Theme : Dreams

Changes in Sleep in Response to Intracerebral Injection of Insulin-Like Growth Factor-1 (IGF-1) in the Rat

Ferenc Obál Jr.1, Levente Kapás2, Balazs Bodosi1 and James M. Krueger3
1Department of Physiology, Albert Szent-Györgyi Medical University, Szeged 6720, Hungary, 2Department of Biological Sciences, Fordham University, Bronx, New York 10458, USA, 3Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington 99164, USA
Abstract
Changes in sleep were studied during 6 hours after intracerebroventricular (ICV) administration of Insulin-like growth factor-1 (IGF-1) or the structurally related insulin. IGF-1 was injected either at dark onset (0.05 or 0.5 µg) or 6 hours after light onset (0.05, 0.5, or 5.0 µg). The small dose of IGF-1 consistently, albeit modestly, enhanced NREMS over the 6 hour postinjection period in both the dark and the light cycles (REMS increased only at night). The NREMS-promoting activity vanished when the dose was increased to 0.5 µg, and 5.0 µg IGF-1 elicited a marked and prompt suppression in NREMS. Heat-inactivated IGF-1 (0.05 µg) did not alter sleep. On a molar base, the NREMS-promoting dose of insulin was higher than that of IGF-1. Late (hours 7-17 postinjection) enhancements in EEG slow wave activity during NREMS were observed after 5.0 µg IGF-1. The results indicate that IGF-1 can promote NREMS and may contribute to the mediation of the effects of GH on sleep. The acute sleep-suppressive activity of the high dose of IGF-1 is attributed to an inhibition of endogenous growth hormone-releasing hormone (GHRH).

Current Claim: IGF-1 may contribute to the mediation of the effects of the somatotropic axis on sleep.

Activate the ShortNotes by clicking on this link. Your notes will be stored in this area and automatically retrieved upon your next visit.
Insulin-like growth factor-1 is a hormone secreted by the liver, and an autocrine/paracrine substance produced in various tissues, including the brain. IGF-1 is structurally related to IGF-2 and insulin. IGF-1 has a low affinity to insulin receptors and a high affinity to type-1 IGF receptors. The same receptors are, however, also implicated in the mediation of the growth promoting and proliferative activity of IGF-2, and they may also bind insulin though with significantly less affinity than IGF-1 or IGF-2 (reviewed in Sara et al., 1996; Stewart and Rotwein, 1996).

IGF-1 is a component of the somatotropic axis which mediates many effects of pituitary growth hormone (GH), such as regulation of tissue growth, cell differentiation and metabolic activity. In addition to IGF-1, the somatotropic axis includes hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin, which stimulate and inhibit pituitary GH secretion, respectively. Several members of the somatotropic axis exhibit sleep-modulating activity. Exogenous GHRH enhances sleep, particularly NREMS, in rats (Ehlers et al., 1986; Obál et al., 1988), rabbits (Obál et al., 1988) and humans (Steiger et al., 1992; Kerkhofs et al., 1993), whereas inhibition of endogenous GHRH is followed by suppression of spontaneous sleep (Obál et al., 1991; 1992). Somatostatin stimulates REMS (Danguir, 1986) and decreases NREMS (Beranek et al., 1997). Acute administration of GH stimulates REMS in rats (Drucker-Colín et al.,1975), cats (Stern et al., 1975) and humans (Mendelson et al., 1980). The sleep findings in patients with chronic alterations in GH secretion are variable. Recent observations, however, indicate that chronic overproduction or deficiency in GH is associated with enhancements and decreases in the intensity of NREMS, respectively, as assessed by determining the slow wave activity in the EEG (Åström and Jochumsen, 1989; Åström and Trojaborg, 1992). Immunoneutralization of GH is followed by decreases in sleep in the rat (Obál et al., 1997). Transgenic mice with excess GH production sleep more than normal mice (Lacmanshing and Rollo, 1994). In contrast, mice deficient in the entire somatotropic axis sleep less than their littermates (Zhang et al., 1996). These findings suggest that, particularly in chronic conditions, GH may have NREMS promoting activities, possibly via some metabolic actions, but the responsiveness of NREMS to GH varies with the species and the age of the subjects (reviewed in Obál et al., 1997). Sleep-associated variations in plasma IGF-1 concentrations have been detected in humans (Prinz et al., 1995). The effects of IGF-1 on sleep, however, have not been studied, and therefore it is not known whether IGF-1 has any role in the mediation of the GH-induced sleep alterations.

The aim of our experiments was to study changes in sleep in response to intracerebroventricular (ICV) injection of IGF-1 in rats. To determine if insulin receptors are involved in the mediation of the sleep responses, sleep-wake activity was also recorded after ICV injection of insulin.

Activate the ShortNotes by clicking on this link. Your notes will be stored in this area and automatically retrieved upon your next visit.
Animals, surgery
Male Sprague-Dawley rats (300-350 g b.w.) were used. Under ketamine-xylazine anesthesia (87 and 13 mg/kg intraperitoneally, respectively), the rats were implanted with stainless steel jewelry screws as electrodes for EEG recording, and a thermistor for recording cortical brain temperature (Tcrt). A guide cannula was implanted into the left lateral ventricle. The position of the cannula was verified during implantation by a sudden drop in resistance against inflow of physiological saline. The placement of the cannula and the drainage of the lateral ventricle was verified by means of the drinking response elicited by ICV injection of angiotensin II (200 ng, 2 µl) a few days before the sleep experiment. At the termination of the sleep recording, trypan blue was injected into the cannula, and the ventricular system was checked for staining. Data were used only from those rats in which the angiotensin tests were positive and the postmortem examination of the brain also confirmed the proper position of the cannula.

Recording

The rats were housed in individual Plexiglas cages in the recording chambers. The ambient temperature was regulated at 26°C, and a 12-12-hour light-dark cycle was maintained with light on at 8:30 a.m. Food and water were continuously available. The rats were allowed 7 to 10 days to recover after surgery. During recovery, the rats were housed in the recording chambers, and they were connected to the recording tethers for habituation. The tethers were attached to commutators. The movements of the rats were recorded by means of electromagnetic transducers attached to the tethers. Cables from the commutators and electromagnetic transducers were connected to amplifiers in an adjacent room. The signals were digitized by an AD converter (64 Hz sampling rate) and stored on a computer. For the evaluation of the states of vigilance, the EEG, motor activity and Tcrt signals were displayed on the computer screen. For each 8-s epoch, the power density spectra were also computed from the EEG. The power density values were determined and displayed in 0.5 Hz bins between 0.5 and 20 Hz. The states of vigilance were scored visually in 8-s intervals (NREMS: high-amplitude EEG slow waves, lack of body movements, and declining Tcrt upon entry; REMS: highly regular theta activity in the EEG, general lack of body movements with occasional twitches, and rapid rise in Tcrt at onset; wakefulness: EEG amplitudes similar but less regular than in REMS, frequent movements, and a gradual increase in Tcrt after arousal). The duration of the states of vigilance was expressed as percent of recording time each hour. Power density values between 0.5 and 4.0 Hz were integrated to characterize EEG slow wave activity (SWA). SWA belonging to artifact-free uninterrupted 8-s epochs of NREMS were averaged and thereby mean SWA during NREMS was computed for each hour. Occasionally, the rats failed to sleep for 1 hour or longer at night. In these particular cases, the mean of the preceding and following hourly SWA was used to fill the missing value for the statistics. The 8-s Tcrt values were averaged for 1 hour intervals.

Experimental protocol

Eight groups of rats were used as follows: Three groups were injected in the light period 6 hours after light onset: 0.05 µg IGF-1 (n=10), 0.5 µg IGF-1 (n=6), and 5.0 IGF-1 (n=10); and five groups were injected at dark onset: 0.05 µg IGF-1 (n=10), 0.5 IGF-1 (n=12), heat-inactivated 0.05 µg IGF-1 (n=7), 0.04 µg insulin (n=8); 0.4 µg insulin (n=8). The doses of insulin (0.04 and 0.4 µg) were selected to match the molar dose of 0.05 and 0.5 µg IGF (0.0065 nmol and 0.065 nmol), respectively. In the rat, sleep propensity is highest at light onset, declines during the day, and is at minimum levels at the beginning of the dark period. Injections at dark and light onsets are generally used to demonstrate increases and decreases in NREMS, respectively, in response to a particular substance (Inoué et al., 1984). It was anticipated that duration of NREMS during the second portion of the light period might be still high enough to detect sleep suppression and already low enough to pick up sleep promotion if IGF-1 exerts these activities. IGF-1 (human recombinant IGF-1) and insulin (human, enzymatically derived from porcin insulin) was obtained from Peninsula Lab, Inc. (CA). For heat inactivation, the IGF-1 solution was exposed to 75°C for 30 min. Both IGF-1 and insulin were dissolved in physiological saline and injected in a volume of 2 µl. Each rat received 2 ICV injections: physiological saline on day 1 (baseline day), and IGF-1 or insulin on day 2 (experimental day). As a growth factor and metabolic hormone, IGF-1 may elicit long-term effects in both glial cells and neurons. IGF-1 or insulin was, therefore, always administered on day 2 of the recording.

ICV injections were performed 10 min before dark onset or 10 min before hour 6 of the light period. The groups injected at dark onset were recorded from for 12 hours in the dark period, and for 11 hours during the subsequent light period. In the groups injected during the light period, recording was started in the morning with light onset, interrupted for injections and then continued during the 6 hours of the second portion of the light period, and for 11 hours at night. If not mentioned otherwise, only the values for a 6 hour postinjection period are reported herein irrespective of the time of the injection; the IGF-1-induced alterations in sleep were over during this period.

Statistics

Two-way analysis of variance (ANOVA) for repeated measures were used to determine the effects of IGF-1 or insulin on a state of vigilance, SWA during NREMS, and Tcrt in a group of rats. Time (6 hour blocks) and treatment (physiological saline or IGF or insulin) were the 2 factors of the ANOVA. Only the results with significant treatment-effects are provided in the current report. Intergroup comparisons (evaluation of the differences in the effects of the various doses of IGF-1) were performed by means of one-way ANOVA followed by the Student-Newman-Keuls test in the light period (3 groups) or by the Student t-test in the dark period (2 groups). The Student t-test was used to analyze the effects of IGF-1 on the states of vigilance in postinjection hour 1. In all tests, an alpha level of p<0.05 was taken as an indication of statistical significance.

Activate the ShortNotes by clicking on this link. Your notes will be stored in this area and automatically retrieved upon your next visit.

Figure 1

The lowest dose of IGF-1 enhanced NREMS during a 6 hour time block after injection in both the light (ANOVA, F(1,9)=11.717, p<0.05) and the dark periods (F(1,9)=13.673, p<0.05) (Table 1, Fig. 1). The increases in NREMS were modest and occurred between hours 1 and 4 postinjection with the most consistent enhancements in hour 2 (dark) or hour 3 (light) postinjection. NREMS was not significantly altered in hour 1 (Student t-test). The NREMS-promoting activity of IGF-1 vanished when the dose was raised to 0.5 µg. Although the mean duration of NREMS per 6 hours did not change in response to 5.0 µg IGF-1, this large dose elicited a prompt and significant suppression in NREMS in postinjection hour 1 (% recording time; baseline: 51.7 ± 1.96, IGF-1: 33.0 ± 4.21; p< 0.05, Student t-test). The NREMS loss was recovered in hour 3 postinjection. There were significant differences in the effects on NREMS among the three doses of IGF-1 injected during the light period (one-way ANOVA: F(2,23)=5.26, p<0.05; Student-Newman-Keuls test: significant difference between the effects of 0.05 µg and 5.0 µg IGF-1) and between the doses administered at dark onset (Student t-test).

SWA in NREMS did not change during 6 hours after IGF-1 injection. Interestingly, consistent (+10.4 ± 1.92%) and statistically significant (F(1,9)=27.424, p<0.05) enhancements in NREMS-associated SWA were found throughout the 11 hour recording during the dark period when 5.0 µg IGF-1 was injected 6 hours after light onset. These changes in SWA were not accompanied by changes in the duration of NREMS.

In general, REMS was not altered by ICV administration of IGF-1 during the day or at night. Increases in REMS were observed after the 0.05 µg IGF-1 injected at dark onset (F(91,9)=8.457, p<0.05). This group of rats, however, produced less REMS on the baseline day than the rat injected with the larger dose (Table 1).

The low dose of insulin did not alter sleep (Table 1). Although NREMS obviously tended to increase after the administration of 0.4 µg insulin (NREMS enhanced in 6 out of the 7 rats) these changes did not reach the level of statistical significance.

Courses of Tcrt did not differ after physiological saline and IGF-1 or insulin injections.

Activate the ShortNotes by clicking on this link. Your notes will be stored in this area and automatically retrieved upon your next visit.
The low dose of ICV IGF-1 elicited modest enhancements of sleep. Increases in NREMS were also reported in response to ICV infusion of insulin (Danguir and Nicolaidis, 1984). The molar dose of IGF-1 was, however, lower than that of insulin required for stimulation of NREMS in our experiments. Therefore, the NREMS-promoting activity of IGF-1 is attributed to stimulation of type-1 IGF-1 receptors and not to insulin receptors. Enhancements in NREMS developed slowly and persisted for several hours after the administration of IGF-1 in both the dark and the light period. This suggests that stimulation of sleep elicited by GHRH is not mediated via GH-IGF-1 for GHRH has a prompt and relatively short-lasting sleep-promoting activity in rats (Ehlers et al., 1986; Obál et al., 1988). In fact, GH-deficiency created by hypophysectomy fails to interfere with the enhancements in NREMS elicited by GHRH (Obál et al., 1996). It was suggested, therefore, that the NREMS-promoting activities of GHRH and GH are independent: GHRH stimulates NREMS via a neurotransmitter-like action in the basal forebrain, whereas GH alters sleep through some metabolic action. Although the mechanisms might be slightly different, GH, IGF-1, and insulin are all characterized by protein anabolic (Russell-Jones and Umpleby, 1996) and NREMS-promoting activities. NREMS is associated with increased rates of cerebral protein synthesis in the rat (Ramm and Smith, 1990) and monkey (Nakanishi et al., 1997). It cannot be excluded that these phenomena are not only correlative, but causally related. Also, the GH-induced rise in the concentration of IGF-1 in the brain or in the blood (IGF-1 seems to be transported from blood into the brain via the choroid plexus [Reinhardt and Bondy, 1994; Davidson et al., 1990]) may contribute to the sleep alterations found in patients with chronic overproduction of GH. In this respect, the late increases in SWA observed after the high dose of IGF-1 might have particular significance: enhanced NREMS intensity is reported to be a characteristic symptom of patients with high plasma GH concentrations (Åström and Trojaborg, 1992).

Acute administration of GH increases REMS in three species (Drucker-Colín et al., 1975; Stern et al., 1975; Mendelson et al., 1980). The low dose of IGF-1, however, stimulated REMS modestly only in the dark period and failed to do so in the afternoon when REMS is normally high. The time of the day variations in the REMS responses to IGF-1 suggest that IGF-1 has no specific REMS-promoting activity. The increases in REMS at night might result from the combined effects of the low baseline and the increases in NREMS. If this speculation is correct then the mechanism of stimulation of REMS by acute GH injection is independent from IGF-1.

The NREMS-promoting effects of IGF-1 vanished when the dose was increased, and the high dose, in fact, elicited an acute suppression in NREMS in postinjection hour 1. IGF-1 acts as a negative feedback in the somatotropic axis inhibiting GH secretion at levels of both the pituitary and the hypothalamus. In the hypothalamus, IGF-1 stimulates somatostatin (Berelowitz et al., 1981; Becker et al., 1995; Gil Ad et al., 1996; Ghigo et al., 1997). Although an acute release of GHRH is also occasionally found in response to IGF-1 (Aguilla et al., 1993), other papers report that IGF-1 suppresses GHRH secretion (Shibasaki et al., 1986; Becker et al., 1995) and GHRH mRNA levels (Sato and Frohman, 1993; Uchiyama et al., 1994). Inhibition of GHRH might require stronger IGF-1 stimulation than the release of somatostatin (Ghigo et al., 1997). Irrespective of which event occurs first, both an inhibition of GHRH and a stimulation of somatostatin are associated with decreases in NREMS. It seems that it is not the blood-borne IGF-1, but the hypothalamic IGF-1 stimulated by pituitary GH which is involved in the hypothalamic inhibition of the somatotropic axis (Sato and Frohman, 1993). The importance of the intracerebral IGF-1 in the regulation of GH secretion is supported by the observation that ICV administration of IGF-1 in itself (Abe et al., 1983; Tannenbaum et al., 1983) or in combination with IGF-2 (Harel and Tannenbaum, 1992) inhibits GH secretion in the rat. The dose of ICV-injected IGF-1 suppressing GH secretion is 0.5 µg or higher (Becker et al., 1995), i.e., in the dose range of IGF-1 that failed to enhance NREMS or caused a suppression in our experiments. It is suggested therefore, that the attenuation of the sleep-promoting activity of IGF-1, and the appearance of NREMS suppression when the dose of ICV IGF-1 is high is due to a gradually developing inhibition of GHRH and/or stimulation of somatostatin.

In conclusion, in addition to the acute NREMS suppressive effect of IGF-1, our experiments indicate that IGF-1 has a sleep-promoting potential. Experiments with chronic administration of IGF-1 can reveal whether this activity of IGF-1 is involved in the mechanisms of sleep alterations in conditions with permanent overproduction of GH.

1. Abe H, Molitch ME, Van Wyk JJ, Underwood JJ. Human growth hormone and somatomedin C suppresses the spontaneous release of growth hormone in unanesthetized rats. Endocrinology 1983; 113: 1319-24.
2. Aguilla MC, Boggaram V, McCann SM. Insulin-like growth factor 1 modulates hypothalamic somatostatin through a growth hormone releasing hormone factor increased somatostatin release and messenger ribonucleic acid levels. Brain Res 1993; 625: 213-8.

3. Åström C, Jochumsen PL. Decrease in delta sleep in growth hormone deficiency assessed by a new power spectrum analysis. Sleep 1989; 12: 508-15.

4. Åström C, Trojaborg W. Effect of growth hormone on human sleep energy. Clin Endocrinol 1992; 36: 241-5.

5. Becker K, Stegenga S, Conway S. Role of insulin-like growth factor 1 in regulating growth hormone release and feedback in the male rat. Neuroendocrinology 1995; 61: 573-83.

6. Beranek L, Obál F JR, Taishi P, Bodosi B, Laczi F, Krueger JM. Changes in rat sleep after single and repeated injections of the long-acting somatostatin analog octreotide. Am J Physiol 1997; 273: R1484-91.

7. Berelowitz M, Szabo M, Frohman LA, Firestone S, Chu L. Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 1981; 212: 1279-81.

8. Danguir J. Intracerebroventricular infusion of somatostatin selectively increases paradoxical sleep in rats. Brain Res 1986; 367: 26-30.

9. Danguir J, Nicolaidis S. Chronic intracerebroventricular infusion of insulin causes selective increase of slow-wave sleep in rats. Brain Res 1984; 306: 97-103.

10. Davidson DA, Bohannon NJ, Corp ES, Lattemann DP, Woods SC, Porte D, Dorsa DM, Baskin DG. Evidence for separate receptors for insulin and insulin-like growth factor-1 in choroid plexus of rat brain by quantitative autoradiography. J Histochem Cytochem 1990; 38: 1289-94.

11. Drucker-Colín RR, Spanis CW, Hunyadi J, Sassin JF, McGaugh JL. Growth hormone effects on sleep and wakefulness in the rat. Neuroendocrinology 1975; 18: 1-8.

12. Ehlers CL, Reed TK, Henriksen SJ. Effects of corticotropine-releasing factor and growth hormone-releasing factor on sleep and activity in rats. Neuroendocrinology 1986; 42: 467-74.

13. Ghigo MC, Torsello A, Grilli R, Luoni M, Guidi M, Cella SG, Locatelli V, Müller EE. Effects of GH and IGF-1 administration on GHRH and somatostatin mRNA levels: I. a study on ad libitum fed and starved adult male rats. J Endocrinol Invest 1997; 20: 144-50.

14. Gil Ad I, Weizman A, Silbergeld A, Dickerman Z, Kaplan B, Laron Z, Koch Y. Differential effect of insulin-like growth factor-1 and growth hormone on hypothalamic regulation of growth hormone secretion in the rat. J Endocrinol Invest 1996; 19: 542-7.

15. Harel Z, Tannenbaum GS. Centrally administered insulin-like growth factor II fails to alter pulsatile growth hormone secretion or food intake. Neuroendocrinology 1992; 56: 161-8.

16. Inoué S, Honda K, Komoda Y, Uchizono K, Ueno R, Hayaishi O. Little sleep-promoting effect of three sleep substances diurnally infused in unrestrained rats. Neurosci Lett 1984; 49: 207-11.

17. Kerkhofs M, van Cauter E, Van Onderbergen A, Caufriez A, Thorner MO, Copinschi G. Sleep-promoting effect of growth hormone-releasing hormone in normal men. Am J Physiol 1993; 264: E594-8.

18. Lachmansingh E, Rollo CD. Evidence for a trade-off between growth and behavioural activity in giant "Supermice" genetically engineered with extra growth hormone genes. Can J Zool 1994; 72: 2158-68.

19. Mendelson WB, Slater S, Gold P, Gillin JC. The effect of growth hormone administration on human sleep: a dose response study. Biol Psychiatry 1980; 15: 613-8.

20. Nakanishi H, Sun Y, Nakamura RK, Mori K, Ito M, Suda S, Namba H, Storch FI, Dang TO, Mendelson W, Mishkin M, Kennedy C, Gillin JC, Smith CB, Sokoloff L. Positive correlations between cerebral protein synthesis rates and deep sleep in Macaca mulatta. Eur J Neurosci 1997; 9: 271-9.

21. Obál F JR, Alföldi P, Cady AB, Johannsen L, Sáry G, Krueger JM. Growth hormone-releasing factor enhances sleep in rats and rabbits. Am J Physiol 1988; 255: R310-6.

22. Obál F JR, Bodosi B, Szilágyi A, Kacsoh B, Krueger JM. Antiserum to growth hormone suppresses sleep in the rat. Neuroendocrinology 1997; 66: 9-16.

23. Obál F JR, Floyd R, Kapás L, Bodosi B, Krueger JM. Effects of systemic GHRH on sleep in intact and hypophysectomized rats. Am J Physiol 1996; 270: E230-7.

24. Obál F JR, Payne L, Kapás L, Opp M, Krueger JM. Inhibition of growth hormone-releasing factor suppresses both sleep and growth hormone secretion in the rat. Brain Res 1991; 557: 149-53.

25. Obál F JR, Payne L, Opp M, Alföldi P, Kapás L, Krueger JM. Growth hormone-releasing hormone antibodies suppress sleep and prevent enhancement of sleep after sleep deprivation. Am J Physiol 1992; 263: R1078-85.

26. Prinz PN, Moe KE, Dulberg EM, Larsen LH, Vitiello MV, Toivola B, Merriam GR. Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men. J Gerontology 1995; 50A: M222-6.

27. Ramm P, Smith CT. Rates of cerebral protein synthesis are linked to slow wave sleep in the rat. Physiol Behav 1990; 48: 749-53.

28. Reinhardt RR, Bondy CA. Insulin-like growth factors cross the blood-brain barrier. Endocrinology 1994; 135: 1753-61.

29. Russell-Jones DL, Umpleby M. Protein anabolic action of insulin, growth hormone and insulin-like growth factor 1. Eur J Endocrinology 1996; 135: 631-42.

30. Sara VR, Clayton K, Cooke P, Craven CJ, Garcia-Aragon J, Harmon B, Harvey M, Haase H, Plenderleith M, Richardson N, Sherrard R, Stahlbom P-A, Walker G, Walsh TP. The brain IGF system: implications for Down's syndrome. Dev Brain Dysfunct 1996; 9: 85-92.

31. Sato M, Frohman LA. Differential effects of central and peripheral administration of growth hormone (GH) and insulin-like growth factor on hypothalamic GH-releasing hormone and somatostatin gene expression in GH-deficient dwarf rats. Endocrinology 1993; 133: 793-9.

32. Shibasaki T, Yamauchi N, Hotta M, Masuda A, Imaki T, Demura H, Ling N, Shizume K. In vitro release of growth hormone-releasing factor from rat hypothalamus: effect of insulin-like growth factor-1. Regulatory Peptides 1986; 15: 47-53.

33. Steiger A, Guldner J, Hemmeter U, Rothe B, Wiedemann K, Holsboer F. Effects of growth hormone-releasing hormone and somatostatin on sleep EEG and nocturnal hormone secretion in male controls. Neuroendocrinology 1992; 56: 566-73.

34. Stern WC, Jalowiec JE, Shabshelowitz H, Morgane P. Effects of growth hormone on sleep-waking patterns in cats. Horm Behav 1975; 6: 189-96.

35. Stewart CEH, Rotwein P. Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev 1996; 76: 1005-26.

36. Tannenbaum GS, Guyda H, Posner BI. Insulin-like growth factors: a role in growth hormone negative feedback and body weight regulation via brain. Science 1983; 220: 77-9.

37. Uchiyama T, Kaji H, Abe H, Chihara K. Negative regulation of hypothalamic growth hormone-releasing factor messenger ribonucleic acid by growth hormone and insulin-like growth factor 1. Neuroendocrinology 1994; 59: 441-50.

38. Zhang J, Obál F JR, Fang J, Collins BJ, Krueger JM. Non-rapid eye movement sleep is suppressed in transgenic mice with a deficiency in the somatotropic system. Neurosci Lett 1996; 220: 97-100.

The authors thank Ms. I. Ponicsan, Mr. Sz. Toth, and Mr. Y. Wang for technical assistance. This work was supported by the Hungarian Science Foundation (OTKA-16080) and the National Institutes of Health (NS-30514, NS-27250 and NS-31453).

Original address of this text :

http://www.sro.org/bin/article.dll?Paper&964&0&0

Please copy this address to the address bar of your internet browser and press the "enter" key.
(We prefer not to put actual links because often page locations change and then our log files get cluttered with error messages
- if the address does not work try to find it from the homepage of the website in question).