Introduction:Sleep is a natural resting state that exist commonly

Introduction:Sleep is a natural resting state that exist commonly in mammals, birds, fish and other animals. Even invertebrates, such as fruit flies, have this phenomenon. Features of sleep include reducing active body movements, diminishing responses to external stimuli, enhancing cell repair and production, reducing cell decomposition. Different from coma, sleep is easier to interrupt and return to a sober state. To wake up from sleep is a protection mechanism that is also necessary for health and survival. For people, sleep accounts for one third of their life time.Scientists divide sleep into two broad types: sleep without eye movement (this period of time is longer and is called non-rapid eye movement (NREM) sleep); and the period during when the eyes move quickly, this period of time is shorter and is called rapid eye movement (REM) sleep. There are identifiable differences between NREM and REM sleep, therefore physiologists classify them as distinct behavioral states. NREM sleep occurs first, then the person transitions to slow wave sleep. REM sleep is a smaller portion of total sleep time and the main occasion for dreams. It is associated with desynchronized and fast brain waves, eye movements, loss of muscle tone and suspension of homeostasis. The American Academy of Sleep Medicine divided NREM into three states: N1, N2, and N3. N3 is also called delta sleep or slow-wave sleep. The whole period of sleep normally proceeds in the order of N1 ? N2 ? N3 ? N2 ? REM. The sleep time for a normal adult is an average of 90 minutes, occurring 4–6 times in a good night’s sleep.People who lack adequate sleep may have problems such as drowsiness during the day, emotional instability, depression, stress, anxiety, decreased immunity, diminished judgment, loss of logical thinking and reduced work efficiency. Every individual has the same sleep time and pattern requirements. If the fundamental pattern, such as the lack of REM or NREM, or the arrangement of NREM and REM occurs, it results in sleep disorders.Human brain has a central structure that regulates sleep and wake. But the regulation of sleep and wake is not done by a single central structure, it involves a complex system. Slow-wave sleep is regulated by 5-HT (5-hydroxytryptamine, also called serotonin). Heterogeneous sleep is regulated by 5-HT and norepinephrine. Brain regions associated with slow-wave sleep include the diencephalon, the caudal reticular network of the brainstem. Brain regions associated with heteroplasmic sleep have pons covered the lateral Ach neurons.In mammals and many other animals that, such as fish, birds, mice and flies, regular sleep is a precondition for survival. In this paper, I will review sleep receptors in animals, such as adenosine receptor, dopamine receptor and other receptors.Dopamine is involved in animal sleep/wake regulation:Many scientists have already investigated the regulatory role of dopamine nervous system in sleep/wake regulation in animals from different perspectives.Dopamine is a critical regulator of sleep and arousal. Dopamine is a neurotransmitter that acts through its corresponding membrane receptor. Dopamine receptor is a family of G protein-coupled receptors. It consists of seven transmembrane regions (Wisor et al. 2001). According to the biochemical and pharmacological properties of dopamine receptors, they can be divided into two groups, D1 and D2 receptors. D1 receptors include D1 and D5 receptors (D1A and D1B receptors in rats), D2 receptors include D2, D3 and D4. D1 receptors and D2 receptors are widely distributed in the central nervous system. D2 receptor’s affinity of endogenous dopamine is far greater than D1 receptor (Gingrich and Caron 1993).Lima and others (2008) hypothesized that D2 receptor blockage could result in reduction in REM sleep period. Electrophysiological studies on rats showed that after 96 h of REM sleep deprivation through D2 receptor blockage, REM sleep period reduced significantly during the rebound period. Experimental data indicates that D2 receptors are involved in REM sleep regulation. Jiang and his team (2016) selectively restored the specific neuroanatomical regions of dopamine receptor in adult drosophila in order to assess dopamine receptor dependent sleep regulation. Nakazawa and his team (2015) used two different D4R agonists (Ro 10-5824 and A-412997) and studied the effects of these two structurally distinct agonists on the sleep-wake states in rats. They found that both D4R agonists increased waking time and reduced NREM sleep time in rats, but only one of the agonist influenced the onset and duration of REM sleep in rats. According to the results of this study I can conclude that D4R regulate sleep-wake states of rats. D2 antagonists can increase NREM sleep (Sebban et al. 1999). Studies have found that in rabbits or rats, selective D2 agonist when given intravenously or intraperitonealy can induce wakefulness. The selective dopamine receptor D1 antagonist has sedative effects on monkeys and rabbits (Ongini and Caporali 1987). These data show that dopamine receptors are important for sleep/wake regulation in animals.Adenosine, adenosine receptors and sleep regulation:Adenosine is an important homeostatic sleep factor. It is a product of brain energy metabolism. In Adenosine receptors, A1 and A2A receptors is closely related to sleep regulation. They act in basal forebrain and preoptic area (Stenberg 2007). A1 receptor inhibits basal forebrain cholinergic neuronal activity. A2A receptor inhibits TMN and other stimulating brain neurons, and activates VLPO neurotrophic neurons.Porkka-Heiskanen and his team (2000) used vivo microdialysis to investigate six brain regions of the cat (basal forebrain, cerebral cortex, thalamus, preoptic area of hypothalamus, dorsal raphe nucleus and pedunculopontine tegmental nucleus). They found that in these basal forebrain, wakefulness adenosine level is higher than sleep states. Results suggest that in the basal forebrain, the increase of extracellular adenosine can mediated the sleep-inducing effects of prolonged wakefulness. Metabolic activity in brain increases adenosine extracellular concentration. This increase can inhibit basal forebrain cholinergic neurons in vitro. Porkka-Heiskanen and others (1997) reported prime adenosine transporter inhibitors increase sleepiness and decrease arousal in cats. Kalinchuk and his colleagues (2003) used 2,4-dinitrophenol (DNP) to block the ATP synthesis in rats basal forebrain.This caused local adenosine levels increase. As a result, rats’ NREM sleep increased.A1 receptor and animal sleep regulation:Thaakkar and his team (2003) used microdialysis perfusion of adenosinergic pharmacological agents in cats. And they concluded that A1 receptor can reduce the activity of wakefulness-promoting neurons. Therefore, adenosine acts via A1 repeptor to promote sleep. In another experiment, Thaakkar and his colleagues (2008) used microdialysis probe to prime cat’s basal forebrain. They used selective adenosine A1 agonist N6-cyclohexyladenosine (CHA) and selective adenosine A1 antagonist 8-cyclopentyl-1-3-Dimethylxanthine (CPT). They found that basal forebrain arousal activity neurons discharge decreased after the perfusion of CHA, while the CPT had the opposite effect. This suggests when adenosine acts through A1 receptors, it inhibits basal forebrain cholinergic neurons to promote sleep. As animals age time in sleep decreases significantly, Murilli-Rodriguez and others (2004) gave adenosine A1 agonist CHA to the basal forebrain of young and old rats. They found that only after receiving high concentration of CHA can old rats experience increased sleep. This suggests that decrease of sleep in old rats are associated with the decrease of A1 receptor sensitivity. I can conclude that adenosine A1 agonists can increase sleep and decrease arousal in animals, while the adenosine receptor antagonists have the contrary effect. Deprivation of sleep can cause A1 receptor upregulation in brain. This suggests that adenosine can promote sleep through A1 receptor. The mechanism is related to the inhibition of basal forebrain cholinergic neuronal activity.A2A receptor and animal sleep regulation:A2A receptor promotes sleep via ventrolateral preoptic area (VLPO). Study found that selective bilateral damage of VLPO can reduce NREM and REM sleep and increase awakening (Lu et al. 2000). Gallopin and his team (2005) investigated that adenosine can promote sleep through A2A receptor. They administered adenosine A1 and A2A agonists and antagonists to rats. They observed that only type 2 neurons were excited by adenosine. This activation was postsynaptic through A2A receptors. Adenosine can affect either directly or indirectly through other neurotransmitters. Administer the adenosine A2A agonists in rat’s VLPO can increase sleep and decrease arousal, while the antagonist had the opposite result (Methippara et al. 2005). Data suggests that adenosine is an important endogenous, homeostatic sleep factor. Evidence indicates that basal forebrain adenosine A1 receptor activate cholinergic neurons can lead to a increase of A1 receptor transcription. This may act in mediating sleep deprivation. In addition, it has been found that prime A2A agonists can induce an increase in sleep through inhibiting orexin neurons in the hypothalamus (Basheer et al. 2004).The use of adenosine A2A agonist CGS21680 can increase animal sleep (Coleman et al. 2006). Scammell and others (2001) reported that A2A agonist cause an increase in NREM sleep period in rats. Studies by Hong and his colleagues (2005) found that A2A agonist can promote the sleep by increasing GABA expression, inhibiting the effects of histamine which promote awakening. And the extra expression of GABA in TMN might be a result of VLPO activity.Other sleep receptors:The NMDA receptor plays an important role in sleep in animals. Tomita and his team (2015) reported the molecular basis of sleep and the similarities of arousal regulation between mammals and drosophila. They founded that the knockdown of NMDA type glutamate receptor channel gene can decrease sleep. The application of the NMDA antagonist decreased sleep in the control group of drosophila. These results suggest that NMDA receptor regulates sleep in drosophila.To show that GABAA receptor can enhance mice sleep, de la Peña and his team (2016) did a research and evaluated the sedative and sleep-promoting effects of bovine ?S1-casein tryptic hydrolysate (CH). Enzymatic hydrolysis of casein produces some peptides that may promote sleep. The results of their study suggest that CH can promote sleep, and it mediated through the GABAA receptor.The peroxisome proliferator-activated receptor alpha (PPAR?) is a member of the nuclear receptor superfamily. Murillo-Rodríguez and others (2016) investigated that the activation of PPAR? can regulate sleep homeostasis in rats. They characterized whether PPAR? regulates sleep rebound or not after a total sleep deprivation (TSD). Results suggest that PPAR? might regulate sleep homeostasis after sleep deprivation in animals.Chen and his colleagues(2016) studied on the neuropeptide QRFP and its receptors in regulating sleep in zebrafish. They found that the overexpression of QRFP inhibit zebrafish’s activity during the day, and the mutation of QRFP or its receptors results in zebrafish’s sleep decreasing. I can conclude that that QRFP overexpression reduces activity, while lack QRFP reduce sleep. These results suggest that QRFP and its receptors participates in the hypothalamic regulation of sleep.Conclusion:Sleep is an essential behavioral state of rest. Many evidences indicate that sleep is important for learning and memory. Sleep is regulated by a variety of factors. Dopamine has been identified as a critical regulator of sleep. Adenosine is an endogenous sleep regulator. Adenosine A1 and A2A receptors play a key role in the regulation of sleep. Animals become a novel model for studying sleep. Studies on sleep receptors in animals can help us understand the mechanisms of study deeply..


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