Trakia Journal of Sciences, No 4, pp 355-376, 2020 Copyright © 2020 Trakia University Available online at: http://www.uni-sz.bg

ISSN 1313-3551 (online) doi:10.15547/tjs.2020.04.011

Review NEUROPHYSIOLOGICAL CONTROL OF WITH SPECIAL EMPHASIS ON MELATONIN

Iv. Penchev Georgiev*

Department of Pharmacology Animal Physiology and Physiological Chemistry, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria

ABSTRACT Sleep and wakefulness are two main types of human and animal behavior. On the average human beings spend about one-third of their lives asleep. The sleep-wake cycle is the most important circadian rhythms which alternates in a periodic manner lasting for about 24 hours. Sleep is determined as the natural periodic suspension of consciousness characterized by relative immobility and reduced responsiveness to external stimuli. The researchers have found and identified many special structures and systems controlling waking, rapid eye movement (REM) sleep and non- rapid eye (NREM) sleep and the transitions among these states. Currently, there is an enhanced interest of researchers toward sleep and its neurophysiological mechanisms of regulation because the number of people suffering from various sleep disturbance such as , delayed , duration and propensity of sleep, worldwide dramatically increases. In addition to the next day drowsiness, nervousness, tiredness and decreased workability, it has been suggested that sleep is important also for the maintaining of mood, memory and cognitive function of the brain and is essential for the normal functioning of the endocrine and immune systems. More recently, new studies show a sustained link between sleep disorders and different serious health problems, including obesity, insulin resistance, type 2 diabetes mellitus, cardio-vascular diseases and depression. Therefore, the purpose of this review is to summarize and analyze the available data about the neurological control of wakefulness, non-rapid-eye-movement (NREM) sleep and rapid- eye- movement (REM) sleep creating a substantial basis for better understanding different sleep disorders. Special attention is paid on the pharmacological aspects and use of some new classes of sleep promoting agents – melatonin, melatonin receptor agonists and orexin receptor antagonists.

Key words: sleep, NREM sleep, REM sleep, circadian regulation of sleep, homeostatic regulation of sleep, melatonin, melatonin receptor agonists, orexin receptor antagonists

INTRODUCTION natural periodic suspension of consciousness Sleep and wakefulness are two hallmark characterized by relative immobility and characteristics of human and animal behavior. reduced responsiveness to external stimuli (1). On average human beings spend about one- In contrast, the waking state is characterized by third of their lives asleep. The sleep-wake purposeful motor activity and increased ability cycle is the most important circadian rhythm to adequate responsiveness to various which alternates in a periodic manner lasting environmental stimuli. The disorders in sleep- for about 24 hours. Sleep is determined as the wake cycle can cause detrimental ______abnormalities in the organism as many other *Correspondence to: Prof. Dr. Ivan Penchev physiological processes are closely associated Georgiev, Dsc., Department of Pharmacology with this cycle. Animal Physiology and Physiological Chemistry, Section of Anima Physiology, Trakia University, Evolutionary, a form of non-rapid-eye- Faculty of Veterinary Medicine, 6000 Stara movement (NREM) sleep is found in most Zagora, Bulgaria, Phone: +359 42 887064791; animals and argued the fact that sleep is an +359 42 699 629, E mail: [email protected] / essential vital function of the organisms. [email protected] Trakia Journal of Sciences, Vol. 18, № 4, 2020 355

PENCHEV IV. Rapid-eye-movement (REM) sleep appears obesity, insulin resistance, type 2 diabetes later in the evolution – in a primitive form in mellitus, cardio-vascular diseases and reptiles and bird and in a true mature form in depression (16-19). mammals (2). It was long time thought that sleep is a passive and relatively constant Despite sleep disorders affect humans of all process of “switch off” of most of the bodily ages, they are more pronounced in adults. functions, while our body “switch back on” Abnormal sleep can lead to dysfunction of when we awake. In other words, till the last other organs and physiological systems and/or century sleep was mainly defined as a disturbance in brain functions and consequence of reduced sensory input and low neuropsychiatric disorders in particular. brain activity (3). Therefore, the simplest Therefore, better understanding the physiology explanation of sleep is the need to recover and of sleep is crucial in the management of repair the cellular metabolism and the neuronal different abnormalities like insomnia, attention networks and brain functions after the active deficit and inability to concentrate, depression, period of wakefulness. In fact, it was found and obesity related diseases. that sleep is a very active state of the brain Therefore, the purpose of this review is to during which many vital physiological summarize and analyze the available data processes occur (4, 5). In addition, the rapid about the neurological control of wakefulness, development of neuroscience, neurophysiology non-rapid-eye-movement (NREM) sleep and and , have clearly indicated rapid- eye-movement (REM) sleep creating a that during sleep the brain activity is even substantial basis for better understanding more varied and more complex than during the different sleep disorders. Special attention is waking state. It is important to note, however, paid on the pharmacological aspects and use of that there is a marked decrease in the some new classes of sleep promoting agents – perception due to the rise of the threshold for melatonin, melatonin receptor agonists and both external and internal stimuli (3). orexin receptor antagonists. Despite the purpose and the need of sleep is Types of sleep one of the biggest mysteries in biology, over Despite sleep is an unconscious state the last 10-15 years great progress has been characterized by decreased responsiveness, in made in understanding the neuronal fact, it is an active physiological process, as all mechanisms that control sleep-wake cycle (6- organs and regulatory systems continue to 8, 4, 2, 9, 5). The researchers have found and function. identified many special brain structures and The current classification of sleep types and systems controlling the occurrence and timing stages was done in 2004 by the American of wake and both phases of sleep – rapid eye Academy of (20, 21). movement (REM) sleep and – REM (NREM) Accordingly, sleep was categorized into 2 sleep and the transitions between them as well distinct types: (9, 3). 1.Non- Currently, there is an enhanced interest of (Non- REM; NREM). Based on the EEG researchers toward sleep and its pattern it is also called “slow wave sleep” neurophysiological mechanisms of regulation (SWS) and is further divided into 4 stages: because the number of people suffering from Stage 1; Stage 2; Stage 3 and Stage 4. various sleep problems such as insomnia, 2. Rapid eye movement (REM) sleep. delayed sleep onset, duration and the Changes in brain activity that take place during propensity of sleep, worldwide dramatically the different type and stages of sleep are increases (8; 10). In addition to the next day measured using an electro encephalogram drowsiness, nervousness, tiredness and (EEG). is a useful decreased workability, new data reveal that method for the recording of small voltage sleep is essential for the maintaining of mood, alterations on the surface of the scalp due to memory and cognitive capacity of the brain the summed activity of in a separate (11-15). It is also involved in the control of the region of brain cortex. As such on the EEG we normal functions of the endocrine system and can detect the increased or decreased activity immunity. More recently, new studies show a of these regions during waking state and/or sustained link between sleep disorders and during different sleep stages. different serious health problems, including 356 Trakia Journal of Sciences, Vol. 18, № 4, 2020

PENCHEV IV. It is important to note that or less important than the others. Therefore, electroencephalogram and brain waves when we refer to a certain brain wave, this markedly differs among types and stages of means that a particular brain wave is dominant sleep and are the basis for such divisions of among others. During waking state throughout sleep. the day and during the sleeping period throughout the night the EEG will display all 5 Brain waves types of brain waves at the same time (22, 2). Electrophysiological studies show that in However, one particular brain wave will humans five main different types of electrical dominate depending on the state of patterns are detected (20, 22, 21, 1). They can consciousness that we are in. be recorded and observed as brain waves on the electroencephalogram (EEG). Actually, The brain waves have at least 2 important electroencephalography is a tool to measure characteristics on EEG, which differ in each the activity of different regions of the brain wave: frequency and amplitude. The frequency cortex by detecting the bioelectrical events i.e. is measured in Hz while the amplitude is action potentials as small voltage changes on measured in µV. The frequency and amplitude the surface of the scalp. Each brain wave has a are in a close inverse interrelation i.e. high specific purpose and is depending on the frequency/low amplitude and high functional activity of the brain during the amplitude/low frequency. The brain waves in waking and sleeping periods (22, 1). If one of order of highest to lowest frequency are as the brain waves is over- or under expressed, it follows: gamma, beta, alpha, theta, and delta. is usually a result of some functional disorders For more details concerning the characteristic in some brain regions. It is important to point features of each brain wave please see (21, 23, out that there is no brain wave which is more 1) (Figure 1):

Figure 1. Normal brain vawes in adult humans (from: https://www.bing.com/images/)

1. Gamma waves - frequency range: 40 Hz depression, learning disabilities. to 100 Hz (fast wave – very low amplitude Meditation is found to increase gamma and very high frequency). Optimal gamma waves. Usually, in clinical practice gamma waves are indicators for binding senses waves can not to be registered with the and perception, cognition, information conventional equipment. processing, learning and REM sleep; too 2. Beta waves - frequency range: 12 Hz to much: -anxiety, stress; too little - 40 Hz (fast wave - low amplitude and high Trakia Journal of Sciences, Vol. 18, № 4, 2020 357

PENCHEV IV. frequency). Beta rhythm is characterized activity. In contrast, as much are the waves with high frequency low amplitude brain with high amplitude and low frequency as waves, which are mainly registered while lower is the brain activity (alpha, teta and we are awake. They are involved in logical especially delta waves during deep sleep – thinking, writing, and reading. In other stage 3 and 4 of NREM sleep) (see next words beta waves characterize our chapter). everyday activity. Optimal beta waves - conscious focus, memory, problem Non-rapid-eye-movement (NREM) sleep solving. Coffee, energy drinks and other NREM sleep is characterized by a stimulants markedly increase beta waves. reduction in physiological activity. As 3. Alpha waves - Frequency range: 8 Hz to sleep gets deeper, the brain waves as 12 Hz (moderate frequency). Alpha measured by EEG get slower and have rhythm is between beta (high) and theta greater amplitude, breathing and heart rate (low) rhythm. It is recorded when the eyes slow down, and blood pressure drops. are closed i.e. first stage of NREM sleep NREM sleep is known also as (see later). Too much : synchronized or quiet sleep. The NREM daydreaming, inability to concentrate and phase consists of four stages as described to focus on; too little - anxiety, big stress, in details (20, 22, 21, 24, 1): insomnia; optimal – complete relaxation.  Stage 1 NREM sleep (Fig. 2): Stage 1 is a The following substances have been found time of drowsiness or transition period to increase alpha rhythm: alcohol, between wakefulness and sleep. Eyes are marijuana and some antidepressants closed and slow rolling eye movements 4. Theta waves - Frequency range: 4 Hz to (0.25-0.5 Hz) are present, but they 8 Hz (slow wave - high amplitude and low disappear in stage 2 and deeper sleep stages frequency). Theta waves are involved in (stage 3 and 4). There is a decrease in the daydreaming and sleep. Too much theta heart and respiratory rates. In addition, a waves are indicators of deep relaxation and marked reduction in muscle tone and body hypnotic state. It is also recorded during temperature are recorded. The brain wave restorative sleep – second and third stage activity is dominated by alpha and theta of NREM sleep (see later). Hypnotic drugs rhythm. Alpha waves are recorded in the and other relaxants such as early phase of stage 1 which are with low benzodiazepines and neuroleptics may frequency (8–13Hz) and high amplitude increase theta waves. and become synchronized. Further in stage 5. Delta waves - frequency range: 0 Hz to 1 sleep, there is a lowing down of alpha 4 Hz (slow wave - very high amplitude and rhythm and an increase in theta waves very low frequency). They are hallmark of activity. Theta waves are characterized by the deepest and restorative sleep. lower frequency (4–7 Hz) and higher Depressant drugs and sleep increase delta amplitude than alpha waves. In this stage, it waves. is easy to awake and if so, people even say that they have not been asleep. During the waking state when we are with  Stage 2 NREM sleep (Figure 2): Stage 2 open eyes and our mind is focused, usually sleep the light sleep period during which on EEG dominate low amplitude high eye movement stop and the body goes into frequency waves (beta rhythm). This a state of almost complete relaxation. It is pattern of EEGis also known as the relatively largest period of a normal desynchronized because many neurons are sleep during the night. As an individual firing independently. Similar moves into stage 2 sleep, the pattern of the desynchronized pattern of EEG is recorded brain activity is dominated by theta waves during the REM sleep which is also called (4-8 Hz) which are interrupted by short paradoxical sleep. In contrast, during the bursts of in ceased frequency waves known NREM sleep the EEG pattern is as sleep spindles. Actually, the sleep synchronized dominated by larger spindle is a rapid burst of high frequency amplitude, lower frequency waves (alpha, brain waves (12-16 Hz) that are probably teta, delta rhythm) (22). As much are the important for learning and memory (25-28). waves with high frequency and low In addition, the appearance of K-complexes amplitude (beta waves in active wake state is often associated with stage 2 sleep. K- and REM sleep) as greater is the brain complexes are transient diphasic waves 358 Trakia Journal of Sciences, Vol. 18, № 4, 2020

PENCHEV IV. with high amplitude pattern (>100) of brain accepted however, that in stage 4 delta activity and last more than 200 ms. waves dominate and are more than 50%. Therefore, the distinctive elements of EEG Blood pressure and body temperature fall, characterizing stage 2 sleep is the breathing frequency slows. Sleep is deeper, appearance of sleep spindles and/or K- with no eye movement and decreased complexes. The presence of sleep spindles muscle activity. This is the period when the however, is enough to define stage 2 sleep body repairs muscles and tissues, stimulates because K-complexes are typically growth and development, boosts immune associated with a spindle. The heart rate function, and produces and stores the and body temperature continue to decrease. energy needed for for the next day activities. It is much more difficult to be  Stage 3 and 4 (Figure 2): Stages 3 and 4 awakened during these stages than during (referred to usually together as stage 3 or as earlier stages. Individuals who are slow wave deep sleep), are characterized by awakened report that they not feel refreshed the domination of high amplitude and low even more they feel tired and disoriented frequency (0-4 Hz) slow brain waves called (29, 30). Sleep walking or night terrors, delta waves. Because the difference experienced by some people also occur in between both stages is quite small usually these stages. they are presented together. It is generally

Figure 2. Normal brain waves during different sleep types and stages (from: https://www.bing.com/images/)

Rapid-eye-movement (REM) sleep movements in different directions i.e. rapid The rapid eye movement (REM) sleep was eyes movements (22, 21, 9). firstly discovered in 1953. Since that period The onset of the first REM sleep period occurs three basic states of behavior have been about 70 minutes after initially falling asleep. defined: wakefulness, rapid eye movement Normally, in adult people, four to six REM (REM) sleep, and non-rapid eye movement periods occur each night depending on the (NREM) sleep. (22, 21, 31, 1). The REM duration of the total sleep time. During this phase of sleep is established in mammals and final phase of each , the brain to a lesser extends in reptiles and birds while in becomes more active. It is thought that REM other animals its presence is less studied (2). sleep plays an essential role in learning and memory function, because the brain REM sleep is an active phase of sleep consolidates and processes information from characterized by intense brain activity. the day so that it can be stored in long-term Physiological mechanisms of REM (32, 22, 33). its importance for health are not well studied. The complex relationships among different Despite a person is deeply asleep during REM groups of neurons involved in the regulation of sleep EEG shows that some brain areas, the main characteristics of REM sleep are not including brain cortex, are in a very active completely elucidated. The name REM sleep state comparable to that during waking state comes from the presence of one of the most (21, 34, 1) (Figure 2). For this reason, REM important feature – rapid conjugate eye sleep is also known as paradoxical, desynchronized or active sleep since the EEG

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PENCHEV IV. has almost the same characteristics as during total sleeping period in NREM phase of sleep waking state i.e. dominated by high- and 20-25% - in REM sleep (36, 23). frequency, low-amplitude desynchronized brain waves (beta waves) despite the level of Normally, during the night 4 to 6 sleep cycles consciousness is very limited. In addition to occur. A full sleep cycle is composed of rapid eye movements, other hallmarks of REM NREM and REM sleep that alternate every 90 sleep include: almost complete lack of skeletal to 110 minutes. The time course of different muscle tone (atonia) leading to paralysis, with types and stages of sleep and their approximate the exception of extraocular muscles length during the night could be presented on a responsible for eyes movement and muscles special graphic called hypnogram as shown in involved in respiration - diaphragm and Figure 3. intercostal muscles); penile erection (35-38, 9). The length of the first sleep cycle is usually Breathing becomes more rapid, irregular and about 90 minutes with the following cycles heart rate and blood pressure increase. This is averaging around 100-120 minutes and being also the sleep stage in which most shorter in children. Each cycle starts and occur. (36, 37). follows the stages of non-REM sleep (stage 1 - The REM sleep is completely different from stage 2 - stage 3/4) and back through the stages all 4 phases of non-REM sleep. Therefore, this (stage 3/4 - stage 2 - stage 1) (Figure 3). Then, is an unique phase of sleep which is regulated instead of waking, starts a short period of REM in a different way and by different neurological sleep, and thereafter going back through the mechanisms анд браин струцтурес as stages (stage 1 - stage 2 and stage 3/4) in a new compared with NREM sleep. Despite there is a cycle (see the hypnogram). Except the first disagreement within the scientific community cycle, after each REM phase there are typically about the relative importanceof NREM and very short periods of waking (lasting several REM sleep for the cognition and memory, it is seconds) but usually they are not essential and generally accepted that similar to NREM sleep, do not break down the sleep. During the night, REM sleep and more specifically, the right the duration of stage 3/4 (deep sleep) decreases balance between both phases of sleep, is while the length of REM sleep periods involved in тхе processes of learning, memory, increases. As a result, the proportion of stage 3 mood and ability to concentrate (39-42). It is sleep is a greater early in the night, and the also important to note that both types of sleep proportion of REM sleep is greater later in the (NREM and REM) function independently and night, especially during the last two sleep cannot replace and compensate each other cycles close to the morning. In the morning (41). For example, if an individual is deprived time, all sleep consists almost of stages 1, 2 of of REM sleep and then allowed to sleep, he NREM sleep and REM sleep (Figure 3). will spend more time in REM sleep. (41). This Usually, adults spend almost half of total sleep phenomenon is known as the REM rebound, time in stage 2 of NREM sleep, about 20 and suggests that REM sleep, similar to NREM percent in REM sleep, and the remaining time sleep, is probably also under homeostatic in the other stages (Figure 3). The duration in regulation. any given stage however, is not constant over the course of a night and may vary among Sleep Architecture individuals. Based on the experimental data from sleep research it has been established that the In addition to these changes in time course of approximate needed duration of sleep is the night, the sleep architecture varies also depending on the age. The adults need on the with age. Normal adults spend 20-25 percent average a range of 7 to 9 hours of sleep; of sleep time in REM, while in newborn babies teenagers need about 9 hours, and infants - the length of REM sleep is about half their around 16 hours per day. For the normal sleep time. In young children deep NREM restorative sleep however, the right sleep (stages 3 and 4) dominate. With advance combination of NREM and REM sleep during age, however, the amount of stages 3 and 4 of the night is of primary importance. As such, in NREM sleep decreases accompanied with an normal sleep, NREM and REM sleep must increase of the lighter sleep periods i.e. stages alternate throughout the night and this pattern 1 and 2. It is important to outline that despite is called “sleep architecture” (43, 23). During a sleep become more fragile in older people, the night an individual spends about 75-80% of need for sleep does not decrease with age. 360 Trakia Journal of Sciences, Vol. 18, № 4, 2020

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Figure 3. Normal hypnogram during different sleep stages and sleep cycles during the night (from: https://www.bing.com/images/)

Neuronal networks regulating wakefulness transmission of impulses toward corresponding About 90 years ago von Economo suggested cortical areas - vision area (occipital lobe), that wakefulness is caused by an ascending auditory and equilibrium areas (temporal lobe), arousal system originating from the brainstem sensory area (parietal lobe - sensation from (8). Consequently, all contemporary theories skin and muscles). The neurons of the PPT and are based mainly on this hypothesis. Indeed, it LDT are very active during wakefulness and has been experimentally proven that such rapid eye movement sleep (REM sleep) and system exists, located in a special brain are almost inactive during slow wave sleep, structure - reticular formation (RF). It was known also as non-REM sleep when the called ascending reticular activating system activity of the brain cortex is markedly (ARAS) which plays a pivotal role in the diminished (7, 2, 23). regulation of sleep-wake cycle. The ARAS extends from the upper part of medulla The axons of the ventral branch of the ARAS oblongata passing through the pons and originate from a number of monoaminergic midbrain up to diencephalon ( and neurons in brain stem comprising hypothalamus). It is predominantly composed noradrenergic in locus coerulus (LC), of loosely clustered neurons and is crossed by dopaminergic in ventral tegmental area (VTA), a network of long bundles of ascending and serotoninergic dorsal and median raphe nuclei descending fibers (22, 8, 23). On the level of in brain stem, glutamatergic in parabrachial diencephalon ARAS separates into two nucleus (23, 2). They synapse onto branches – dorsal and ventral (7, 2). The dorsal glutamatergic, histaminergic and orexinergic pathway of the ARAS comprises glutamatergic neurons in the posterior/lateral hypothalamus neurons of reticular formation in midbrain, and converge and contact with caudal basal pons and medulla oblongata and originates forebrain , GABA-ergeticand from cholinergic neurons in the glutamatergic neurons. Axons of the pedunculopontine tegmental (PPT) and later cholinergic caudal basal forebrain neurons dorsal tegmental (LDT) nuclei in brainstem. project directly and activate cortex (2). The cholinergic axons of this branch of ARAS Recently it has been found that orexin innervates and activates neurons in the specific (hypocretin) containing efferent neurons in relay thalamic nuclei, responsible for the lateral hypothalamus activates brain cortex in

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PENCHEV IV. two ways: directly, and indirectly, by “flip-flop” or “on-off” model ensure rapid activating almost all above mentioned change between sleep and waking state (23, components of the ARAS (23, 2). The 44). This model may, therefore explain the monoaminergic and orexinergic neurons are very short sleep-wake transition periods most active during wakefulness and less active (taking about 1% to 2% of the wake-sleep during slow wave and REM sleep, while basal cycle). forebrain cholinergic neurons are equally active during wakefulness and REM sleep. Despite many debates on explaining the need Therefore, the waking state is caused and for sleep, it is generally accepted that the main maintained by orchestrated and coordinated purpose of sleep is the restoration of the activity of the monoaminergic and cholinergic equilibrium in body functions which is neurons included in the two branches of the disturbed to some extend during wakefulness. ARAS and orexigenic neurons in lateral Therefore, sleep is an important component of hypothalamus. the homeostasis but the underlying mechanisms regulating sleep however, remain Regulation of non-rapid-eye-movement uncertain. Therefore, the real debate is on the sleep (non-REM sleep; NREM sleep) elucidation of the key mechanisms regulating Because the main characteristics of NREM the onset and maintenance of sleep behavior sleep on EEG are high amplitude-low and the change between sleep and arousal frequency waves (4-8 Hz theta waves and 1-4 state. A strong dependence between the Hz delta waves) this types of sleep is also changes of light-dark and wake-sleep cycle is known as slow wave sleep (SWS). It is evident. In this sense two separate mechanisms important to note that there is no nerve centers of regulation of sleep have been proposed: or nuclei that directly induce sleep, in other homeostatic (called process S) and circadian words there is no sleeping center in the brain. (called process C) drives for sleep, respectively However, it has been found that in anterior (45, 22, 23). The timing of sleep is regulated hypothalamus there is a special population of by the circadian pacemaker (process C),located neurons included into ventrolateral preoptic in the hypothalamic nucleus (SCN) (46). The nucleus (VLPO) which are strongly active depth of sleep is however, regulated during non-REM sleep (22, 8, 23, 44). The homeostatic ally (process S), with increasing efferent fibers of VLPO release the main sleep propensity during waking and decreasing inhibitory in the brain – of sleep pressure during sleep (47).Prolonged gama-aminobutiric acid (GABA) and galanin. waking is compensated by deeper and The efferents of the VLPO connect with some prolonged sleep. The homeostatic sleep of the nuclei of the ARAS such as the process is registered on electroencephalogram noradrenergic LC in brainstem and also the (EEG) as slow-wave activity (SWA; EEG is histaminergic TMN in posterior hypothalamus dominated by delta waves with high amplitude which are well known to stimulate the activity and low frequency - below 5 Hz) during non- of brain cortex directly and indirectly, via rapid eye-movement (NREM) sleep as a result connections with cholinergic PPT and BF of higher homeostatic sleep pressure (48, 49) nuclei (LC) (23; 44). As such, VLPO markedly decreases the activity of the arousal system Homeostatic regulation of NREM sleep during non-REM sleep. During wakefulness The assumption that there is a homeostatic however, afferent noradrenergic nerve fibers element in sleep control comes from the from LC inhibits VLPO neurons via binding to observation that is followed alpha-2 noradrenergic receptors. Hence, it was by an extra compensatory period of sleep the suggested that there are reciprocal inhibitory duration of which is proportional to the period interactions between arousal and sleep of deprivation. It has been found that the two promoting neurons (6, 22, 9, 23, 44). As a types of sleep, NREM and REM sleep, have result, the activity of VLPO is down-regulated different homeostatic mechanisms of during waking state by some of the regulation as during prolonged periods of sleep monoaminergic components of the arousal deprivation NREM sleep is predominantly system it blocks during sleep which is an restored first. It is important also to point out important neurological mechanism regulating that according to Deboer, 2018 (49) the sleep-wake cycle in mammals. Such reciprocal amount of sleep lost (NREM or REM sleep) is bidirectional interactions among waking- and not totally regained during following hours sleep-inducing nuclei acting on the basis of the and/or days and thus the sleep homeostatic 362 Trakia Journal of Sciences, Vol. 18, № 4, 2020

PENCHEV IV. response does not completely restore the in cats or adenosine A2 receptor agonist amount of sleep lost during sleep deprivation. around VLPO nucleus in rats were able to Using data from EEG the same author suggests induce sleep in treated animals. The pivotal that mammals can compensate sleep loss with role of adenosine A1 receptor in mediating the two different ways: by increasing the amount inhibitory effect of adenosine on cholinergic of sleep and by increasing the depth of sleep BF neurons is also confirmed by micro dialysis detected by enhanced slow wave amplitude. perfusion of antisense deoxy oligonucleotides (ODNs) against A1 receptor in rats (53). These The homeostatic mechanism is thought to be authors found that micro dialysis perfusion of due to the accumulation of one or more A1 receptor antisense in the BF caused a substances during wakefulness as a result of marked reduction in non-REM sleep duration, the increased activity of the nuclei involved in which was accompanied by a significant maintaining wakefulness, leading to enhanced increase in wakefulness. On the other hands, it need for sleep in order to restore normal brain has been also hypothesized that adenosine functions. The underlying mechanisms of these could abolish the inhibitory effect of GABA- homeostatic determinants however are not ergic dorsomedial hypothalamic nucleus or completely understood. During prolonged noradrenergic input originating from LC in wakefulness an increased hydrolysis of ATP, brainstem on VLPO neurons by presynaptic coming from glucose oxidation probably can binding to A1 receptors, leading to the lead to an increased accumulation of ADP, activation VLPO nucleus (6). Therefore, based AMP and adenosine in extracellular fluid in on these observations it can be assumed that some brain areas responsible for the arousal adenosine could cause sleep at least in part by drive (22). Adenosine may accumulate reducing the activity of some of the wake extracellularly as a result of cellular provoking nuclei (BF) and/or by activating the metabolism during waking. It is well known sleep promoting neurons (VLPO) (6). that astrocytes are the main energy store in the brain. They contain significant amount of Because apart adenosine, astrocytes release glycogen droplets which are depleted during several transmitters it cannot be discount the waking suggesting that astrocytesmay cause an possibility that additional sleep promoting increase in extracellular adenosine, which in gliotransmitters may be identified in the near turn promotes sleep (50-52). This phenomenon future. In mammalsnitric oxide (NO) and was experimentally demonstrated, indicating prostaglandin D2 are also reported to be that astrocytic adenosine acting through A1 involved in mediating the homeostatic process receptors contributes to the modulation of (2). sleep pressure and the regulation of sleep homeostasis following sleep deprivation (53- Circadian regulation of sleep-wake cycle 55). As such it has been demonstrated that a Various physiological functions in the body non-neuronal cell type of the brain, the such as temperature, feeding, hormonal astrocytes, modulates sleep behavior. Indeed, secretions, autonomic activity, sleep-wake elevated extracellular concentration of cycle etc. are closely associated with changes adenosine in basal forebrain has been found to in daily light/dark time and show fluctuations be associated with increased need for sleep that occur over a 24h period (22, 18). These (53, 8). Adenosine is a purine nucleoside internal 24h fluctuations in some physiological composed of adenine which is attached to a functions and behavior are called circadian ribose molecule. Derivatives of adenosine are rhythms and are synchronized and correspond widely found in nature, including living to the external physical environment. Circadian organisms and play an important role in many means “about a day”. In both humans and biochemical processes, such asenergy transfer diurnal animals the light is thought as the most as adenosine triphosphate (ATP) and powerful agent, responsible for the adenosine diphosphate (ADP). synchronization of circadian rhythms. The (SCN) of the The eventual role of adenosine as one of the hypothalamus is the brain’s internal biological important homeostatic factors inducing sleep master clock acting as central pacemaker was further supported by the experimental generating circadian rhythms and thus, linking data, showing that the exogenous the sleep-wake cycle to daily light-dark periods microinjection of adenosine and an agonist of change (46). The SCN synchronizes the adenosine A1 receptor into the basal forebrain circadian physiological and behavioural Trakia Journal of Sciences, Vol. 18, № 4, 2020 363

PENCHEV IV. rhythms, including sleep and wakefulness, thесе neurons are maximally active as a result temperature, feeding, neuroendocrine and of effect of light almost no melatonin is autonomic activities, within a period 24 h to secreted in pineal gland; in contrast, during the match the environmental light–dark cycle and night time, when these neurons are not active thus, establishing an optimal internal cyclic there is marked increase in the synthesis and order in numerous important body functions secretion of melatonin (9). (56, 18;). Actually, there are two suprachyasmatic nuclei located in anterior Regulation of rapid eye movement sleep hypothalamus superior to chyasma optici (22) (REM sleep) The question now is how the light works to Electroencelographic characteristics of the promote waking and how the decrease in light REM sleep intensity promotes sleep? (22). Light excites The electroencelographic studies in mammals, the photoreceptors in retina and via including humans, indicate the presence of at retinohypothalamic pathway the generated least2 main types of brain waves, PGO and impulses using glutamate as theta waves/spikes, generated by different stimulates SCN (23). It has been established brain structures during REM sleep. This that there is no direct connection between SCN electrical activity is closely associated with the and VLPO nucleus. SCN affects sleep-wake features of REM. cycle by indirect connections to VLPO and LH The transition of NREM to REM sleep is nuclei. There are excitatory output initiated by electrical bursts called ponto- glutamatergic neurons in SCN which project to geniculo-occipital (PGO) spikes or waves 2 hypothalamic regions the sub-paraventricular originating from some special regions in brain zone (SPZ) and dorsomedial hypothalamus stem reticular formation, lateral geniculate (DMH) (22, 7, 9, 23). The SPZ has 2 distinct bodies in thalamus and occipital cortex (57; parts – dorsal and ventral. Dorsal SPZ is 22). More specifically, the regions in brain responsible for the circadian rhythm of body stem includes cholinergic neurons known as temperature. The ventral SPZ projects to the subcoeruleus – SubC, LDT and PPT areas and DMH which is involved in the regulation of glutamatergic neurons, termed sublaterodorsal sleep-wake cycle in two ways: by sending nucleus - SLD (23). PGO spikes lead to large excitatory glutamatergic projections to LH and fluctuations in respiration, thermoregulation, LC and by sending inhibitory GABA-ergic blood circulation, loose of skeletal muscle tone projections to VLPO nucleus (8, 7, 9). As such (atonia) and rapid eye movement which do not the light exerts its wake-promoting effect. In occur in any other sleeping phase or waking addition, there is an inhibitory pathway from state (22, 2, 23, 58). The PGO spikes are high SCN using GABA as neurotransmitter to the amplitude-low frequency waves. They are hypothalamic paraventricular nucleus (PVN). registered only in the period just before the During the dark period, when this inhibitory onset of REM sleep, known as transitional pathway is not active, PVN using vasopressin REM period lasting about 30-90 s while during as neurotransmitter stimulates pre-ganglioner the REM sleep itself bursts of low amplitude- sympathetic neurons in intermediolateral high frequency waves (2, 23). It is believed column of the lower cervical and upper that PGO spikes are source of dreaming thoracic part of the spinal cord and thus the periods and visual imagery during REM sleep outflow to the m. dilatator pupilae and the as they correlate with rapid eye movements pineal gland (8, 9). As a result there is a and are predominant in visual thalamocortical marked increase in the release of melatonin, circuits (22, 2). However, the exact which has strong sleep promoting propensity neurological network, responsible for the mediated by its stimulation of the inhibitory regulation of REM sleep is not yet well MT1 receptors on wake-promoting neuronsof understood. The thalamocortical component of the SCN. In this way during the dark period, the PGO waves is generated in lateral the wake-promoting region of SCN is inhibited genigulate nucleus (LGN) and subthalamic by the decreased light stimulation from nucleus and is induced by cholinergic input retinohypothalamic pathway and by melatonin, from LDT/PPT area (22, 2, 23). The pontine which allows the rapid switch between wake component of PGO waves is generated by and sleep. The GABA-ergic output neurons of noncholinergicbrain stem reticular formation the SCN regulate the circadian changes in the neurons, such as SubC and parabrachial secretion of melatonin – during the day when nucleus (PBN) (2, 59, 60, 58). 364 Trakia Journal of Sciences, Vol. 18, № 4, 2020

PENCHEV IV. Regulation of the transition between non- triggered by melanin concentrating hormone of REM and REM sleep the lateral hypothalamus neurons which Recently, two types of neurons regulating inactivate the REM sleep inhibiting neurons REM sleep and related somatic and behavior mentioned above – serotoninergic, changes were found – REM sleep promoting noradrenergic and GABA-ergic neurons in (REM-on) and REM sleep inhibiting (REM- brain stem and thus disinhibiting (activating) off) as described 22, 9, 23). The REM sleep cholinergic in PPT/LDT and glutamatergic promoting nuclei are located in lateral (SLD, PC and PBN) REM sleep promoting hypothalamus (LH), PPT/LTD and in pons – neurons (59, 60, 58). sublaterodorsal (SLDN), SubCN and PBN 59; 60). The neurotransmitters used by the neurons A non-reciprocal transition model has also in these area are melanin concentrating been evidenced in some studies The hormone (LH), (PPT/LDT) and involvement of GABA-ergic neurons, nitric glutamate (SLDN, SubCN and PBN) (22, 7,; oxide, lateral and preoptic hypothalamus in the 59, 23). REM sleep inhibiting neurons are complex neurological mechanisms regulating confined predominantly in brain stem: locus the non-REM – REM sleep interactions has coereleus – LC, dorsal raphe nucleus-DRN and been proposed as well (2). It is important to ventrolateralperiaqueductal grey matter note however, that most of the experimental (vlPAGM) using as neurotransmitters data in these studies complete and try to noradrenaline, and GABA, elucidate some aspects of the neuronal respectively (59, 60, 23, 58). The REM sleep interactions of the reciprocal model regulating promoting neurons are called “REM-on REM sleep. neurons” as they are maximally active during Regulation of brain cortexactivation during REM sleep and totally inactive during waking REM sleep and non-REM sleep while the REM sleep The general activation of cortex and cortical inhibiting neurons are called “REM-off center of vision (visual cortex) during REM neurons” as they are active during waking and sleep are regulated by different neuronal non-REM sleep and quiescent during REM mechanisms. Cortical activations due to the sleep (9; 58). direct excitatory stimulation by the REM sleep An important question is the master control promoting nuclei in brain stem, such as mechanisms of REM sleep. More specifically, cholinergic PPT/LTD and glutamatergic SLD, the neuronal interactions controlling non-REM PC and PBN as shown (2, 9, 58). These - REM sleep transition and alteration are of authors also reports that visual cortex is particular interest. Based on the results from in activated via an excitatory output from the vitro and in vivo studies in different thalamic lateral geniculate nucleus (LGN), experimental models the hypothesis for the which is stimulated itself by mesopontine existence of a “flip-flop” model for cholinergic PPT/LTD nuclei generating the switchingin and out of REM sleep similar to PGO spikes and dreaming during REM sleep. that of sleep-wake cycle regulation has been Regulation of skeletalmuscle atonia during proposed (7, 2, 60). Indeed, some authors have REM sleep reported such reciprocal inhibitory links The disruption of skeletal muscle tonus or between the REM sleep promoting and REM atonia in REM sleep is due to the disturbance sleep inhibiting nuclei (2). This model has of the physiological mechanisms of regulation been described in details in some recent papers of their activity. It is well known that the (7, 2, 59, 60, 9, 58). According to this theory activity of striated muscles is stimulated by during non-REM sleep the REM-off neurons facilitatory effects of noradrenergic LC on of the brain stem such as serotoninergic alpha motor neurons in ventral horns of the neurons in dorsal raphe nucleus, noradrenergic spinal cord while the inhibition signals are neurons in locus coeruleus and GABA-ergic generated in the glycinergic and/or GABA- neurons in ventral periaqueductal grey matter ergic neurons of the medullar gigantocellular inhibit the REM-on neurons in brain stem – nucleus (GC) (7). Two mechanisms of the cholinergic neurons in PPT/LDT and atonia of the skeletal muscles during REM glutamatergic neurons in sublaterodorsal sleep have been suggested - inhibition of the nucleus, precoerruleus nucleus and noradrenergic stimulation of motor neurons parabrachial nucleus. As a result, REM sleep is and glutamatergic activation of glycinergic and inhibited. The switch on REM sleep is Trakia Journal of Sciences, Vol. 18, № 4, 2020 365

PENCHEV IV. GABA-ergic neurons in the GC by SLD (59, 9, the sleep promoting effects of melatonin are 61, 58). Krenzer et al., 2011 (62) reported a mostly associated with the circadian descending nerve fibers from the SLD to the component of sleep regulation. spinal inhibitory interneurons proving the existence of a network between medulla It has been found that the pineal gland is oblongata glutamatergic neurons and spinal involved in the control of many functions of interneurons which is implemented in the REM the organism via secretion of melatonin (66). sleep associated skeletal muscles atonia. The primary physiological function of melatonin is the regulation and Regulation of rapid eye movements during synchronization of biological rhythms in REM sleep response to the light-dark circadian cycle, It is thought that the horizontal conjugate eye including (68- 73). In addition movements or rapid eye movements during to this, however, it has also strong antioxidant REM sleep are regulated by the action and appears to be involved in the tegmentopontine reticular nucleus (TPR) regulation of immune reactions and the which activates the nuclei of the III and VI protection of the organism from carcinogenesis cranial nerves - n. oculumotorius and n. and neurodegenerative disorders, including abducens, respectively (9). The impulses for Alazheimer’s and Parkinson diseases (74, 75, the activation of TPR nucleus are generated in 66). glutamatergic SLD nucleus in brain stem (9) Melatonin is the main hormone secreted by the Physiological role of melatonin in the pineal gland. The biosynthesis of melatonin regulation of sleep-wake cycle occurs through a 4 steps pathway starting with As we already described in details, sleep its main precursor, the amino acid L- propensity is caused by two processes - the tryptophan: hydroxylation, decarboxylation, amount of sleep deprivation (homeostatic acetylation and methylation. In the pineal component) and on the circadian clock phase gland, tryptophan is hydroxylated to 5- (circadian component). Both processes work in hydroxy-tryptophan in the mitochondria, then a coordinated way to cause sleep at night and decarboxylated in the pineal cytosol to wakefulness during the day. A close generate 5-hydroxitryptamine called also as interaction exists between circadian rhythms serotonin, another important neurotransmitter. such as body temperature, blood pressure, Serotonin can continue to either melatonin immune and hormonal rhythms and the sleep- synthesis, or participates in other metabolic wake cycle leading to optimization of the pathways. For melatonin synthesis, 5- internal temporal order (63, 66, 56). hydroxitryptamine is firstly acetylated on its free amine then O-methylated on the hydroxyl Melatonin is an important physiological factor group to generate the final product of involved in the regulation of sleep-wake cycle melatonin. in diurnal species, including humans. Melatonin is high water and lipid soluble, In invertebrates, melatonin secretion is which facilitates it to easy diffuse through stimulated by and this effect is membranes in most cell, including the blood- mediated by β-1 adrenergic receptor on brain barrier. Its plasma half-life is about 30-40 pinealocytes (9). This occurs in the evening as minutes and is inactivated mostly in the liver a result of the activation of sympathetic and then excreted in the urine as 6- neurons in the superior cervical ganglion by sulfatoxymelatonin. the decreased light. Norepinephrine elevates the intracellular cAMP concentration in It is important to note that melatonin refers to pinealocytes and activates the cAMP- a circadian clock synchronizer and indirect dependent protein kinase A (PKA) which is sleep regulator. As the main function of responsible for the control of the above- melatonin is to mediate dark signals and to mentioned steps in melatonin pathway provide them to the brain and SCN, it is a synthesis. On exposure to daylight, “hormone of darkness,” rather than a hormone noradrenergic stimulation stops and the of sleep. It has been demonstrated that synthesis of melatonin is almost totally melatonin does not increase the amount of inhibited (9). The synthesis of melatonin starts SWS which is the main marker of the again in the evening when daily light decreases homeostatic sleep pressure (63, 67). Therefore, at the point called the dim-light melatonin

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PENCHEV IV. onset. As such the dim light melatonin onset is melatonin promotes sleep by modulating the a consistent and reliable marker of the intrinsic internal circadian clock and by directly circadian phase (63). affecting sleep regulatory network in brain. More specifically, it has been demonstrated Melatonin plays a significant role in promoting that the sleep-promoting effect of melatonin is both the initiation and maintenance of sleep at mainly due to the inhibition of thewakefulness night (73). This assumption comes from the generating nucleiin hypothalamus and SCN in experimental data, showing that the marked particular (73, 63, 56). Moreover, the rise in sleep propensity at night normally molecular and functional brain imaging studies occurs about 2h after the beginning of indicate that exogenous melatonin affects brain endogenous melatonin secretion by the pineal network and activity in a manner similar to real gland. On the other hand, the duration of the sleep in fully awake subjects (76, 63). increased nocturnal melatonin concentration “informs” the brain and the SCN itself about Actually, the light can exert two main effects the night (dark) length (63, 56). on melatonin production: 1. Physiologically, light-dark cycle entrains the circadian In most diurnal mammals, including humans, pacemaker and synchronizes the rhythm of melatonin is secreted at night. The peak plasma secretion i.e. increase in the evening and concentrations could be detected between 2- 3h decrease during the day; 2. Acute light AM. There is a good correlation between the exposure at night however, causes a drastic rise of melatonin secretion and sleep inhibition in melatonin synthesis leading to a propensity beginning about 2 hours before the rapid fall in melatonin levels in cerebro-spinal regular . The rhythmic pattern of fluid and blood (77). A number of recent melatonin release is regulated by the central studies suggest that the chronic exposure to circadian rhythm generator known also as the artificial blue light at night (for ex. TV, cell internal biological clock - the suprachiasmatic phone, PC) results in a dramatic disruption of nucleus (SCN) of the anterior hypothalamus. the circadian system and internal master clock The physiological effects of melatonin are which has deleterious effect on health and may mediated by two membrane receptors: MT1 lead to increased risk for various abnormalities and MT2 which are members of the G-protein- and diseases, such as metabolic syndrome, linked receptor family (63). Despite the high cardiovascular diseases, diabetes type 2, cancer density of both types in SCN, they are also (17, 78, 79, 18, 80). It is important to point out expressed throughout other brain parts and that these disorders are closely associated with other organs, such as ovaries, pancreas, disturbed pineal melatonin secretion. cerebral and peripheral arteries, immune cells, indicating that melatonin probably affects Melatonin serves as a time cue and conveys function of different physiological systems signals of darkness toSCN and therefore its (66). The phase shifting effects of melatonin phase-shifting effects are opposite to effect of are mostly mediated through the MT2 receptor, light (56). As a result of its synchronizing while the MT1 receptor is more closely related effect on the central biological clock, i.e. SCN, to sleep onset (63). melatonin is able to entrain the circadian changes in the body, including sleep-wake As we mentioned earlier, two distinct cycle, body temperature, hormonal secretion mechanisms of regulation of sleep have been etc. (81, 82). Similarly, exogenous melatonin proposed: homeostatic, called process S, and administration modifies the light effects on circadian, called process C, respectively. In circadian phase shifts and can also entrain the this respect, it has been suggested that circadian rhythms which are mediated by the melatonin has two probable interacting effects SCN (83, 84). on the sleep-wake cycle (63, 56). First, it advance and shifts the circadian rhythm Advanced age, neuro-degenerative diseases, (process C) in a “chronobiotic” manner. diabetic neuropathy, brain tumors, Alzheimer’s Second, it promotes sleep onset and continuity disease and administration of some drugs i.e. in a“hypnotic”function by increasing the β-blockers and non steroid anti-inflammatory homeostatic drive to sleep (process S). drugs inhibit melatonin synthesis at night and can cause sleep disorders (85, 63). Day-time Using diurnal zebra fish model, Gandhi et al., intake of melatonin when its endogenous rate 2015 (73) have suggested that endogenous of production is almost absent induces events

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PENCHEV IV. such as fatigue and sleepiness seen in early (18). In addition, a physiological link between night time in response to the physiological circadian clocks and glucose metabolism has dim-light melatonin onset (86-88).The sleep- been described, while there is current evidence promoting effects of melatonin appears about 2 for a relationship between circadian disruption hours after exogenous administration which is and insulin resistance (18). Importantly, these in line with the physiological sequence at night authors propose several new strategies for the caused by endogenous melatonin - heat loss, implementation of chronobiological reduced arousal activity and delay in cortisol knowledge with the aim to improve human secretion (89-92). In addition, exogenous metabolic health. melatonin intake induces similar architecture of sleep as during natural sleep detected by The widespread sleep disorders imply the daily EEG (89). Of note, it has been reported that the intake of different hypnotic medication. The sleep promoting effect of melatonin is best hypnotic should match at least the comparable to that of some other hypnotics following criteria: 1) no effect on memory or such as GABA receptor allosteric agonists cognition; 2) maintenance of physiological zopiclone and zolpidem (88, 90). sleep; 3) no residual effects; 4) optimal half- life; 5) no potential for abuse, tolerance or Molecular and functional brain imaging studies dependence. reveal some new aspects concerning the effects of exogenous melatonin administration on the Hypnotic drugs could be classified in the activity in some brain areas and especially in following groups: the hippocampus (95, 93). It has been 1.Benzodiazepines suggested that melatonin may affect the 2.Z-drugs – cyclopyrrolones memory processing and storage as in actual (Zopiclone), imidazopyridines (Zolpidem), sleep. Some of these patterns resembled those pyrazolopyrimidine (Zaleplone) in subjects tested in the late evening, when 3.Sedative antidepressants - there is an increased endogenous melatonin trazodone, mirtazapine, doxepin secretion (93, 94, 63). Gorfine et al., 2006 (95) 4.Antihistaminergic drugs – have demonstrated that the mechanism of antagonists of type 1 histaminergic receptors melatonin induced fatigue on brain activity is 5.Antipsyhotics known also as markedly different from that after sleep neuroleptics - Chlorpromazine, Thioridazine, deprivation. These studies indicated that Haloperidol, Droperidol melatonin modulates brain activity patterns in 6.Melatonin, including prolonged awake subjects in a manner similar to natural melatonin release drugs and melatonin receptor sleep (95). agonists – Agomelatin, Tasimeltieon, Ramelteon Pharmacology of sleep 7.Orexin receptors antagonists - Epidemiological studies have shown that almorexant, filorexant, suvorexant approximately 10% of the total population in the world has different sleep problems and Because the sleep promoting effects of insomnia in particular, women being about 1.5 benzodiazepines, Z-drugs, antipsyhotics, times more affected (63). Insomnia is more antihistaminergic drugs and sedative frequent in adults (30%) and reaching 50% in antidepressants are relatively well known, we the over 65 year olds, while the prevalence in will pay more attention to some new hypnotic 18-35 year olds is 10-15 % (63; 108). The formulations such as prolonged melatonin insomnia is a serious health problem often release drugs, melatonin receptors agonists and leading to decreased concentration, depression, orexin receptor antagonists. increased anxiety and general worsening of the The most frequently prescribed medication well-being. In addition, cognitive functions, includes benzodiazipines (short- and memory and immune system can also be intermediate acting) and non-benzodiazepines disturbed (11-14). or Z-drugs – i.e. Zolpidem, Zopiclone, More recently, it has been suggested that Zaleplon (64, 65). The hypnotic effect of both chronic insomnia and/or disturbed sleep can types of drugs is due to their binding and lead to increased risk for obesity and related activation of A1 GABA-ergic receptors abnormality such as metabolic syndrome, (allosteric activators) in central nervous diabetes type 2 and cardio-vascular diseases system. Benzodiazepines are generally

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PENCHEV IV. effective and safe for short-term use only, novel pharmacological agents which are able lasting no longer than 2-3 weeks. Long-term to restore both non-REM and REM sleep. use of benzodiazipines, however is controversial and not recommended because of The main purpose of the therapy of sleep many severe side effects concerning decreased disorders must now change from improving effectiveness, tolerability, physical symptoms such as disturbance in initiating and dependence, increased risk of amnesia, maintaining sleep to re-establishing restorative dementia and serious withdrawal syndrome sleep, i.e. improving sleep quality and when the patients attempt to discontinue the efficiency by keeping normal sleep hypnotic drugs (65). architecture, sleep latency and total sleep time and thus improving daytime functioning (56, The relatively new classes of hypnotic 63, 65). medication - Z-drugs are non-benzidiazepines type A GABA receptor agonist which works In this respect, melatonin seems as a good also by increasing GABA effects in brain as alternative medication to hypnotic drugs due to benzodiazipines. In addition to some residual its well documented synchronizing effect on “hangover” effects such as sleepiness and the central biological clock, i.e. SCN, and its disturbance in psychomotor and cognitive ability to entrain the circadian changes in the functions, the usage of Z-drugs, similar to body, including sleep-wake cycle. It is well benzodiazepines, is associated with drug known that the endogenous synthesis of tolerance and substance dependence. That is melatonin decreases with age and is usually why they are recommended and prescribed low in elderly patients suffering from insomnia only for sever insomnia and for a short period (56). A number of studies suggest that this is of use (<2 weeks) at the lowest effective dose probably due to age related calcification of the (64, 65). pineal gland (96, 63). These age-related decline in melatonin levels are often associated It is important to note that benzodiazepines and with sleep disturbances and worsening of sleep Z-drugs treat insomnia especially to quality (97). In addition, disturbances of SCN quantitative aspects of sleep problems i.e. circadian activity seen amongst elderly people increased sleep latency and decreased total have also been reported (97, 63, 56). sleep time but none of them affects sleep quality and/or doesn’t improves the restorative According to "melatonin replacement value of sleep (63-65; 56). In addition, their hypothesis” the well established age-related hypnotic mechanism of action is mainly based decrease in pineal melatonin production is on activation of GABA effects as allosteric closely associated with sleep disturbance and activators of GABA-ergic receptors in the poor sleep quality and thus, exogenous central nervous system, which differs markedly melatonin administration may compensate for from the naturally occurring sleep. As we the reduction in the endogenous melatonin already described in details, however, the secretion and may improve sleep disorders physiological regulation of the sleep-wake (98). cycle is a result of complex interrelations The sleep promoting influence of exogenous among nuclei located in different brain areas, melatonin in humans however, is not yet fully using specific neurotransmitters and acting on elucidated. Some important questions the basis of the “flip-flop” or “on-off” model in concerning age, doses and especially the long- close association with circadian changes in the term effects of melatonin administration are dark-light period. Furthermore, GABA- still subject of debate. Improvement of sleep in mimetic medication used at this time elderly people by high doses of melatonin (> 5 (benzodiazepines and non-benzodiazepines Z- mg) was reported whereas the use of low doses drugs) are effective in restoring mainly slow of melatonin didn’t show significant effects on wave non-REM sleep (4, 64, 65). Almost all of sleep in younger insomnia patients (63, 99, these drugs however, suppress REM sleep and 100). Later the efficacy of lower doses (0.3-5 thus do not match completely the physiological mg) of melatonin in shortening of sleep latency mechanisms of normal sleep architectures in in insomnia elderly patients has been reported humans. Therefore, according to Datta, 2010 (99, 63). It is generally accepted that the (4) the big challenge now to sleep research and exogenous melatonin should be taken by sleep medicine is to identify and/or to generate patients at the age of 50-55 years and older

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PENCHEV IV. when the pineal gland doesn’t function of M1 and M2 melatonin receptors - properly and marked decrease in hormone ramelteon. production is observed (99). Importantly, it has been shown that melatonin Despite these positive effects of exogenous potentiates the effects of GABA-A receptor melatonin therapy there are some important allosteric activators (benzodiazepines and Z- limitations. Melatonin is quickly metabolized drugs), and thus can be used during the in liver which results in extremely short withdrawal period to facilitate the unfavorable plasma half-life - 40-50 min (63). After oral symptoms of discontinuation of these drugs intake, melatonin is rapidly absorbed the peak (102, 90, 63, 56). plasma levels occurring between 20 minutes and 2 hours depending on the dose. Therefore, About 10 years ago a PRM formulation - in order to ensure adequate concentration Circadin®, Neurim Pharmaceuticals, has been during the night-time period, very high doses authorised by the European Commission on 26 or repeated administration of melatonin is July 2007 for the short-term treatment of needed. Experimental data in rats and in cell primary insomnia and poor quality of sleep in culture suggest, however, that the use of high patients who are aged over 55 (63; 56). This is melatonin doses can causes resistance to the the first melatonin receptor agonist approved effects of melatonin and desensitizes and for clinical use in the European Union. inactivates its receptors in SCN (63). Despite Circadin® containing 2 mg PRM was designed no such studies in humans, new formulations to provide following intake in the evening of the hormone that would follow the about 2 hours before bedtime a melatonin physiological nocturnal increase in melatonin concentration and dynamics in the blood more concentrations are needed for melatonin closely related to the normal physiological replacement therapy (99, 63, 56). release pattern of the hormone (63). This author reports data from a pharmacokinetic A new approach has been recently proposed study (CMEA. Circadian EPA report, 2007) on for melatonin substitution therapy using a melatonin blood concentration profile in prolonged-release formulation (PRM) (99). patients following intake of the 2 mg dose at 9 The idea is to avoid the intake of high doses PM. The peak melatonin levels in the blood and/or repeated intake of melatonin during the were found 2.6 hours which persisted over 3.5 night. Such formulation would effectively hours after ingestion and then gradually mimic the physiological pattern of nocturnal decreased towards the morning which would secretion and profile of the hormone and may correspond to the normal brain melatonin be an appropriate alternative to benzodiazepine levels at night. and non-benzodiazepine treatment of insomnia in older patients (63, 56, 100). The More recently, melatonin receptor agonists experimental data from a number of large- were designed and officially recognized for scale, randomized, placebo-controlled clinical treatment of insomnia – Agomelatin, trials in insomnia patients aged 55 years and Tasimeltieon, Ramelteon.These drugs have older, indicate that PRM gave for short (3 demonstrated no affinity for the GABA weeks) or long term (6 months or 1 year and receptors. Miming the physiological effects of longer) improves sleep quality, facilitates sleep melatonin, they work through a different onset, improves morning alertness and quality neurochemical pathway. Due to lack of GABA of life and as a result reduced the use of activity they have many great advantages as hypnotic drugs (63; 56; 100). In addition, there they have not the potential for abuse or were none of the severe side effects and risks dependence and withdrawal symptoms or associated with the use of hypnotic drugs such rebound insomnia. Agomelatine which is also as memory and cognitive disturbance, residual an antagonist of serotonin 5HT-2C receptors is daytime or ‘hangover' effects, rebound available as Valdoxane® (Servier), for the insomnia and withdrawal symptoms (63, 56, treatment of major depression, associated with 100). Moreover, it has been demonstrated that sleep disorders in adults. Experimental data the sleep promoting effects of PRM are similar show that Agomelatine improves sleep and to those of the more frequently used hypnotics daytime fatigue in patients (103). Tasimelteon of the benzodiazepine and non-benzodiazepine (HETLIOZ™) is an agonist of the melatonin groups, i.e. Z-drugs and new generated agonist MT1 and MT2 receptors that has been approved in the USA for the treatment of non-

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PENCHEV IV. 24-hoursleep–wake disorder (63, 104). the physiological meaning of this link is that Ramelteon (Rozerem®, Takeda), was orexin must maintain wakefulness which authorized in USA for the treatment of enables animals to look for food and to avoid insomnia especially due to the difficulty in dangers. Additional actions of orexinergic falling asleep (63, 56). system is to stabilize and modulate the rapid transition between sleep and wakefulness Treatment with melatonin and melatonin known as “flip-flop” switch and the receptor agonists seems to be a very promising involvement in memory, cognition, attention, approach, with long-term benefits in sleep emotion, motivation, feeding behaviour and disorders because of its ability to increase energy homeostasis (105). Two types sleep propensity and to synchronize the excitatory orexinergic receptors (OX1R and internal clock and other internal body rhythms. OX2R) are identified which are located mainly However, an important question is about the in wake promoting nuclei and brain cortex effective dose as in different trials a dose rate (106, 107, 105, 108). Since that time dual between 0.5-10 mg has been reported, without orexin receptor antagonists (DORAs) have a clear dose-effect relationship. This is been developed such as Almorexant, probably related to the large inter-individual Filorexant, Suvorexant. Because of some variability in melatonin bioavailability and serious side effects especially related to endogenous melatonin secretion/level and abnormal increase in liver enzyme which may vary 20 fold among healthy adult concentration some of them (Almorexant) is people (63). In addition, the duration of the ultimately discontinued while others are still treatment period is also under debate. under clinical examinations. Suvorexant (MK- Unfortunately, in addition to these officially 4305, Merck),a dual orexin receptor authorized melatonin formulations, a big antagonist, isa new class of drugsin number of uncontrolled melatonin products are development and seems very promising agent however available as food supplements for for the treatment of insomnia. Suvorexant was which there are no studies and thus, no certain approved by the FDA in 2014 for the treatment data, about their quality, pharmacokinetics or of insomnia (107; 108). Experimental data safety. Therefore, further well controlled show that it promotes the natural transition clinical experiments are warranted to establish from wakefulness to sleep by inhibiting the the efficacy and safety of melatonin wakefulness-promoting orexin neurons of the preparations administration in the treatment of arousal system (106, 105, 108). In addition, it different sleep abnormalities. has been shown that Suvorexant improves both sleep onset and sleep maintenance and has a In addition to melatonin formulations, taking favorable tolerability and limited side effects into account some serious adverse effects of compared to other hypnotic drugs (107, 108). most of benzodiazepines and Z-drugs during Moreover, in contrast to the drugs acting via the last 10-15 years some new pharmacological activating the whole-brain GABA neurons agents for treatment of sleep disorders have (benzodiazepines and Z-drugs), the scope of been designed. In 1998 a novel neuropeptide orexin signaling in the brain is much more called hypocretin or orexin was discovered. It targeted resulting in less adverse reactions is produced by the lateral hypothalamus and (105). Initial trials suggest also that Suvorexant has various physiological effects mostly maintains normal sleep architecture as it related to the maintaining the wakefulness. promotes both NREM and REM sleep, unlike Orexinergic neurons constitute an important the GABA-mediating agents which are well part of the wake-promoting system via their known to promote NREM-sleep and to inhibit direct projections to the cortex and some REM-sleep (105). These authors report, that important wake promoting nuclei – despite these positive effects however, some histaminergic TMN in posterior hypothalamus, mild to moderate side effects () noradrenergic LC, dopaminergic VTA, have been reported for Suvorexant. The cholinergic lateral dorsal available data on the safety of Suvorexant is tegmentum/pedunculopontine tegmentum limited because of the small number of the (LDT/PPT) and serotoninergic dorsal raphe published studies using mostly healthy nucleus (DR) in brain stem. An important volunteers (108). Therefore, more, well modulator of the synthesis of orexin is ghrelin controlled clinical trials are needed to better which is produced by endocrinocytes of stomach mucosa during fasting. Evolutionary, Trakia Journal of Sciences, Vol. 18, № 4, 2020 371

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