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Neuropeptide-Y Y2-receptor agonist, PYY3–36 promotes non-rapid eye movement sleep in rat
Neuroscience Research 54 (2006) 165–170 www.elsevier.com/locate/neures
Neuropeptide-Y Y2-receptor agonist, PYY3–36 promotes non-rapid eye movement sleep in rat Moses A. Akanmu a,c, Otas E. Ukponmwan d, Yoshifumi Katayama b, Kazuki Honda a,* a
Department of Biosystem Regulation, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan b Department of Autonomic Physiology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan c Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria d Department of Physiological Sciences, Obafemi Awolowo University, Ile-Ife, Osun-state, Nigeria Received 24 August 2005; accepted 18 November 2005 Available online 27 December 2005
Abstract PYY3–36 is a major component of the gut–brain axis and peripheral administration has been reported to exert significant effects on feeding, brain function and is more selective for neuropeptide Y2 receptor. Therefore, we investigated the effects of nocturnal intraperitoneal administration of single doses of PYY3–36 (30 and 100 mg/kg i.p.) on food intake, water intake and the sleep–wake cycle in rats. Sleep recordings were carried out in male Sprague–Dawley rats implanted with cortical electroencephalogram (EEG) and neck electromyogram (EMG) electrodes. The EEG, EMG, food intake and water intake were assessed. The electrographic recordings obtained were scored visually as rapid eye movement (REM) sleep, nonREM (NREM) sleep and wakefulness. PYY3–36 administration 15 min prior to dark onset significantly ( p < 0.05) increased non-rapid eye movement (NREM) sleep and decreased wakefulness. Analysis of the dark-period at 4-h time intervals showed that nocturnal administration of PYY3–36 (30 and 100 mg/kg) significantly suppressed wakefulness and increased non-REM sleep during the first 4-h time interval. Time spent in wakefulness was significantly decreased after administration of PYY3–36 (30 and 100 mg/kg) when compared with administration of vehicle. In addition, PYY3–36 (30 and 100 mg/kg i.p.) induced an increase in the time spent in NREM sleep. The nocturnal intraperitoneal administration of the lower dose of PYY3–36 (30 mg/kg) also significantly decreased food intake [F (2,23) = 4.90, p < 0.05] but had no effect on water intake. These findings suggest that PYY3–36 may play an important role in the enhancement of NREM sleep and feeding behavior. # 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. Keywords: PYY; PYY3–36; NREM; REM; Wake; Food intake; Water intake; Behavior
1. Introduction Peptide tyrosine–tyrosine (PYY) is a gut hormone that, like neuropeptide Y (NPY), is a member of the pancreatic polypeptide (PP) family (Conlon, 2002). This hormone is produced in either a 36-amino acid form (PYY1–36) or a truncated state, consisting of amino acids 3–36 (PYY3–36), after processing by the enzyme, dipeptidylpeptidase-IV (DPP-IV). The two forms of PYY (PYY1–36 and PYY3–36) act via different subtypes (Y1, Y2, Y4 and Y5) of the NPY receptor (Larhammar,
* Corresponding author. Tel.: +81 3 5280 8098; fax: +81 3 5280 8098. E-mail address: [email protected] (K. Honda).
1996) to alter feeding behavior. For example, PYY1–36 is an agonist at the Y1/Y2 receptors and promotes feeding, while PYY3–36 that is more selective for the Y2 receptor acts to inhibit feeding (Batterham et al., 2002; Dumont et al., 1996; Keire et al., 2000). Previous studies have demonstrated that peripheral administration of PYY3–36 can cross the blood–brain barrier to decrease food intake and increase c-fos immunoreactivity in the arcuate nucleus of rodents (Bonaz et al., 1993). Other studies have shown that PYY3–36 can influence neuronal activity in the arcuate nucleus to alter appetite (Batterham et al., 2002; Nonaka et al., 2003; Halatchev and Cone, 2005). Lundberg et al. (1984) have characterized PYY-containing neurons in the hypothalamus and hindbrain regions of rat. It has also been shown that Y2R is widely distributed within the
0168-0102/$ – see front matter # 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. doi:10.1016/j.neures.2005.11.006
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central nervous system in both rodents and humans in areas such as the arcuate nucleus, preoptic nucleus, dorsomedial nucleus, posterior hypothalamic nuclei, medial nucleus of the amygdala, parabrachial area, substantia nigra, paraventricular thalamic nucleus, dentate gyrus and cerebral cortex (Broberger et al., 1997; Caberlotto et al., 1998; Dumont et al., 1996; Gustafson et al., 1997). Furthermore, peripheral PYY injection evoked expression of c-fos immunoreactivity in the area postrema, the nucleus solitary tract, the amygdala and the thalamus (Bonaz et al., 1993). These areas contain neurons that are involved in sleep–wake regulation, drinking and feeding behaviors (Amaral and Price, 1983; Amaral et al., 1992; Benca et al., 2000; Chemelli et al., 1999; de Lecea et al., 1998; Sakurai et al., 1998; Willie et al., 2001). Some reports have demonstrated that various appetite-modulating substances, including orexins, cholecystokinin (CCK), NPY and leptin, also have significant effects on sleep–wake stages. It is also known that PYY3–36 is released in response to food intake, and that food consumption and metabolic status can influence sleep (Danguir et al., 1979). Thus, the present study was designed to examine the effects of nocturnal intraperitoneal administration of the neuropeptide Y Y2-receptor agonist, PYY3–36, on food intake, water intake and the sleep–wake cycle in rats. 2. Materials and methods 2.1. Animals Eight male Sprague–Dawley rats (250–300 g) were obtained from Crea Japan Inc. (Tokyo, Japan) and were kept for 10 days in cages under controlled conditions. The room was controlled at 25 1 8C with a relative humidity of 60 6% and 12-h light:12-h dark (lights on 8:00 h and lights off 20:00 h). The Tokyo Medical and Dental University Animal Resource Center approved all experimental procedures involving animals. All animals had free access to water and food throughout the experiments.
2.2. Preparation and administration of PYY3–36 Peptide YY3–36 was purchased from Peptide Institute Inc., Osaka, Japan and was dissolved in normal saline. Peptides or saline vehicle were administered intraperitoneally in aliquots of 500 ml. Freely behaving rats were administered single doses of PYY3–36 (30 or 100 mg/kg) in 500 ml of solution or were administered vehicle alone intraperitoneally 15 min prior to dark onset. These doses and time of administration were selected because previous study demonstrated that these doses produced robust behavioral effects (Batterham et al., 2002). All injections and recordings were separated by at least 2 days, and each rat received all three treatments [vehicle or PYY3–36 (30 or 100 mg/kg)]. EEG, EMG, food intake and water intake were assessed during the experiment.
EEG electrodes for recording EEG. Two stainless-steel electrodes were implanted in the neck musculature for recording EMG. Electrodes were then cemented in place with dental acrylic resin, and the cable from the electrodes was attached to a socket. After surgery, each animal received a total of 20,000 U of penicillin G potassium subcutaneously.
2.3.2. Sleep recording and analysis Rats were allowed to recover for at least 10 days after surgical operation before being transferred to an individual experimental cage for continuous monitoring of EEG and EMG. The experimental cages were placed in a soundproof, electromagnetically shielded room with the same environmental conditions as described above. For measurements, lead wires of the electrodes were connected to an EEG/EMG amplifier (Nihon-Kohden, MEG-6116, Tokyo) through a 5-strand cable with a slip-ring that allowed the rats to move freely. The amplifier was connected to a personal computer with an analog–digital converter and software (Kissei Comtec, SleepSign, Nagano) for acquiring and processing data. Data was sampled at 128 Hz and was subjected to online spectral analysis by Fast Fourier transformation over 8-s epochs. Subsequently, data were stored on a magnetic optical (MO) disk that was later visually analyzed offline after auto-analysis of the sleep–wake stages. EEG and EMG were measured for 2 consecutive days (a baseline day and an experimental day), starting at lights off. Sleep-waking state was classified as wakefulness (W), rapid eye movement (REM) sleep and non-REM (NREM) sleep from the EEG and EMG waveforms using software (Kissei Comtec, SleepSign, Nagano) and the results were verified visually according to standard criteria (Akanmu et al., 2004; Akanmu and Honda, 2005; Honda et al., 1994). We discriminated among wakefulness (high EMG amplitude, low EEG amplitude), non-REM sleep [(low EMG amplitude, high EEG amplitude with high power density in the delta band (0.5–4.0 Hz)], and rapid-eye-movement (REM) sleep [(silent low EMG amplitude, low EEG amplitude with high values in the theta band (4.0–8.0 Hz)] (Akanmu et al., 2004; Akanmu and Honda, 2005; Honda et al., 1994). The analyzed sleep variables included the amount of NREM sleep, REM sleep and total sleep.
2.4. Assessment of drinking and feeding behaviors At the beginning of the experiment, graduated water bottles and preweighed rat chow pellets (CE-2, Clea, Japan, Tokyo) were placed in individual testing cages. Water intake was measured at the end of the experimental 24-h time period. Rats were given free access to preweighed chow, and food intake was determined by measuring the difference between the preweighed chow and the remaining chow at the end of the experimental 24-h time period.
2.5. Statistical analysis Data were analyzed using repeated measures analyses of variance (ANOVA) followed by post hoc analysis of significance by the Student–Newman–Keuls test. Probability ( p)-values less than 0.05 were considered to represent statistical significance.
3. Results 3.1. Effect of PYY3–36 on sleep–wake cycle
2.3. Electroencephalography/electromyography Simultaneous electroencephalogram (EEG) and electromyogram (EMG) recordings were performed as described previously and were used to assess sleep–wake states (Akanmu et al., 2004; Akanmu and Honda, 2005; Honda et al., 1994). 2.3.1. Electrodes implantation Male Sprague–Dawley rats (n = 8) were anesthetized with pentobarbital sodium (50 mg/kg, i.p.), fixed on a stereotaxic apparatus and implanted with three cortical gold-plated screw electrodes through the skull to serve as dural
The nocturnal intraperitoneal injection of PYY3–36 to freely behaving rats significantly affected the sleep–wake stages (Table 1 and Fig. 1). The results obtained in relation to the effects of administration of PYY3–36 on episode frequency, episode duration and total time are as shown in Table 1. PYY3–36 at the dose of 30 mg/kg significantly decreased wakefulness and increased NREM sleep and total sleep but had no effect on REM sleep (Fig. 1). However, in time interval analysis, these effects of this dose of PYY3–36 on sleep–wake
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stages were only significant during the first 4-h time interval and not in the other time intervals (Fig. 1). During the first 4-h time interval, both doses of PYY3–36 produced a decrease in the time spent in wakefulness (F (2,23) = 7.54, p = 0.006); increased NREM sleep (F (2,23) = 10.29; p = 0.002) and increased total sleep (F (2,23) = 11.53, p = 0.001) but had no effect on REM sleep (F (2,23) = 0.48, p = 0.627) (Fig. 1). Furthermore, the results obtained showed that an intraperitoneal injection of both doses of PYY3–36 to freely behaving rats 15 min prior to dark-onset had no effect on sleep–wake states during the subsequent light-period (NREM sleep: saline, 473.7 8.4 min; PYY3–36 30 mg/kg, 489.9 10.0 min; PYY3– 36 100 mg/kg, 476.24 12.4 min [F (2,23) = 2.47, p = 0.121];
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REM sleep: saline: 74.1 6.6 min; PYY3–36 30 mg/kg, 81.2 5.7 min; PYY3–36 100 mg/kg, 76.0 5.9 min [F (2,23) = 2.63, p = 0.107]. 3.2. Effect of PYY3–36 on food and water intake Food intake was significantly reduced after intraperitoneal injection of low dose PYY3–36 but not after high dose PYY3–36 when compared to injection of saline (F (2,23) = 4.9, p = 0.024) (Fig. 2), but injection of PYY3–36 had no effect on drinking behavior (saline, 54.8 2.88 ml; PYY3–36 30 mg/ kg, 62.5 5.4 ml; PYY3–36 100 mg/kg, 64.3 6.6 ml [F (2,23) = 1.92, p = 0.184]).
Table 1 Effects of intraperitoneal administration of PYY3–36 on episode frequency, episode duration and total time of sleep–wake stages in rat (n = 8) Doses in 500 ml
Episode frequency
Episode duration (s)
Total time (min)
Saline (Baseline) 30 mg/kg 100 mg/kg
41.1 4.7 47.6 4.1 49.9 3.1
233.9 45.4 156.5 22.7* 142.8 12.0*
137.3 6.3 114.6 8.5* 115.3 6.5*
REM sleep
Baseline 30 mg/kg 100 mg/kg
11.5 2.0 12.9 2.0 15.0 2.1 *
94.1 7.3 72.6 5.9 * 78.8 5.3
16.6 2.2 16.0 2.8 18.8 2.1
NREM sleep
Baseline 30 mg/kg 100 mg/kg
42.4 5.4 49.3 4.1 52.8 2.8 *
131.0 12.0 139.1 7.8 * 120.5 6.5
85.4 5.7 112.7 9.0* 104.8 5.3*
Total sleep
Baseline 30 mg/kg 100 mg/kg
53.8 6.4 62.1 4.8 67.8 4.1 *
225.0 16.0 211.8 9.7 * 199.3 9.0
102.0 6.2 128.7 8.5* 123.8 6.4*
Baseline 30 mg/kg 100 mg/kg
48.9 4.3 50.9 4.9 43.0 2.8
179.8 20.2 155.5 16.5 191.3 13.9
137.0 6.3 122.8 4.7 133.3 5.2
REM sleep
Baseline 30 mg/kg 100 mg/kg
12.4 1.4 13.3 1.3 12.8 1.1
77.3 7.4 81.5 8.0 79.8 7.1
15.0 0.9 17.6 2.3 16.2 1.0
NREM sleep
Baseline 30 mg/kg 100 mg/kg
49.6 4.7 52.1 4.6 44.6 3.0
108.9 7.2 120.4 11.9 124.5 9.9
87.3 5.9 99.0 3.7 89.8 4.7
Total sleep
Baseline 30 mg/kg 100 mg/kg
62.0 5.4 65.4 4.9 57.4 3.4
186.1 10.7 201.9 16.0 204.3 12.7
102.3 6.3 116.6 4.7 106.1 5.2
Baseline 30 mg/kg 100 mg/kg
38.5 2.9 36.9 3.6 35.4 2.0
239.0 27.6 282.6 51.3 249.1 21.4
145.0 8.6 153.6 6.2 143.0 7.2
REM sleep
Baseline 30 mg/kg 100 mg/kg
6.9 1.2 6.0 1.1 7.0 1.0
81.9 10.7 67.8 11.3 73.8 8.1
9.3 2.0 6.3 1.3 8.3 1.3
NREM sleep
Baseline 30 mg/kg 100 mg/kg
39.9 2.6 37.0 3.7 35.8 2.1
129.9 8.5 137.0 13.0 150.0 11.7
85.2 6.9 79.5 5.3 88.4 6.9
Total sleep
Baseline 30 mg/kg 100 mg/kg
46.8 2.4 43.0 4.3 42.8 2.3
211.8 14.9 204.8 16.9 223.8 11.0
94.5 8.5 85.8 6.2 96.7 7.2
Sleep–wake stages First 4-h time interval Wakefulness
Second 4-h time interval Wakefulness
Third 4-h time interval Wakefulness
Values are mean S.E.M. * p < 0.05 compared to baseline (saline).
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Fig. 1. Effects of intraperitoneal administration of PYY3–36 (30 or 100 mg/kg) or saline on waking state, rapid eye movement (REM) sleep, non-REM (NREM) sleep and total sleep in rats (n = 8) during the dark-period. Each bar represents the mean S.E.M. Compared with saline (baseline) values; * p < 0.05; #p < 0.01.
Fig. 2. Effects of intraperitoneal administration of PYY3–36 (30 or 100 mg/kg) on food intake in rats (n = 8). Each bar represents the mean S.E.M. Compared with saline (baseline) values; *p < 0.05.
4. Discussion Previous studies have demonstrated that peripherally administered PYY3–36 crosses the blood–brain barrier (Nonaka et al., 2003) and stimulates presynaptic Y2 receptors in the
arcuate nucleus (Batterham et al., 2002). As in prior investigation (Batterham et al., 2002), intraperitoneal administration of PYY3–36 significantly decreased food intake, in the present study, however, the maximal effect was observed with the administration of 30 mg/kg body weight. Furthermore, the present study also demonstrated that intraperitoneal administration of the Y2 receptor agonist, PYY3–36 modulated the sleep–wake states by decreasing wakefulness and concomitantly increased NREM sleep and total sleep particularly during the first 4-h of administration. Specifically, both doses administered significantly increased the total time spent in NREM sleep and total sleep while there was differential effects on the episode frequency and episode duration (Table 1). PYY3–36 at the dose of 30 mg/kg has more robust effect on episode duration while the effect on episode frequency was more profound with the administration at the dose level of 100 mg/kg body weight. Thus, the present data suggest that PYY3–36 may have significant effects on feeding and sleep– wake state. The exact mechanism by which PYY3–36 modulates sleep-wakes is not known. It is however known that PYY3–36 receptors are localized in the amygdala, an area that is involved in the regulation of the sleep–wake state (Benca et al., 2000). This limbic brain nucleus is interconnected with a number of brain regions that are also involved in sleep regulation, such areas include the basal forebrain, hypothalamus and brainstem (Amaral et al., 1992). Furthermore, reciprocal connections exist between the amygdala and brainstem areas, including the parabrachial region, dorsal raphe nuclei, pedunculopontine tegmentum (PPT) and laterodorsal tegmental nuclei that are also involved in the regulation of waking and REM sleep. The sleep–wake modulation by PYY3–36 may be due to its influence on these neural circuits. Alternatively, the sleep enhancing effect may be related to action on HPA axis and other neurotransmitters. For example, neuropeptide Y promotes sleep and inhibits the hypothalamopituitary-adrenocortical (HPA) axis in humans. Therefore, since PYY also acts via NPY Y2 receptors, it may promote sleep through inhibition of the HPA axis. PYY3–36 is released from the gastrointestinal tract postprandially in amounts that are proportionate to the calorie content of a meal (Adrian et al., 1985; Grandt et al., 1994). After its release, the hormone acts on the central nervous system by binding to Y2R, a putative inhibitory presynaptic receptor highly expressed on NPY neurons (Broberger et al., 1997) in the arcuate nucleus (Kalra et al., 1999) and thereby inhibits feeding. Other gastrointestinal hormones may also play a key role in the mechanisms of postprandial sleep. For example insulin has been reported to enhance NREM sleep (Danguir and Nicolaidis, 1984) while CCK suppressed motor activity (Crawley and Corwin, 1994) and selectively stimulated NREM sleep in rats and rabbits (Kapa´s et al., 1988, 1991; Hirosue et al., 1993). Reports also showed that administration of bombesin (de Saint Hilaire-Kafi et al., 1989; Gibbs et al., 1981), NPY or leptin (Antonijevic et al., 2000; Sinton et al., 1999) decreased feeding and increased sleep. It is not clear whether PYY acts directly or whether it acts via modulation of other neurotransmitters. Administration of drugs
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that enhance serotonergic transmission decreased food intake (Leibowitz et al., 1990) and 5-HT1 receptor has been reported to play an inhibitory role in feeding (Dourish, 1992; Kitchener and Dourish, 1994). Since 5-HT2C, 5-HT1B and 5-HT2A agonist receptors suppress food intake in food-deprived and nondeprived rats, these receptor subtypes may be relevant in feeding behavior and sleep–wake modulating effects of PYY3– 36. Moreover, the relationship between serotonin and PYY had earlier been reported (Hagan and Moss, 1993). The NREM sleep promoting effects of PYY3–36 are probably due to inhibition of wake promoting or activation of sleep promoting mechanisms. Therefore, the role of this neurotransmitter and other neurotransmitters in the behavioral effects of PYY3–36 should be investigated in future studies. In conclusion, the present study demonstrated that intraperitoneal injection of low dose PYY3–36 resulted in decreased food intake, increased NREM sleep and decreased wakefulness, particularly during the first 4-h time period, but had no effect on drinking behavior. These findings suggest that PYY3–36 may play an important role in the modulation of the sleep–wake state and of behavioral responses. Further study to determine the mechanisms by which PYY3–36 produces these effects would be of benefit. Acknowledgement This study was supported by a Grant-in-Aid for Scientific Research (C) (No. 16614003) to K.H. References Adrian, T.E., Ferri, N., Bacarese-Hamilton, A.J., 1985. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89, 1070–1077. Akanmu, M.A., Honda, K., 2005. Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats. Brain Res. 1048, 138–145. Akanmu, M.A., Songkram, C., Kagechika, H., Honda, K., 2004. A novel melatonin derivative modulates sleep–wake cycle in rats. Neurosci. Lett. 364, 199–202. Amaral, D.G., Price, J.L., 1983. An air pressure system for injection of tracer substances into the brain. J. Neurosci. Methods 9, 35–43. Amaral, D.G., Price, J.L., Pitkanen, A., Carmichael, S.T., 1992. Anatomical organization of the primate amygdaloid complex. In: Aggleton, J. (Ed.), The Amygdala. Wiley-Liss, New York, pp. 1–67. Antonijevic, I.A., Murck, H., Bohlhalter, S., Frieboes, R.M., Holsboeer, F., Steiger, A., 2000. Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men. Neuropharmacology 39, 1474–1481. Batterham, R.L., Cowley, M.A., Small, C.J., Herzog, H., Cohen, M.A., Dakin, C.L., Wren, A.M., et al., 2002. Gut hormone PYY3-36 physiologically inhibits food intake. Nature 418, 650–654. Benca, R.M., Obermeyer, W.H., Shelton, S.E., Droster, J., Kalin, N.H., 2000. Effects of amygdala lesions on sleep in rhesus monkeys. Brain Res. 879, 130–138. Bonaz, B., Taylor, I., Tache, Y., 1993. Peripheral peptide YY induces c-fos-like immunoreactivity in the rat brain. Neurosci. Lett. 163, 77–80. Broberger, C., Landry, M., Wong, H., Walsh, J.N., Hokfelt, T., 1997. Subtypes of Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in prio-opiomelanocorrrtin and neuropeptide-Y- containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 66, 393–4082. Caberlotto, L., Fuxe, K., Rimland, J.M., et al., 1998. Regional distribution of neuropeptide Y Y2 receptor messenger RNA in the human post mortem brain. Neuroscience 86, 167–178.
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Neuropeptide-Y Y2-receptor agonist, PYY3–36 promotes non-rapid eye movement sleep in rat Moses A. Akanmu a,c, Otas E. Ukponmwan d, Yoshifumi Katayama b, Kazuki Honda a,* a
Department of Biosystem Regulation, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan b Department of Autonomic Physiology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan c Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria d Department of Physiological Sciences, Obafemi Awolowo University, Ile-Ife, Osun-state, Nigeria Received 24 August 2005; accepted 18 November 2005 Available online 27 December 2005
Abstract PYY3–36 is a major component of the gut–brain axis and peripheral administration has been reported to exert significant effects on feeding, brain function and is more selective for neuropeptide Y2 receptor. Therefore, we investigated the effects of nocturnal intraperitoneal administration of single doses of PYY3–36 (30 and 100 mg/kg i.p.) on food intake, water intake and the sleep–wake cycle in rats. Sleep recordings were carried out in male Sprague–Dawley rats implanted with cortical electroencephalogram (EEG) and neck electromyogram (EMG) electrodes. The EEG, EMG, food intake and water intake were assessed. The electrographic recordings obtained were scored visually as rapid eye movement (REM) sleep, nonREM (NREM) sleep and wakefulness. PYY3–36 administration 15 min prior to dark onset significantly ( p < 0.05) increased non-rapid eye movement (NREM) sleep and decreased wakefulness. Analysis of the dark-period at 4-h time intervals showed that nocturnal administration of PYY3–36 (30 and 100 mg/kg) significantly suppressed wakefulness and increased non-REM sleep during the first 4-h time interval. Time spent in wakefulness was significantly decreased after administration of PYY3–36 (30 and 100 mg/kg) when compared with administration of vehicle. In addition, PYY3–36 (30 and 100 mg/kg i.p.) induced an increase in the time spent in NREM sleep. The nocturnal intraperitoneal administration of the lower dose of PYY3–36 (30 mg/kg) also significantly decreased food intake [F (2,23) = 4.90, p < 0.05] but had no effect on water intake. These findings suggest that PYY3–36 may play an important role in the enhancement of NREM sleep and feeding behavior. # 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. Keywords: PYY; PYY3–36; NREM; REM; Wake; Food intake; Water intake; Behavior
1. Introduction Peptide tyrosine–tyrosine (PYY) is a gut hormone that, like neuropeptide Y (NPY), is a member of the pancreatic polypeptide (PP) family (Conlon, 2002). This hormone is produced in either a 36-amino acid form (PYY1–36) or a truncated state, consisting of amino acids 3–36 (PYY3–36), after processing by the enzyme, dipeptidylpeptidase-IV (DPP-IV). The two forms of PYY (PYY1–36 and PYY3–36) act via different subtypes (Y1, Y2, Y4 and Y5) of the NPY receptor (Larhammar,
* Corresponding author. Tel.: +81 3 5280 8098; fax: +81 3 5280 8098. E-mail address: [email protected] (K. Honda).
1996) to alter feeding behavior. For example, PYY1–36 is an agonist at the Y1/Y2 receptors and promotes feeding, while PYY3–36 that is more selective for the Y2 receptor acts to inhibit feeding (Batterham et al., 2002; Dumont et al., 1996; Keire et al., 2000). Previous studies have demonstrated that peripheral administration of PYY3–36 can cross the blood–brain barrier to decrease food intake and increase c-fos immunoreactivity in the arcuate nucleus of rodents (Bonaz et al., 1993). Other studies have shown that PYY3–36 can influence neuronal activity in the arcuate nucleus to alter appetite (Batterham et al., 2002; Nonaka et al., 2003; Halatchev and Cone, 2005). Lundberg et al. (1984) have characterized PYY-containing neurons in the hypothalamus and hindbrain regions of rat. It has also been shown that Y2R is widely distributed within the
0168-0102/$ – see front matter # 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. doi:10.1016/j.neures.2005.11.006
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central nervous system in both rodents and humans in areas such as the arcuate nucleus, preoptic nucleus, dorsomedial nucleus, posterior hypothalamic nuclei, medial nucleus of the amygdala, parabrachial area, substantia nigra, paraventricular thalamic nucleus, dentate gyrus and cerebral cortex (Broberger et al., 1997; Caberlotto et al., 1998; Dumont et al., 1996; Gustafson et al., 1997). Furthermore, peripheral PYY injection evoked expression of c-fos immunoreactivity in the area postrema, the nucleus solitary tract, the amygdala and the thalamus (Bonaz et al., 1993). These areas contain neurons that are involved in sleep–wake regulation, drinking and feeding behaviors (Amaral and Price, 1983; Amaral et al., 1992; Benca et al., 2000; Chemelli et al., 1999; de Lecea et al., 1998; Sakurai et al., 1998; Willie et al., 2001). Some reports have demonstrated that various appetite-modulating substances, including orexins, cholecystokinin (CCK), NPY and leptin, also have significant effects on sleep–wake stages. It is also known that PYY3–36 is released in response to food intake, and that food consumption and metabolic status can influence sleep (Danguir et al., 1979). Thus, the present study was designed to examine the effects of nocturnal intraperitoneal administration of the neuropeptide Y Y2-receptor agonist, PYY3–36, on food intake, water intake and the sleep–wake cycle in rats. 2. Materials and methods 2.1. Animals Eight male Sprague–Dawley rats (250–300 g) were obtained from Crea Japan Inc. (Tokyo, Japan) and were kept for 10 days in cages under controlled conditions. The room was controlled at 25 1 8C with a relative humidity of 60 6% and 12-h light:12-h dark (lights on 8:00 h and lights off 20:00 h). The Tokyo Medical and Dental University Animal Resource Center approved all experimental procedures involving animals. All animals had free access to water and food throughout the experiments.
2.2. Preparation and administration of PYY3–36 Peptide YY3–36 was purchased from Peptide Institute Inc., Osaka, Japan and was dissolved in normal saline. Peptides or saline vehicle were administered intraperitoneally in aliquots of 500 ml. Freely behaving rats were administered single doses of PYY3–36 (30 or 100 mg/kg) in 500 ml of solution or were administered vehicle alone intraperitoneally 15 min prior to dark onset. These doses and time of administration were selected because previous study demonstrated that these doses produced robust behavioral effects (Batterham et al., 2002). All injections and recordings were separated by at least 2 days, and each rat received all three treatments [vehicle or PYY3–36 (30 or 100 mg/kg)]. EEG, EMG, food intake and water intake were assessed during the experiment.
EEG electrodes for recording EEG. Two stainless-steel electrodes were implanted in the neck musculature for recording EMG. Electrodes were then cemented in place with dental acrylic resin, and the cable from the electrodes was attached to a socket. After surgery, each animal received a total of 20,000 U of penicillin G potassium subcutaneously.
2.3.2. Sleep recording and analysis Rats were allowed to recover for at least 10 days after surgical operation before being transferred to an individual experimental cage for continuous monitoring of EEG and EMG. The experimental cages were placed in a soundproof, electromagnetically shielded room with the same environmental conditions as described above. For measurements, lead wires of the electrodes were connected to an EEG/EMG amplifier (Nihon-Kohden, MEG-6116, Tokyo) through a 5-strand cable with a slip-ring that allowed the rats to move freely. The amplifier was connected to a personal computer with an analog–digital converter and software (Kissei Comtec, SleepSign, Nagano) for acquiring and processing data. Data was sampled at 128 Hz and was subjected to online spectral analysis by Fast Fourier transformation over 8-s epochs. Subsequently, data were stored on a magnetic optical (MO) disk that was later visually analyzed offline after auto-analysis of the sleep–wake stages. EEG and EMG were measured for 2 consecutive days (a baseline day and an experimental day), starting at lights off. Sleep-waking state was classified as wakefulness (W), rapid eye movement (REM) sleep and non-REM (NREM) sleep from the EEG and EMG waveforms using software (Kissei Comtec, SleepSign, Nagano) and the results were verified visually according to standard criteria (Akanmu et al., 2004; Akanmu and Honda, 2005; Honda et al., 1994). We discriminated among wakefulness (high EMG amplitude, low EEG amplitude), non-REM sleep [(low EMG amplitude, high EEG amplitude with high power density in the delta band (0.5–4.0 Hz)], and rapid-eye-movement (REM) sleep [(silent low EMG amplitude, low EEG amplitude with high values in the theta band (4.0–8.0 Hz)] (Akanmu et al., 2004; Akanmu and Honda, 2005; Honda et al., 1994). The analyzed sleep variables included the amount of NREM sleep, REM sleep and total sleep.
2.4. Assessment of drinking and feeding behaviors At the beginning of the experiment, graduated water bottles and preweighed rat chow pellets (CE-2, Clea, Japan, Tokyo) were placed in individual testing cages. Water intake was measured at the end of the experimental 24-h time period. Rats were given free access to preweighed chow, and food intake was determined by measuring the difference between the preweighed chow and the remaining chow at the end of the experimental 24-h time period.
2.5. Statistical analysis Data were analyzed using repeated measures analyses of variance (ANOVA) followed by post hoc analysis of significance by the Student–Newman–Keuls test. Probability ( p)-values less than 0.05 were considered to represent statistical significance.
3. Results 3.1. Effect of PYY3–36 on sleep–wake cycle
2.3. Electroencephalography/electromyography Simultaneous electroencephalogram (EEG) and electromyogram (EMG) recordings were performed as described previously and were used to assess sleep–wake states (Akanmu et al., 2004; Akanmu and Honda, 2005; Honda et al., 1994). 2.3.1. Electrodes implantation Male Sprague–Dawley rats (n = 8) were anesthetized with pentobarbital sodium (50 mg/kg, i.p.), fixed on a stereotaxic apparatus and implanted with three cortical gold-plated screw electrodes through the skull to serve as dural
The nocturnal intraperitoneal injection of PYY3–36 to freely behaving rats significantly affected the sleep–wake stages (Table 1 and Fig. 1). The results obtained in relation to the effects of administration of PYY3–36 on episode frequency, episode duration and total time are as shown in Table 1. PYY3–36 at the dose of 30 mg/kg significantly decreased wakefulness and increased NREM sleep and total sleep but had no effect on REM sleep (Fig. 1). However, in time interval analysis, these effects of this dose of PYY3–36 on sleep–wake
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stages were only significant during the first 4-h time interval and not in the other time intervals (Fig. 1). During the first 4-h time interval, both doses of PYY3–36 produced a decrease in the time spent in wakefulness (F (2,23) = 7.54, p = 0.006); increased NREM sleep (F (2,23) = 10.29; p = 0.002) and increased total sleep (F (2,23) = 11.53, p = 0.001) but had no effect on REM sleep (F (2,23) = 0.48, p = 0.627) (Fig. 1). Furthermore, the results obtained showed that an intraperitoneal injection of both doses of PYY3–36 to freely behaving rats 15 min prior to dark-onset had no effect on sleep–wake states during the subsequent light-period (NREM sleep: saline, 473.7 8.4 min; PYY3–36 30 mg/kg, 489.9 10.0 min; PYY3– 36 100 mg/kg, 476.24 12.4 min [F (2,23) = 2.47, p = 0.121];
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REM sleep: saline: 74.1 6.6 min; PYY3–36 30 mg/kg, 81.2 5.7 min; PYY3–36 100 mg/kg, 76.0 5.9 min [F (2,23) = 2.63, p = 0.107]. 3.2. Effect of PYY3–36 on food and water intake Food intake was significantly reduced after intraperitoneal injection of low dose PYY3–36 but not after high dose PYY3–36 when compared to injection of saline (F (2,23) = 4.9, p = 0.024) (Fig. 2), but injection of PYY3–36 had no effect on drinking behavior (saline, 54.8 2.88 ml; PYY3–36 30 mg/ kg, 62.5 5.4 ml; PYY3–36 100 mg/kg, 64.3 6.6 ml [F (2,23) = 1.92, p = 0.184]).
Table 1 Effects of intraperitoneal administration of PYY3–36 on episode frequency, episode duration and total time of sleep–wake stages in rat (n = 8) Doses in 500 ml
Episode frequency
Episode duration (s)
Total time (min)
Saline (Baseline) 30 mg/kg 100 mg/kg
41.1 4.7 47.6 4.1 49.9 3.1
233.9 45.4 156.5 22.7* 142.8 12.0*
137.3 6.3 114.6 8.5* 115.3 6.5*
REM sleep
Baseline 30 mg/kg 100 mg/kg
11.5 2.0 12.9 2.0 15.0 2.1 *
94.1 7.3 72.6 5.9 * 78.8 5.3
16.6 2.2 16.0 2.8 18.8 2.1
NREM sleep
Baseline 30 mg/kg 100 mg/kg
42.4 5.4 49.3 4.1 52.8 2.8 *
131.0 12.0 139.1 7.8 * 120.5 6.5
85.4 5.7 112.7 9.0* 104.8 5.3*
Total sleep
Baseline 30 mg/kg 100 mg/kg
53.8 6.4 62.1 4.8 67.8 4.1 *
225.0 16.0 211.8 9.7 * 199.3 9.0
102.0 6.2 128.7 8.5* 123.8 6.4*
Baseline 30 mg/kg 100 mg/kg
48.9 4.3 50.9 4.9 43.0 2.8
179.8 20.2 155.5 16.5 191.3 13.9
137.0 6.3 122.8 4.7 133.3 5.2
REM sleep
Baseline 30 mg/kg 100 mg/kg
12.4 1.4 13.3 1.3 12.8 1.1
77.3 7.4 81.5 8.0 79.8 7.1
15.0 0.9 17.6 2.3 16.2 1.0
NREM sleep
Baseline 30 mg/kg 100 mg/kg
49.6 4.7 52.1 4.6 44.6 3.0
108.9 7.2 120.4 11.9 124.5 9.9
87.3 5.9 99.0 3.7 89.8 4.7
Total sleep
Baseline 30 mg/kg 100 mg/kg
62.0 5.4 65.4 4.9 57.4 3.4
186.1 10.7 201.9 16.0 204.3 12.7
102.3 6.3 116.6 4.7 106.1 5.2
Baseline 30 mg/kg 100 mg/kg
38.5 2.9 36.9 3.6 35.4 2.0
239.0 27.6 282.6 51.3 249.1 21.4
145.0 8.6 153.6 6.2 143.0 7.2
REM sleep
Baseline 30 mg/kg 100 mg/kg
6.9 1.2 6.0 1.1 7.0 1.0
81.9 10.7 67.8 11.3 73.8 8.1
9.3 2.0 6.3 1.3 8.3 1.3
NREM sleep
Baseline 30 mg/kg 100 mg/kg
39.9 2.6 37.0 3.7 35.8 2.1
129.9 8.5 137.0 13.0 150.0 11.7
85.2 6.9 79.5 5.3 88.4 6.9
Total sleep
Baseline 30 mg/kg 100 mg/kg
46.8 2.4 43.0 4.3 42.8 2.3
211.8 14.9 204.8 16.9 223.8 11.0
94.5 8.5 85.8 6.2 96.7 7.2
Sleep–wake stages First 4-h time interval Wakefulness
Second 4-h time interval Wakefulness
Third 4-h time interval Wakefulness
Values are mean S.E.M. * p < 0.05 compared to baseline (saline).
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Fig. 1. Effects of intraperitoneal administration of PYY3–36 (30 or 100 mg/kg) or saline on waking state, rapid eye movement (REM) sleep, non-REM (NREM) sleep and total sleep in rats (n = 8) during the dark-period. Each bar represents the mean S.E.M. Compared with saline (baseline) values; * p < 0.05; #p < 0.01.
Fig. 2. Effects of intraperitoneal administration of PYY3–36 (30 or 100 mg/kg) on food intake in rats (n = 8). Each bar represents the mean S.E.M. Compared with saline (baseline) values; *p < 0.05.
4. Discussion Previous studies have demonstrated that peripherally administered PYY3–36 crosses the blood–brain barrier (Nonaka et al., 2003) and stimulates presynaptic Y2 receptors in the
arcuate nucleus (Batterham et al., 2002). As in prior investigation (Batterham et al., 2002), intraperitoneal administration of PYY3–36 significantly decreased food intake, in the present study, however, the maximal effect was observed with the administration of 30 mg/kg body weight. Furthermore, the present study also demonstrated that intraperitoneal administration of the Y2 receptor agonist, PYY3–36 modulated the sleep–wake states by decreasing wakefulness and concomitantly increased NREM sleep and total sleep particularly during the first 4-h of administration. Specifically, both doses administered significantly increased the total time spent in NREM sleep and total sleep while there was differential effects on the episode frequency and episode duration (Table 1). PYY3–36 at the dose of 30 mg/kg has more robust effect on episode duration while the effect on episode frequency was more profound with the administration at the dose level of 100 mg/kg body weight. Thus, the present data suggest that PYY3–36 may have significant effects on feeding and sleep– wake state. The exact mechanism by which PYY3–36 modulates sleep-wakes is not known. It is however known that PYY3–36 receptors are localized in the amygdala, an area that is involved in the regulation of the sleep–wake state (Benca et al., 2000). This limbic brain nucleus is interconnected with a number of brain regions that are also involved in sleep regulation, such areas include the basal forebrain, hypothalamus and brainstem (Amaral et al., 1992). Furthermore, reciprocal connections exist between the amygdala and brainstem areas, including the parabrachial region, dorsal raphe nuclei, pedunculopontine tegmentum (PPT) and laterodorsal tegmental nuclei that are also involved in the regulation of waking and REM sleep. The sleep–wake modulation by PYY3–36 may be due to its influence on these neural circuits. Alternatively, the sleep enhancing effect may be related to action on HPA axis and other neurotransmitters. For example, neuropeptide Y promotes sleep and inhibits the hypothalamopituitary-adrenocortical (HPA) axis in humans. Therefore, since PYY also acts via NPY Y2 receptors, it may promote sleep through inhibition of the HPA axis. PYY3–36 is released from the gastrointestinal tract postprandially in amounts that are proportionate to the calorie content of a meal (Adrian et al., 1985; Grandt et al., 1994). After its release, the hormone acts on the central nervous system by binding to Y2R, a putative inhibitory presynaptic receptor highly expressed on NPY neurons (Broberger et al., 1997) in the arcuate nucleus (Kalra et al., 1999) and thereby inhibits feeding. Other gastrointestinal hormones may also play a key role in the mechanisms of postprandial sleep. For example insulin has been reported to enhance NREM sleep (Danguir and Nicolaidis, 1984) while CCK suppressed motor activity (Crawley and Corwin, 1994) and selectively stimulated NREM sleep in rats and rabbits (Kapa´s et al., 1988, 1991; Hirosue et al., 1993). Reports also showed that administration of bombesin (de Saint Hilaire-Kafi et al., 1989; Gibbs et al., 1981), NPY or leptin (Antonijevic et al., 2000; Sinton et al., 1999) decreased feeding and increased sleep. It is not clear whether PYY acts directly or whether it acts via modulation of other neurotransmitters. Administration of drugs
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that enhance serotonergic transmission decreased food intake (Leibowitz et al., 1990) and 5-HT1 receptor has been reported to play an inhibitory role in feeding (Dourish, 1992; Kitchener and Dourish, 1994). Since 5-HT2C, 5-HT1B and 5-HT2A agonist receptors suppress food intake in food-deprived and nondeprived rats, these receptor subtypes may be relevant in feeding behavior and sleep–wake modulating effects of PYY3– 36. Moreover, the relationship between serotonin and PYY had earlier been reported (Hagan and Moss, 1993). The NREM sleep promoting effects of PYY3–36 are probably due to inhibition of wake promoting or activation of sleep promoting mechanisms. Therefore, the role of this neurotransmitter and other neurotransmitters in the behavioral effects of PYY3–36 should be investigated in future studies. In conclusion, the present study demonstrated that intraperitoneal injection of low dose PYY3–36 resulted in decreased food intake, increased NREM sleep and decreased wakefulness, particularly during the first 4-h time period, but had no effect on drinking behavior. These findings suggest that PYY3–36 may play an important role in the modulation of the sleep–wake state and of behavioral responses. Further study to determine the mechanisms by which PYY3–36 produces these effects would be of benefit. Acknowledgement This study was supported by a Grant-in-Aid for Scientific Research (C) (No. 16614003) to K.H. References Adrian, T.E., Ferri, N., Bacarese-Hamilton, A.J., 1985. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89, 1070–1077. Akanmu, M.A., Honda, K., 2005. Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats. Brain Res. 1048, 138–145. Akanmu, M.A., Songkram, C., Kagechika, H., Honda, K., 2004. A novel melatonin derivative modulates sleep–wake cycle in rats. Neurosci. Lett. 364, 199–202. Amaral, D.G., Price, J.L., 1983. An air pressure system for injection of tracer substances into the brain. J. Neurosci. Methods 9, 35–43. Amaral, D.G., Price, J.L., Pitkanen, A., Carmichael, S.T., 1992. Anatomical organization of the primate amygdaloid complex. In: Aggleton, J. (Ed.), The Amygdala. Wiley-Liss, New York, pp. 1–67. Antonijevic, I.A., Murck, H., Bohlhalter, S., Frieboes, R.M., Holsboeer, F., Steiger, A., 2000. Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men. Neuropharmacology 39, 1474–1481. Batterham, R.L., Cowley, M.A., Small, C.J., Herzog, H., Cohen, M.A., Dakin, C.L., Wren, A.M., et al., 2002. Gut hormone PYY3-36 physiologically inhibits food intake. Nature 418, 650–654. Benca, R.M., Obermeyer, W.H., Shelton, S.E., Droster, J., Kalin, N.H., 2000. Effects of amygdala lesions on sleep in rhesus monkeys. Brain Res. 879, 130–138. Bonaz, B., Taylor, I., Tache, Y., 1993. Peripheral peptide YY induces c-fos-like immunoreactivity in the rat brain. Neurosci. Lett. 163, 77–80. Broberger, C., Landry, M., Wong, H., Walsh, J.N., Hokfelt, T., 1997. Subtypes of Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in prio-opiomelanocorrrtin and neuropeptide-Y- containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 66, 393–4082. Caberlotto, L., Fuxe, K., Rimland, J.M., et al., 1998. Regional distribution of neuropeptide Y Y2 receptor messenger RNA in the human post mortem brain. Neuroscience 86, 167–178.
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G protein-coupled receptors that regulates feeding behavior. Cell 92, 573– 578. Sinton, C.M., Fitch, T.E., Gershenfeld, H.K., 1999. The effects of leptin on REM sleep and slow wave delta in rats are reversed by food deprivation. J. Sleep Res. 8, 197–203. Willie, J.T., Chemelli, R.M., Sinton, C.M., Yanagisawa, M., 2001. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu. Rev. Neurosci. 24, 429–458.