Brazilian Journal of Medical and Biological Research (1999) 3: 17-114 Effect of SX-38 on sleep and waking ISSN 1-879X 17 Effect of SX-38, a selective ligand for the BZ 1 receptor, on sleep and waking during the light-dark cycle in the rat F. Alvariño 1, J.M. Monti 1, H. Jantos 1 and D. Monti 1 Department of Pharmacology and Therapeutics, Clinics Hospital, Montevideo, Uruguay Department of Psychiatry, University of Utah at Salt Lake City, Salt Lake City, UT, USA Correspondence J.M. Monti 833/6 Zudañez Street Montevideo 113 Uruguay Fax: 598--487-3787 E-mail: jmonti@chasque.apc.org Received December 3, 1998 Accepted May 18, 1999 Abstract Key words SX-38 Benzodiazepine 1 receptor Sleep Waking REM sleep Zolpidem Light-dark cycle Introduction
18 F. Alvariño et al. a a Material and Methods
Effect of SX-38 on sleep and waking 19 Experiment 1 Experiment Procedures Data analysis Statistical analysis Results Experiments carried out during the light phase
11 F. Alvariño et al. 35 Wakefulness 1 Light sleep 3 5 15 1 Control SX.5 SX 1. SX.5 1 8 6 4 5 5 4 Slow wave sleep 1 1 REMS 3 8 6 4 1 Figure 1 - The effect of SX-38 (SX) on wakefulness, light sleep, slow wave sleep and rapid-eye-movement sleep (REMS) during the light phase of the light-dark cycle. Ordinate: mean amount in minutes of behavioral state according to EEG criteria. All values are the means (min) ± SEM collected at 1-h intervals. Six animals were in each experimental group. Doses are reported in mg/kg. P<.5; P<.1 compared to control (Newman-Keuls test). Table 1 - Effect of SX-38 on sleep latencies during the light phase of the light-dark cycle. Data are reported as means ± SEM. Six animals were in each experimental group. The doses are reported as mg/kg. P<.5 compared to control (Newman-Keuls test). REMS, Rapid-eye-movement sleep. Slow wave sleep latency (min) REMS latency (min) Control 9.8 ±. 65.3 ± 17.7 SX-38.5 9. ±. 61.8 ± 9.1 1. 4.8 ±. 85.5 ± 17.9.5 7.7 ± 3.4 14.5 ± 13.5 Experiments carried out during the dark phase
Effect of SX-38 on sleep and waking 111 6 5 4 3 Wakefulness Control SX.5 SX 1. SX.5 1 1 8 6 4 Light sleep 1 4 Slow wave sleep REMS 3 1 6 5 4 3 1 Figure - The effect of SX-38 (SX) on sleep and waking during the dark phase of the light-dark cycle. All values are the means (min) ± SEM collected at 1-h intervals. Six animals were in each experimental group. Doses are reported in mg/kg. P<.5; P<.1 compared to control (Newman-Keuls test). REMS, Rapid-eye-movement sleep. Table - Effect of SX-38 on sleep latencies during the dark phase of the light-dark cycle. Values are reported as means ± SEM. Six animals were in each experimental group. The doses are reported as mg/kg. P<.5; P<.1 compared to control (Newman-Keuls test). REMS, Rapid-eyemovement sleep. Slow wave sleep latency (min) REMS latency (min) Control.6 ± 6. 141.3 ± 38.5 SX-38.5 8.7 ±.7 119.4 ± 1.4 1. 4.9 ±. 5.7 ± 17..5 5.9 ±. 71.7 ±.6
11 F. Alvariño et al. EEG power density in nonrems (% of control) 45 4 35 3 5 15 1 5 Discussion SX-38.5 mg/kg SX-38 1. mg/kg SX-38.5 mg/kg.3-1 1- -3 3-4 4-6 6-8 8-1 1-15 15-3 3-3 Frequency (Hz) Figure 3 - Effect of SX-38 on the mean EEG power density of nonrems (non-rapid-eyemovement sleep) (relative to baseline) during the dark period of the light-dark cycle. The curves indicate mean values of successive frequencies which are reported as percent of the placebo reference value (= 1%) during a 6-h period. SX-38 significantly and dosedependently increased power density in the delta and theta regions ( P<.5; Newman- Keuls test).
Effect of SX-38 on sleep and waking 113 Acknowledgments
114 F. Alvariño et al. References 1. Macdonald RL & Olsen RW (1994). GABA A receptor channels. Annual Review of Neuroscience, 17: 569-6.. Besnard F, Avenet P, Itier V, Granger P, Partiséti M, Depoortere H, Graham D & Langer SZ (1996). GABA A receptor subtypes and the mechanism of action of zolpidem. In: Freeman H, Puech AJ & Roth T (Editors), Zolpidem: An Update of its Pharmacological Properties and Therapeutic Place in the Management of Insomnia. Elsevier, Paris, 1-31. 3. Muller WE (1995). Pharmacology of the GABAergic/benzodiazepine system. In: Kales A (Editor), Pharmacology of Sleep. Springer, Berlin, 11-4. 4. Langer SZ, Arbilla S, Benavides J, Depoortere H & Scatton B (199). Receptors involved in the mechanism of action of the imidazopyridine zolpidem. In: Barthouil P (Editor), Insomnie et Imidazopyridines. Excerpta Medica, Amsterdam, 7-18. 5. Furukawa K, Oka M, Kohayakawa H, Kurumiya S, Saruwatari T, Ono K, Odai O & Karasawa T (1994). SX-38, a putative nonbenzodiazepine hypnotic. I. Neuropharmacological profile. Neuropsychopharmacology, 1 (Suppl): 7S (Abstract P-174-6). 6. Oka M, Furukawa K, Noda Y, Ochi Y, Kitazono Y, Ono K, Odai O & Karasawa T (1994). SX-38, a putative non-benzodiazepine hypnotic. II. Behavioral effects. Neuropsychopharmacology, 1 (Suppl): 7S (Abstract P-174-61). 7. Zivkovic B, Perrault G, Morel E & Sanger DJ (199). Neuropsychopharmacological profile of zolpidem, a new imidazopyridine hypnotic. In: Barthouil P (Editor), Insomnie et Imidazopyridines. Excerpta Medica, Amsterdam, 19-3. 8. Kurumiya S, Nagai R, Furukawa K, Oka M & Karasawa T (1994). SX-38, a putative non-benzodiazepine hypnotic. II. Electroencephalographic and sleep studies. Neuropsychopharmacology, 1 (Suppl): 8S (Abstract P-174-6). 9. Halperin JM, Miller D & Iorio LC (1981). Sleep inducing effects of three hypnotics in a new model of insomnia in rats. Pharmacology, Biochemistry and Behavior, 14: 811-814. 1. Michaud JC, Muyard JP, Capdevielle G, Ferran E, Geiordano-Orsini JP, Veyrun J, Roncucci R & Mouret J (198). Mild insomnia induced by environmental perturbations in the rat: A study of this new model and of its possible applications in pharmacological research. Archives Internationales de Pharmacodynamie et de Therapie, 59: 93-15. 11. Monti JM (1979). The effects of neuroleptics with central dopamine and noradrenaline receptor blocking properties in the l- dopa and ()-amphetamine-induced waking EEG in the rat. British Journal of Pharmacology, 67: 87-91. 1. Radulovacki M, Miletich RS & Green RD (198). N 6 (L-phenylisopropyl)adenosine (L-PIA) increases slow-wave sleep (S ) and decreases wakefulness in rats. Brain Research, 46: 178-18. 13. Grant L, Hopkinson P, Jennings G & Jenner FA (1971). Period of adjustment of rats used for experimental studies. Nature, 3: 135. 14. Monti JM, Hawkins M, Jantos H, Labraga P & Fernandez J (1988). Biphasic effects of dopamine D- receptor agonists on sleep and wakefulness in the rat. Psychopharmacology, 95: 395-4. 15. Arbilla S, Depoortere H, George P & Langer SZ (1985). Pharmacological profile of the imidazopyridine zolpidem at benzodiazepine receptors and electrocorticogram in rats. Archives of Pharmacology, 33: 48-51. 16. Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ & Bartholini G (1986). Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. Journal of Pharmacology and Experimental Therapeutics, 37: 649-658. 17. Depoortere H & Granger P (1985). Differentiation of EEG sleep stages in the rat and the cat by automatic analysis. In: Kubicki S & Herrmann WM (Editors), Methods of Sleep Research. Gustav Fischer, Stuttgart, 37-45. 18. Depoortere H (1985). A comparative EEG study of some benzodiazepine (BZD) and non-bzd sedative or hypnotic drugs. Pharmacopsychiatry, 18: 17-19. 19. McCormick DA (199). Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Progress in Neurobiology, 39: 337-388.. Lancel M & Faulhaber J (1996). The GABA A agonist THIP (gaboxadol) increases non-rem sleep and enhances delta activity in the rat. Neuroreport, 7: 41-45. 1. Lancel M, Crönlein TAM & Faulhaber J (1996). Role of GABA A receptors in sleep regulation: Differential effects of muscimol and midazolam on sleep in rats. Neuropsychopharmacology, 15: 63-74.. McCarley RW & Hobson JA (1975). Neuronal excitability modulation over the sleep cycle: a structural and mathematical model. Science, 189: 58-6. 3. Trulson ME & Jacobs BL (1979). Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Research, 163: 135-15. 4. Nitz D & Siegel J (1997). GABA release in the dorsal raphe nucleus: role in the control of REM sleep. American Journal of Physiology, 73: R451-R455. 5. Nitz D & Siegel J (1977). GABA release in the locus coeruleus as a function of sleep/ wake state. Neuroscience, 78: 795-81.