior of the cell via specific transporters. For ANA the putative transporter is the ANA membrane transporter (AMT). Once the lipid modulator is inside the cell, a hydrolysis mechanism is initiated by the fatty acid amide hydrolase (FAAH). Drugs targeting the AMT [110] or FAAH have been shown to modulate endogenous levels of ANA.
 
The physiological role of ANA on sleep is under investigation. The first approach to answer this question was carried out by Santucci and co-workers in 1996. Systemically injected a CB1 cannabinoid receptor antagonist, SR141716A, to rats increased W and reduced NREM sleep. As a conclusion they suggested that the wake-inducing properties of SR141716A might be due to the blocking of the CB1 cannabinoid receptor.
 
Later, our laboratory demonstrated that the endocannabinoid ANA also modulated sleep. I.c. v injections of ANA in rats induced an opposite effect to that observed by Santucci and colleagues. We found a significant decrease in W and an enhancement in NREM and REM sleep. We also observed that the effects caused by ANA on sleep were more significant once injected into the pedunculopontine tegmental nucleus, a brain region suggested as a key element in sleep promotion. If the changes observed in sleep after the administration of ANA were due to the activation of the CB1 cannabinoid receptor, we hypothesized that the administration of the CB1 cannabinoid receptor antagonist SR141716A before the injection of ANA might block the effects on sleep. This experimental manipulation showed that SR141716A efficiently blocked the effects caused by ANA on sleep. Furthermore, it is known that the CB1 cannabinoid receptor activates intracellular elements such as phospholipase C. Furthermore, we found that the injection of the phospholipase C inhibitor U73122 before ANA administration blocked the sleep-inducing effects caused by the endocannabinoid. Finally, we showed that systemic administration of ANA induced an increase in sleep, and perhaps more importantly, a considerable enhancement of the levels of the sleep-inducing molecule AD.
 
[....]
 
CONCLUSIONS
 
To date, the SIFs differ in several aspects, from their chemical nature and function per se of each to the effect that they have on the mechanisms of induction and/or maintenance of sleep. These SIFs also work in concert with the substances that regulate W. Within this perspective it is difficult to define to a single substance as one directly responsible for the humoral regulation of sleep. Instead the regulating effects of these substances are dependent not only on the interactions among them, but on their involvement with the cerebral regions which are directly responsible for the effects observed in the sleep pattern.
 
One hundred years after the discoveries of Ishimori and Piéron, the number of sleep regulating substances have grown substantially. However, current data indicate that sleep is not the result of the action of any one particular substance on a specific brain site, but rather that sleep is the result of a chain of biochemical events, which lead to the cellular processes necessary for the transitional states required by the sleep-wake cycle.