PRL and Sleep Regulation

In 1986 Michel Jouvet showed that the systemic administration of PRL enhances the total time of REMS in cats (Jouvet et al. 1986). Studies in hypoprolactinemic rats showed that REMS duration was decreased, also circadian rhythm of REMS disappeared, while that of nonrapid eye movements sleep (NREMS) remains unchanged (Valatx and Jouvet 1988).

Figure 5.2. Representation of PRL and its receptor (PRLR) signaling pathways. Long and short isoforms of the PRLR are represented. PRLR activates STAT1, and STAT3. The MAP kinase pathway involves the Shc, Grb2, Sos, Ras, Raf cascade and is presumably activated by both PRLR isoforms. Connections between the JAK/STAT and MAP kinase pathways have been suggested.

Figure 5.2. Representation of PRL and its receptor (PRLR) signaling pathways. Long and short isoforms of the PRLR are represented. PRLR activates STAT1, and STAT3. The MAP kinase pathway involves the Shc, Grb2, Sos, Ras, Raf cascade and is presumably activated by both PRLR isoforms. Connections between the JAK/STAT and MAP kinase pathways have been suggested.

These studies were the first to evidence that involvement of PRL in sleep regulation. Further studies have shown that the administration of exogenous PRL in different animal species including rabbits and rats induced REMS (Obal et al. 1989; Roky, Valatx, and Jouvet 1993; Zhang, Kimura, and Inoue 1999).

Additionally, administration of anti-PRL antibodies and antiserum in rats reduced REMS (Obal et al. 1992; Roky, Valatx, Paut-Pagano, and Jouvet 1994). Likewise, it has been observed that the effect of PRL on REMS is photoperiod-dependent, because the amount of REMS decreased or increased when PRL is administered during the dark or light period, respectively (Obal et al. 1989; Roky et al. 1993). Furthermore, it has been reported that PRL-releasing peptide (PrRP) also promotes REMS when it is administered to rats (Zhang, Inoue, and Kimura 2001; Zhang, Kimura, and Inoue 2000). These results suggest that PRL stimulated by i.c.v. injection of PrRP could be responsible to induce REMS.

PRL administered locally into the dorsolateral hypothalamus, an area that contain PRL-immunoreactive neurons (Paut-Pagano, Roky, Valatx, Kitahama, and Jouvet 1993), either increase REMS when is given diurnally or decreases REMS when is given nocturnally (Roky et al. 1994). Also, it has been demonstrated that in hypoprolactinemic (IPL) rats under light-dark conditions, the circadian rhythms of

NREMS and REMS display an alteration of their phase relation (Valatx et al. 1988). This result suggests that the promoting effect of REMS by PRL could be regulated by circadian factors and probably through the relationship between other hormones, for example melatonin, since melatonin is involved in the regulation of circadian PRL secretion (Bispink, Zimmermann, Weise, and Leidenberger 1990), and sleep (Tobler, Jaggi, and Borbely 1994). It is possible that PRL could have its effect on REMS through a circadian mechanism (Roky et al. 1995).

Furthermore, it has been observed that the firing of frequency of mesopontine tegmental neurons, an area involved in REMS generation (Baghdoyan et al. 1993) was increased after PRL injection (Takahashi, Koyama, Kayama, and Yamamoto 2000). These results suggest that PRL is capable of inducing REMS and modulate cholinergic activity, but the mechanisms remain unclear. Additionally, there are other studies that show that PRL injection into the central nucleus of the amygdale, an area where microinjections of cholinergic agonist produced REMS (Calvo, Simon-Arceo, and Fernandez-Mas 1996) and also containing high concentration of PRL-immunoreactive fibers and receptors (Siaud, Manzoni, Balmefrezol, Barbanel, Assenmacher, and Alonso 1989; Roky et al. 1996), decrease NREMS (Sanford, Nassar, Ross, Schulkin, and Morrison 1998).

In addition, it has been shown that high secretion of PRL occurs during NREMS and that PRL secretion is coupled to delta waves in humans, in contrast alpha and beta bands frequencies were inversely proportional to PRL secretion (Spiegel et al. 1995). Thus, it has been suggested that endogenous PRL accumulation during NREMS is responsible to induce the subsequent REMS periods. For example, it is well established that plasma PRL concentrations exhibit a sleep-dependent pattern, the high levels occurring during sleep and the low levels during waking (Spiegel et al. 1995; Sassin, Frantz, Weitzman, and Kapen 1972; Sassin, Frantz, Kapen, and Weitzman 1973; Van Cauter, L'Hermite, Copinschi, Refetoff, Desir, and Robyn 1981; Linkowski et al. 1998; Appelberg, Katila, and Rimon 2002). However, some reports show that occasionally poor sleep does not influence PRL secretion in normal humans (Spiegel, Follenius, Simon, Saini, Ehrhart, and Brandenberger 1994).

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