Sleep is regulated by a combination of homeostatic and circadian mechanisms. The homeostatic process refers to sleep needs or pressure, and the circadian one, entrainment to the light/dark cycle. Besides the homeostatic factor, the circadian aspect is important and is related to the animal’s expression of daily preference for sleep/rest. Also, the duration of the sleep episodes appears to be greater in animals that are at the top of the food chain, since preys need to monitor the environment constantly to ensure their integrity, thus sleeping very short bouts (9, 10). The interaction between homeostatic (called “S process”) and circadian factors (called “C process”) in sleep regulation led some authors to propose a model in which the two processes would act together. Sleep begins wherever there is a conjunction of larger homeostatic pressure (need for sleep) and greater circadian predisposition (proximity to the phase of the cycle that sleep normally occurs), whereas it ends when this interaction decreases (11, 12).

Sleep homeostasis depends, among many factors, on the length and quality of the preceding waking period. Therefore, longer periods of waking lead to greater compensatory sleep, also known as rebound sleep. Interestingly, brief periods of sleep deprivation (SD) (3–6 h) result only in increased NREMS without affecting REMS (13). A total of 12–24 h of total sleep deprivation increases both NREMS and REMS (14–16), whereas total SD for 96 h induces a very pronounced increase in REMS (17). In 1960, few years after the discovery of REMS, William Dement (18) reported, for the first time in humans, that selective REMS deprivation induces a compensatory increase of this specific phase, e.g., REMS rebound. These effects have been replicated in rats, using the platform method that produces a complete suppression of REMS and some loss of NREMS (19, 20).

It is interesting to note that REMS deprivation induces the activation of the hypothalamic–pituitary–adrenal (HPA) axis, with increased production (21, 22) and release (23) of corticotropin-releasing hormone (CRH), and increased ACTH (24, 25) and corticosterone plasma levels (22, 26–28). This constellation of neuroendocrine changes indicates the stressful nature of this manipulation, thereby leading some authors to question whether sleep rebound would be an outcome of stress exposure. It soon became clear that stressful events can alter sleep pattern in a stimulus- and length-related fashion, inasmuch as immobilization stress increases REMS (29), social conflict (30) and exposure to cold (31) induce NREMS, whereas unpredictable footshock stress decreases REM sleep (32, 33). One to two hours of immobilization stress in the beginning of the dark phase, increase REMS, but longer periods of stress blunt the expression of sleep rebound (34), similar to what is seen with repeated immobilization (29). These opposite effects between acute and chronic exposure to the stress seem to be due to an adaptation phenomenon, which is also observed with footshock stress (32, 35). Either increased or reduced stress-induced REMS appear to be related to corticosterone secretion, in an inverted U shape fashion (36, 37).

Abnormal functioning of the HPA axis substantially changes the sleep pattern, as observed in Addison’s disease patients who exhibit adrenal insufficiency and display more NREMS and less REMS (34); this sleep abnormality can be corrected by corticoid replacement therapy (38). Conversely, patients with Cushing’s syndrome, who exhibit exaggerated cortisol secretion, display less NREMS and more awakenings during the night, which can also be corrected by interventions that decrease production of glucocorticoids (GCs) (39, 40). These findings strongly suggest that optimal GC concentrations are essential for normal sleep patterns in humans (41, 42). In rats, a similar phenomenon is also observed, with high levels of corticosterone being especially detrimental to NREMS (43).

The 41-aminoacid peptide CRH, its mRNA, and receptors are increased in stress situations, such as electric footshock (44), immobilization (45), restriction of food (46), and sleep deprivation (21, 23). CRH stimulates the release of other proopiomelonocortin (POMC)-derived peptides, including β-endorphin and alpha-melanocyte-stimulating hormone (α-MSH) (47–49). It differentially stimulates the activity of the prohormone convertases (PC1 and PC2, mainly), which cleave POMC in its bioactive peptides (50, 51).

CRH reduces REM and NREMS and increases awakenings when injected intravenously (52) or after i.c.v. administration (53), whereas CRH type 1 receptor (CRH-R1) antagonists promote sleep (54, 55). CRH effects on sleep homeostatic regulation are also evident, for its administration immediately after sleep deprivation increases REMS rebound (56). Conversely, α-helical-CRH₉₋₄₁, a CRH-R1 antagonist inhibits REMS rebound induced by immobilization (57). Recently, we have demonstrated that both i.c.v. CRH or α-helical-CRH₉₋₄₁ administration during REMS deprivation impairs sleep homeostasis, thereby decreasing the length of REMS episodes in the theta band energy (6.0–9.0 Hz), and decreases the time of REM and NREMS in the recovery period (58).

CLIP is a POMC derivative, well known for inducing long REMS episodes (59, 60). ACTH cleavage to CLIP and α-MSH is mediated by prohormone convertase 2 (PC2) and is stimulated by serotonin, via 5-HT_2C receptors (61–63). This process occurs in the melanocytes of the pituitary pars intermedia and in two other distinct locations in the brain: the arcuate nucleus—Arc (and peri-arcuate) in the basomedial hypothalamus and in a cell group of the nucleus of the solitary tract (NST) (64, 65). There are also CLIP-containing fibers, originating in the Arc and projecting to the lateral, paraventricular, basal and preoptic hypothalamic regions, dorsal and medial raphe nucleus (DRN and MRN, respectively), and septal area (66–70) (Figure 2).

Initial studies on the effects of stress-induced REMS rebound show that 1 h of immobilization stress increases REMS 3 h after the end of the stressor, a time point that corresponds to the increased content of phosphorylated CLIP in the Arc (71, 72). Conversely, micro-infusion of CLIP into the DRN increases REMS, similar to that observed after acute immobilization stress (73–75). It has been hypothesized that stress induces 5-HT release from the raphe nuclei, which projections to the Arc lead to CLIP processing from POMC. When the stress finishes, 5-HT is reuptaken, whereas CLIP synthesis and release from the Arc still go on. Interestingly, immunoreactive CLIP fibers are found in the DRN, which are postulated to trigger the dendritic release of serotonin (76) by a process of extracellular diffusion (67). The dendritic release of 5-HT within the DRN inhibits further 5-HT synthesis and release, via 5HT_1A autoreceptors (77, 78), a process commonly observed during REMS (79, 80). Confirmation of this mechanism was obtained by electrical stimulation of the DRN leading to release of 5-HT and indol compounds in the Arc, followed, 3 h later, by increased REMS (81) (Figure 2). It is worth mentioning that REMS induced by CLIP, more precisely the amino-terminal fragment ACTH_20–24 (Val-Lys-Tyr-Pro), is characterized by extremely long episodes, usually above 7 min. This effect on REMS is not obtained with ACTH (ACTH_1–39) or other active fragments, such as ACTH_18–24 (60).

Prolactin (PRL) is a polypeptide hormone consisting of 199 amino acid residues (in rats and mice, by 197 amino acid residues), which is synthesized and secreted by the anterior pituitary lactotrophs, under tonic dopaminergic inhibitory control (82, 83); the main function of pituitary PRL is to stimulate lactation in mammals (84). In humans, PRL is secreted mostly in the second half of the night (85), with a very clear circadian rhythm (86).

This hormone exhibits anxiolytic effects (87), inhibits the development of stress-induced gastric ulcers (88), and mitigates hormonal and neuronal responses to various stressors (89, 90). PRL also has an important neurotrophic effect and is involved with neurogenesis in various brain structures and cell cultures (91–96), preventing stress-induced decrease in neurogenesis in an animal model of chronic stress (96). PRL is closely associated with physiological stress response (97–99), and immunoreactive neurons are found in the lateral hypothalamus, Arc, and surrounding areas, thereby innervating other hypothalamic nuclei, amygdala, nucleus accumbens, olfactory cortex, septum, the reticular formation region, parabrachial region, locus coeruleus, periaqueductal gray, and DRN (100), and presenting practically the same distribution of POMC and its derivatives, as evidenced by double labeling studies (101). Interestingly, such structures are particularly involved in the regulation of sleep and stress response (Figure 2).

Numerous evidence indicates that PRL may be another mediator of stress-induced REMS rebound phenomenon. On the one hand, movement restriction (102) and ether vapor exposure (103) increase PRL plasma levels and time in REMS in rodents. On the other hand, PRL infusion in the dorsolateral hypothalamus or in the lateral ventricle increases REMS during the light phase (104, 105). Recently, we also showed that footshock stress applied concomitantly to REMS deprivation produces substantial REMS rebound, by virtue of very long REM episodes. Plasma PRL and hypothalamic serotonin (5-HT) were the likely mediators of the major increase in REMS episode length (37). Serotonin stimulates PRL release (106, 107) and PRL also increases serotonin synthesis (108–111) (Figure 2). In addition, both PRL micro-infusion into the DRN (112) and systemic administration of PRL increases REMS (113), whereas anti-PRL antibody suppresses REMS in rats (114), and this phase of sleep is naturally reduced in mice genetically deficient for PRL (115).

Prolactin-releasing peptide (PRL-RP) acts on a seven-transmembrane G protein-coupled receptor promoting PRL release in vitro and in vivo (116, 117). Central PRL-RP administration increases REMS in rats in parallel to PRL circulating levels (118, 119). Intriguingly, high PRL-RP concentrations also increase NREMS and have no effect on REMS (118, 119). In a somewhat contradictory way, PRL-RP has the ability to reduce the oscillatory activity in sections of the reticular thalamic tissue (120), which plays a fundamental role in the generation of NREMS (121).