臺灣博碩士論文加值系統

我們實驗室研究指出，自主神經活性會隨著睡眠不同期有週期性明顯之變動，且這些變動出現異常可能與某些疾病有關。而失眠是現代人常見症狀，易引起心臟循環系統相關疾病。因此，監測睡眠時之自主神經功能變化有其不可或缺之重要性。安眠藥為目前治療失眠最有效之方式，新一代安眠藥zolpidem與傳統之促GABA作用之安眠藥triazolam比較，有較少之副作用，且對睡眠時自主神經活性變化之研究並不足。因此，本論文使用本實驗室建立之大鼠腦波及自主神經活性研究相關模式，探討zolpidem及triazolam對睡眠型式ヽ睡眠腦波，及睡眠時自主神經活性之差異。 可自由活動Wistar-Kyoto rats (WKY)經餵食針隨機給予vehicle, zolpidem 3, 30 mg/kg及triazolam 0.075, 0.75 mg/kg，並連續記錄腦波ヽ肌電波，和心電訊號，比較總記錄時間ヽ清醒ヽ安靜睡眠及奇異睡眠之變化。 觀察0至2小時，發現zolpidem於會明顯增加安靜睡眠時間，大劑量會抑制奇異睡眠時間。任一劑量皆會增加腦波總功率 (TPEEG)ヽdelta頻域 (0.5-4 Hz)之功率及百分比。較特別的是小劑量會增加睡眠各期之R-R間距ヽ心率變異性之高頻功率 (HF)，而大劑量反而抑制對心率變異性之總功率 (TPHRV)ヽ高頻功率ヽ低頻功率 (LF)。Triazolam 任一劑量皆會增加安靜睡眠時間，且皆減少奇異睡眠時間，而僅於大劑量會增加delta頻域之百分比。小劑量雖未使R-R間距明顯下降，但對心率變異性各參數皆明顯抑制，大劑量則更降低R-R間距。 至給藥後第3至5小時，Zolpidem對睡眠型式已無影響，但腦波總功率及各頻域功率增加現象依然存在，而其分布百分比已回復如控制組。對心率變異性各成分之影響，小劑量組已恢復，而大劑量組則仍持續抑制。Triazolam僅於大劑量對睡眠型式仍有作用，且不論大小劑量對腦波已無影響，但對自主神經功能之抑制則仍然存在。 比較兩種安眠藥對0至2小時之影響，發現對睡眠型式之影響相似，但小劑量zolpidem不會抑制奇異睡眠時間。Zolpidem會增加腦波之功率ヽdelta頻域之功率及百分比，而triazolam於大劑量才會影響。且除了小劑量zolpidem會增加自主神經功能外，大劑量zolpidem及任一劑量triazolam皆為抑制。 根據上述結果推論，對睡眠型式等效劑量下，zolpidem對對心臟自主神經功能抑制作用較少，更特別的是於低劑量時有效促進心臟迷走神經功能。

Our laboratory has demonstrated that autonomic regulation plays an important role in different sleep stages, and that disregulatory of their activities may be related to certain diseases. Insomnia, a common symptom nowadays, can cause cardiovascular disease. Accordingly, it is important to monitor autonomic function during sleep. Nowadays, hypnoitcs were the most effective treatment on insomnia. Zolpidem, a new generation sedative-hypnotic, has less undesirable effects than traditional GABA-ergic hypnotics, such as triazolam, and related studies on sleep-related autonomic functions are deficient. Therefore, this experiment was designed to explore the effects of zolpidem and triazolam on sleep patterns, sleep-related EEG, and sleep-related autonomic functions. The present study used an animal model established by our laboratory. Vehicle, zolpidem 3 and 30 mg/kg as well as triazolam 0.075 and 0.75 mg/kg were randomized given by gavage in Wistar-Kyoto rats (WKY). Continuous power spectral analysis of electroencephalogram (EEG), electromyogram (EMG), and heart rate variability (HRV) were performed in unanesthetized freely moving rats during daytime sleep. Differences among active waking (AW), quiet sleep (QS), and paradoxical sleep (PS) were compared. On 0 to 2 h window, zolpidem significantly increased QS time but suppressed PS time at higher dose. The EEG profile of zolpidem was significantly increased in total power of EEG (TPEEG), delta power (0.5-4 Hz) and percentage of delta power. It especially caused an increase in mean of R-R interval (RR) and high frequency (HF) power of HRV at lower dose, while it revealed a decrease in total power of HRV (TPHRV), HF and LF at higher dose. Like zolpidem, triazolam revealed an increase in QS time and a decrease in PS time at any doses. The EEG profile of triazolam revealed an increase on delta power and percentage of delta power only at higher dose. Lower dose of triazolam did not show the effect on RR, but it decreased TPHRV, HF, LF, and LF/HF. Higher dose of triazolam caused a decrease in RR even more. On 3 to 5 hour window, there are no effects on sleep patterns, and the EEG effects of zolpidem were increased in TPEEG , but not in EEG%. Zolpidem did not show the effects on HRV at lower dose while the effects on HRV were surpressed at higher dose. Triazolam increased QS time only at higher dose. Meanwhile, triazolam showed no effects on EEG but suppressed autonomic function. As compared to two hypnotics on 0 to 2 hours window, both caused almost the same effects on sleep patterns, and low dose of zolpidem did not suppress PS time. Zolpidem increased the EEG power and percentage of delta power, but not in lower dose of triazolam. Lower dose of zolpidem increased the autonomic functions, while triazolam caused a decrease. These results suggest that under equivalent dose on sleep patterns zolpidem has a less vagolytic effect on cardiac neural regulation as compared to triazolam, and that, zolpidem is effective in promoting cardiac vagal function at lower dose especially.

致謝 I 中文摘要 V 英文摘要 VII 目錄 X 研究背景介紹 1 睡眠生理學 1 睡眠之定義 1 睡眠相關之生理變化 2 睡眠相關之理論基礎 4 睡眠型式及睡眠腦波 8 睡眠與自主神經活性 9 自主神經活性之測量方法 10 心率變異性分析 12 睡眠時自主神經活性的變化 15 失眠 17 失眠之定義 18 失眠之評估方式 19 失眠之流行病學研究 20 失眠與自主神經功能之關係 21 安眠藥物分類及作用機轉 22 Barbiturate 24 Benzodiazepine 24 Non-benzodiazepine 25 其他幫助睡眠藥物 26 安眠藥對睡眠型式及睡眠腦波之影響 26 研究動機與目的 28 研究動機 28 研究目的 28 研究材料與方法 29 腦波及心電電極植入手術 29 動物分組及設計 30 安眠藥物來源及給予方式 30 實驗器材設置 31 資料收集 31 睡眠型式分析 32 睡眠腦波分析 33 心率變異性分析 33 統計 36 研究結果 37 Zolpidem對睡眠腦波及睡眠時自主神經活性之影響 37 給藥後0至2小時 37 Zolpidem對睡眠型式及睡眠腦波之影響 38 Zolpidem對睡眠時心率變異性參數之影響 38 給藥後0至2小時及3至5小時時間窗口之比較 39 Zolpidem對不同分析時間窗口睡眠型式及睡眠腦波之影響 40 Zolpidem對不同分析時間窗口睡眠時心率變異性參數之影響 41 Triazolam對睡眠腦波及睡眠時自主神經活性之影響 41 給藥後0至2小時 41 Triazolam對睡眠型式及睡眠腦波之影響 42 Triazolam對睡眠時心率變異性參數之影響 43 給藥後0至2小時及3至5小時時間窗口之比較 43 Triazolam對不同分析時間窗口睡眠型式及睡眠腦波之影響 45 Triazolam對不同分析時間窗口睡眠時心率變異性參數之影響 46 Zolpidem與triazolam對睡眠腦波及睡眠時心率變異參數影響之比較 46 綜合討論 47 本論文最重要之發現 47 Zolpidem之作用 47 Zolpidem對睡眠型式及睡眠腦波之影響 47 Zolpidem對睡眠時自主神經功能之影響 49 Triazolam之作用 50 Triazolam對睡眠型式及睡眠腦波之影響 50 Triazolam對睡眠時自主神經功能之影響 51 兩種藥物之比較及其可能影響之機轉 53 對睡眠型式及睡眠腦波之影響 53 對自主神經功能之影響 54 手術及分析方法討論 55 手術及記錄方法 55 實驗環境 56 電腦程式分析 57 睡眠分期 58 本研究之檢討 60 動物數目 60 其他生理訊號 60 電腦程式分析 60 未來可能發展 62 結論 64 附圖 65 Figure 1―Polysomnograms during 0 to 2 h of day time sleep after vechicle and zolpidem 3 and 30 mg/kg in a rat. 65 Figure 2―Dosage effects of zolpidem on sleep pattern on 0 to 2 h window. 67 Figure 3―Dosage effects of zolpidem on EEG on 0 to 2 h window. 69 Figure 4―Dosage effects of zolpidem on EEG on 0 to 2 h window. 71 Figure 5―Sample recordings of 3-min R-R intervals and average periodograms after vehicle, zolpidem 3 and 30 mg/kg in a rat. 73 Figure 6―Dosage effects of zolpidem on HRV on 0 to 2 h window. 75 Figure 7―Polysomnogram during 5 hours of day time sleep after vechicle in a rat. 77 Figure 8―Polysomnogram during 5 hours of day time sleep after zolpidem 3 mg/kg in a rat. 79 Figure 9―Polysomnogram during 5 hours of day time sleep after zolpidem 30 mg/kg in a rat. 81 Figure 10―A comparison of dosage effects of zolpidem on sleep patterns on 0 to 2 h window and 3 to 5 h window. 83 Figure 11―A comparison of dosage effects of zolpidem on EEG on 0 to 2 h window and 3 to 5 h window. 85 Figure 12―A comparison of dosage effects of zolpidem on EEG on 0 to 2 h window and 3 to 5 h window. 87 Figure 13―A comparison of dosage effects of zolpidem on HRV on 0 to 2 h window and 3 to 5 h window. 89 Figure 14―Polysomnograms during 0 to 2 h of day time sleep after vechicle and triazolam 0.075 and 0.75 mg/kg in a rat. 91 Figure 15―Dosage effects of triazolam on sleep pattern on 0 to 2 h window. 93 Figure 16―Dosage effects of triazolam on EEG on 0 to 2 h window. 95 Figure 17―Dosage effects of triazolam on EEG on 0 to 2 h window. 97 Figure 18―Sample recordings of 3-min R-R intervals and average periodograms after vehicle, zolpidem 3 and 30 mg/kg in a rat. 99 Figure 19―Dosage effects of triazolam on HRV on 0 to 2 h window. 101 Figure 20―Polysomnogram during 5 hours of day time sleep after vehicle in a rat. 103 Figure 21―Polysomnogram during 5 hours of day time sleep after triazolam 0.075 mg/kg in a rat. 105 Figure 22―Polysomnogram during 5 hours of day time sleep after triazolam 0.75 mg/kg in a rat. 107 Figure 23―A comparison of dosage effects of triazolam window on sleep patterns on 0 to 2 h window and 3 to 5 h. 109 Figure 24―A comparison of dosage effects of triazolam on EEG on 0 to 2 h window and 3 to 5 h window. 111 Figure 25―A comparison of dosage effects of triazolam on EEG on 0 to 2 h window and 3 to 5 h window. 113 Figure 26―A comparison of dosage effects of triazolam 0 to 2 h window and 3 to 5 h window on HRV. 115 Figure 27―A comparison of equivalent dosage effects of zolpidem and triazolam on sleep patterns. 117 Figure 28―A comparison of equivalent dosage effects of zolpidem and triazolam on EEG. 119 Figure 29―A comparison of equivalent dosage effects of zolpidem and triazolam on EEG. 121 Figure 30―A comparison of equivalent dosage effects of zolpidem and triazolam on HRV. 123 參考文獻 125

Agelink MW, Majewski TB, Andrich J & Mueck-Weymann M (2002). Short-term effects of intravenous benzodiazepines on autonomic neurocardiac regulation in humans: a comparison between midazolam, diazepam, and lorazepam. Crit Care Med 30, 997-1006. Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC & Cohen RJ (1981). Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 213, 220-222. Andre P & Arrighi P (2001). Modulation of Purkinje cell response to glutamate during the sleep-waking cycle. Neuroscience 105, 731-746. Arbilla S, Depoortere H, George P & Langer SZ (1985). Pharmacological profile of the imidazopyridine zolpidem at benzodiazepine receptors and electrocorticogram in rats. Naunyn Schmiedebergs Arch Pharmacol 330, 248-251. Aserinsky E & Kleitman N (1953). Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 118, 273-274. Barron KW, Pavelka SM & Garrett KM (1997). Diazepam-sensitive GABA(A) receptors in the NTS participate in cardiovascular control. Brain Res 773, 53-60. Bataillard A, Sannajust F, Yoccoz D, Blanchet G, Sentenac-Roumanou H & Sassard J (1990). Cardiovascular consequences of organophosphorus poisoning and of antidotes in conscious unrestrained rats. Pharmacol Toxicol 67, 27-35. Benington JH & Heller HC (1994). Does the function of REM sleep concern non-REM sleep or waking? Prog Neurobiol 44, 433-449. Bergmann BM, Winter JB, Rosenberg RS & Rechtschaffen A (1987). NREM sleep with low-voltage EEG in the rat. Sleep 10, 1-11. Binkley PF, Nunziata E, Haas GJ, Nelson SD & Cody RJ (1991). Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure: demonstration in human subjects and verification in a paced canine model of ventricular failure. J Am Coll Cardiol 18, 464-472. Blanchard JC, Boireau A, Garret C & Julou L (1979). In vitro and in vivo inhibition by zopiclone of benzodiazepine binding to rodent brain receptors. Life Sci 24, 2417-2420. Bormann J (1988). Electrophysiology of GABAA and GABAB receptor subtypes. Trends Neurosci 11, 112-116. Burgess HJ, Trinder J, Kim Y & Luke D (1997). Sleep and circadian influences on cardiac autonomic nervous system activity. Am J Physiol 273, H1761-1768. Cabot JB, Wild JM & Cohen DH (1979). Raphe inhibition of sympathetic preganglionic neurons. Science 203, 184-186. Chou CL, Kao NT, Kuo TBJ, Liu TJ & Chan RC (1998). Heart rate variability as an assessment of acute rejection after heart transplantation. Zhonghua Yi Xue Za Zhi (Taipei) 61, 561-567. Crochet S & Sakai K (2003). A neural mechanism of sleep and wakefulness. Sleep biol rhythms 1, 29-42. DeFeudis FV (1983). gamma-Aminobutyric acid and cardiovascular function. Experientia 39, 845-849. 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. J Pharmacol Exp Ther 237, 649-658. DiMicco JA (1987). Evidence for control of cardiac vagal tone by benzodiazepine receptors. Neuropharmacology 26, 553-559. DiMicco JA, Gale K, Hamilton B & Gillis RA (1979). GABA receptor control of parasympathetic outflow to heart: characterization and brainstem localization. Science 204, 1106-1109. Doble A, Canton T, Piot O, Zundel JL, Stutzmann JM, Cotrel C & Blanchard JC (1992). The pharmacology of cyclopyrrolone derivatives acting at the GABAA/benzodiazepine receptor. Adv Biochem Psychopharmacol 47, 407-418. Drake CL, Roehrs TA, Mangano RM & Roth T (2000). Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia. Hum Psychopharmacol 15, 595-604. Duncan GE, Breese GR, Criswell HE, McCown TJ, Herbert JS, Devaud LL & Morrow AL (1995). Distribution of [3H]zolpidem binding sites in relation to messenger RNA encoding the alpha 1, beta 2 and gamma 2 subunits of GABAA receptors in rat brain. Neuroscience 64, 1113-1128. Ferini-Strambi L, Oldani A, Zucconi M, Stankov B, Castronovo C, Fraschini F & Smirne S (1995a). Triazolam and melatonin effects on cardiac autonomic function during sleep. Clin Neuropharmacol 18, 405-409. Ferini-Strambi L, Rovaris M, Oldani A, Martinelli V, Filippi M, Smirne S, Zucconi M & Comi G (1995b). Cardiac autonomic function during sleep and wakefulness in multiple sclerosis. J Neurol 242, 639-643. Fewell JE, Williams BJ & Hill DE (1985). Control of blood pressure during sleep in lambs. Sleep 8, 254-260. Fiorica V, Higgins EA, Iampietro PF, Lategola MT & Davis AW (1968). Physiological responses of men during sleep deprivation. J Appl Physiol 24, 167-176. Gandolfo G, Glin L, Lacoste G, Rodi M & Gottesmann G (1988). Automatic sleep-wake scoring in the rat on microcomputer APPLE II. Int J Biomed Comput 23, 83-95. Garrigou-Gadenne D, Burke JT, Durand A, Depoortere H, Thenot JP & Morselli PL (1989). Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat. J Pharmacol Exp Ther 248, 1283-1288 George CF & Kryger MH (1985). Sleep and control of heart rate. Clin Chest Med 6, 595-601. Gottesmann C, Gandolfo G, Arnaud C & Gauthier P (1998). The intermediate stage and paradoxical sleep in the rat: influence of three generations of hypnotics. Eur J Neurosci 10, 409-414. Gurtu S, Pant KK, Sinha JN & Bhargava KP (1984). An investigation into the mechanism of cardiovascular responses elicited by electrical stimulation of locus coeruleus and subcoeruleus in the cat. Brain Res 301, 59-64. Hinman DJ & Okamoto M (1984). Sleep patterns in cats during chronic low-dose barbiturate treatment and withdrawal. Sleep 7, 69-76. Hoehns JD & Perry PJ (1993). Zolpidem: a nonbenzodiazepine hypnotic for treatment of insomnia. Clin Pharm 12, 814-828. Hohnloser SH, Klingenheben T, van de Loo A, Hablawetz E, Just H & Schwartz PJ (1994). Reflex versus tonic vagal activity as a prognostic parameter in patients with sustained ventricular tachycardia or ventricular fibrillation. Circulation 89, 1068-1073. Hon EH & Lee ST (1963). Electronic evaluation of the fetal heart rate. VIII. Patterns preceding fetal death, further observations. Am J Obstet Gynecol 87, 814-826. Horne JA (1978). A review of the biological effects of total sleep deprivation in man. Biol Psychol 7, 55-102. Horner R, Sanford L, Annis D, Pack A & Morrison A (1997). Serotonin at the laterodorsal tegmental nucleus suppresses rapid-eye-movement sleep in freely behaving rats. J Neurosci 17, 7541-7552. Itier V, Depoortere H, Scatton B & Avenet P (1996). Zolpidem functionally discriminates subtypes of native GABAA receptors in acutely dissociated rat striatal and cerebellar neurons. Neuropharmacology 35, 137-145. Jaradeh SS & Prieto TE (2003). Evaluation of the autonomic nervous system. Phys Med Rehabil Clin N Am 14, 287-305. Johnson LC, Slye ES & Dement W (1965). Electroencephalographic and autonomic activity during and after prolonged sleep deprivation. Psychosom Med 27, 415-423. Jones BE (2004). Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex. Prog Brain Res 145, 157-169. Julou L, Blanchard JC & Dreyfus JF (1985). Pharmacological and clinical studies of cyclopyrrolones: zopiclone and suriclone. Pharmacol Biochem Behav 23, 653-659. Kanno O, Sasaki T, Watanabe H, Takazawa S, Nakagome K, Nakajima T, Ichikawa I, Akaho R & Suzuki M (2000). Comparison of the effects of zolpidem and triazolam on nocturnal sleep and sleep latency in the morning: a cross-over study in healthy young volunteers. Prog Neuropsychopharmacol Biol Psychiatry 24, 897-910. Kayama Y & Koyama Y (1998). Brainstem neural mechanisms of sleep and wakefulness. Eur Urol 33, 12-15. Kleinlogel H (1990). Analysis of the vigilance stages in the rat by fast Fourier transformation. Neuropsychobiology 23, 197-204. Kollar EJ, Slater GR, Palmer JO, Doctor RF & Mandell AJ (1966). Stress in subjects undergoing sleep deprivation. Psychosom Med 28, 101-113. Korpi ER, Herb A & Luddens H (1995). Effects of ethanol on recombinant rat GABAA receptors: [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding study. Pharmacol Toxicol 77, 87-90. Kripke DF & Garfinkel L (1984). Excess nocturnal deaths related to sleeping pill and tranquilliser use. Lancet 1, 99. Kripke DF, Garfinkel L, Wingard DL, Klauber MR & Marler MR (2002). Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry 59, 131-136. Kripke DF, Klauber MR, Wingard DL, Fell RL, Assmus JD & Garfinkel L (1998). Mortality hazard associated with prescription hypnotics. Biol Psychiatry 43, 687-693. Kripke DF, Simons RN, Garfinkel L & Hammond EC (1979). Short and long sleep and sleeping pills. Is increased mortality associated? Arch Gen Psychiatry 36, 103-116. Kuo TBJ, Lai CJ, Shaw FZ, Lai CW & Yang CCH (2004a). Sleep-related sympathovagal imbalance in SHR. Am J Physiol 286, H1170-1176. Kuo TBJ, Lin T, Yang CCH, Li CL, Chen CF & Chou P (1999). Effect of aging on gender differences in neural control of heart rate. Am J Physiol 277, H2233-2239. Kuo TBJ, Shaw FZ, Lai CJ, Lai CW & Yang CCH (2004b). Changes in sleep patterns in spontaneously hypertensive rats. Sleep 27, 406-412. Kuo TBJ & Yang CCH (2000). Altered frequency characteristic of central vasomotor control in SHR. Am J Physiol 278, H201-207. Kuo TBJ & Yang CCH (2002). Sexual dimorphism in the complexity of cardiac pacemaker activity. Am J Physiol 283, H1695-1702. Kuo TBJ & Yang CCH (2004). Scatterplot analysis of EEG slow-wave magnitude and heart rate variability: an intergrative exploration of cerebral cortical and autonomic functions. Sleep 27, in press Langewitz W, Ruddel H & Schachinger H (1994). Reduced parasympathetic cardiac control in patients with hypertension at rest and under mental stress. Am Heart J 127, 122-128. Laurie DJ, Seeburg PH & Wisden W (1992). The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J Neurosci 12, 1063-1076. Lavery CE, Mittleman MA, Cohen MC, Muller JE & Verrier RL (1997). Nonuniform nighttime distribution of acute cardiac events: a possible effect of sleep states. Circulation 96, 3321-3327. Leary AC & Murphy MB (1998). Sleep disturbance during ambulatory blood pressure monitoring of hypertensive patients. Blood Press Monit 3, 11-15. Li SG, Lawler JE, Randall DC & Brown DR (1997). Sympathetic nervous activity and arterial pressure responses during rest and acute behavioral stress in SHR versus WKY rats. J Auton Nerv Syst 62, 147-154. Libert JP, Amoros C, Muzet A, Ehrhart J & Di Nisi J (1988). Effects of triazolam on heart rate level and on phasic cardiac response to noise during sleep. Psychopharmacology (Berl) 96, 188-193. Lin JS, Hou Y, Sakai K & Jouvet M (1996). Histaminergic descending inputs to the mesopontine tegmentum and their role in the control of cortical activation and wakefulness in the cat. J Neurosci 16, 1523-1537. Lobo BL & Greene WL (1997). Zolpidem: distinct from triazolam? Ann Pharmacother 31, 625-632 Luboshitzky R (2000). Endocrine activity during sleep. J Pediatr Endocrinol Metab 13, 13-20. Luddens H & Korpi ER (1995). GABA antagonists differentiate between recombinant GABAA/benzodiazepine receptor subtypes. J Neurosci 15, 6957-6962. Lytton WW, Destexhe A & Sejnowski TJ (1996). Control of slow oscillations in the thalamocortical neuron: a computer model. Neuroscience 70, 673-684. Macadar O, Roig JA, Monti JM & Budelli R (1970). The functional relationship between septal and hippocampal unit activity and hippocampal theta rhythm. Physiol Behav 5, 1443-1449. Macdonald RL & Olsen RW (1994). GABAA receptor channels. Annu Rev Neurosci 17, 569-602. Mailliet F, Galloux P & Poisson D (2001). Comparative effects of melatonin, zolpidem and diazepam on sleep, body temperature, blood pressure and heart rate measured by radiotelemetry in Wistar rats. Psychopharmacology (Berl) 156, 417-426. McCann CC, Quera-Salva MA, Boudet J, Frisk M, Barthouil P, Borderies P & Meyer P (1993). Effect of zolpidem during sleep on ventilation and cardiovascular variables in normal subjects. Fundam Clin Pharmacol 7, 305-310. Miki K, Kato M & Kajii S (2003). Relationship between renal sympathetic nerve activity and arterial pressure during REM sleep in rats. Am J Physiol 284, R467-473. Monti A, Medigue C, Nedelcoux H & Escourrou P (2002). Autonomic control of the cardiovascular system during sleep in normal subjects. Eur J Appl Physiol 87, 174-181. Monti JM, Alvarino F & Monti D (2000). Conventional and power spectrum analysis of the effects of zolpidem on sleep EEG in patients with chronic primary insomnia. Sleep 23, 1075-1084. Morison RS & Dempsey EW (1942). A study of thalamo-cortical relations. Am J Physiol 135, 281-292. Moruzzi G & Magoun H (1949). Brain stem reticular formation and activation of the EEG. Electroenceph Clin Neurophysiol 1, 455. Mraovitch S, Kumada M & Reis DJ (1982). Role of the nucleus parabrachialis in cardiovascular regulation in cat. Brain Res 232, 57-75. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK, Passamani E, Roberts R, Robertson T & et al. (1985). Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 313, 1315-1322. Murali NS, Svatikova A & Somers VK (2003). Cardiovascular physiology and sleep. Front Biosci 8, S636-652. Myers GA, Martin GJ, Magid NM, Barnett PS, Schaad JW, Weiss JS, Lesch M & Singer DH (1986). Power spectral analysis of heart rate variability in sudden cardiac death: comparison to other methods. IEEE Trans Biomed Eng 33, 1149-1156. Naitoh P, Pasnau RO & Kollar EJ (1971). Psychophysiological changes after prolonged deprivation of sleep. Biol Psychiatry 3, 309-320. Niddam R, Dubois A, Scatton B, Arbilla S & Langer SZ (1987). Autoradiographic localization of [3H]zolpidem binding sites in the rat CNS: comparison with the distribution of [3H]flunitrazepam binding sites. J Neurochem 49, 890-899. Noguchi H, Kitazumi K, Mori M & Shiba T (2004). Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats. J Pharmacol Sci 94, 246-251. Nunez A, Curro Dossi R, Contreras D & Steriade M (1992). Intracellular evidence for incompatibility between spindle and delta oscillations in thalamocortical neurons of cat. Neuroscience 48, 75-85. Pace-Schott EF & Hobson JA (2002). The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 3, 591-605. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG & Kilduff TS (1998). Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18, 9996-10015. Puia G, Vicini S, Seeburg PH & Costa E (1991). Influence of recombinant gamma-aminobutyric acid-A receptor subunit composition on the action of allosteric modulators of gamma-aminobutyric acid-gated Cl- currents. Mol Pharmacol 39, 691-696. Rosekind MR (1992). The epidemiology and occurrence of insomnia. J Clin Psychiatry 53, 4-6. Rumble R & Morgan K (1992). Hypnotics, sleep, and mortality in elderly people. J Am Geriatr Soc 40, 787-791. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ & Yanagisawa M (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573-585. Sanford LD, Silvestri AJ, Ross RJ & Morrison AR (2001). Influence of fear conditioning on elicited ponto-geniculo-occipital waves and rapid eye movement sleep. Arch Ital Biol 139, 169-183. Sanna E, Busonero F, Talani G, Carta M, Massa F, Peis M, Maciocco E & Biggio G (2002). Comparison of the effects of zaleplon, zolpidem, and triazolam at various GABA(A) receptor subtypes. Eur J Pharmacol 451, 103-110. Saper CB, Chou TC & Scammell TE (2001). The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24, 726-731. Sayers BM (1973). Analysis of heart rate variability. Ergonomics 16, 17-32. Schwartz PJ, La Rovere MT & Vanoli E (1992). Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation 85, I77-91. Shaw FZ, Lai CJ & Chiu TH (2002). A low-noise flexible integrated system for recording and analysis of multiple electrical signals during sleep-wake states in rats. J Neurosci Methods 118, 77-87. Sherin JE, Shiromani PJ, McCarley RW & Saper CB (1996). Activation of ventrolateral preoptic neurons during sleep. Science 271, 216-219. Shi SJ, Garcia KM & Meck JV (2003). Temazepam, but not zolpidem, causes orthostatic hypotension in astronauts after spaceflight. J Cardiovasc Pharmacol 41, 31-39. Sieghart W (1995). Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev 47, 181-234. Singh JP, Larson MG, Tsuji H, Evans JC, O'Donnell CJ & Levy D (1998). Reduced heart rate variability and new-onset hypertension: insights into pathogenesis of hypertension: the Framingham Heart Study. Hypertension 32, 293-297. Somers VK, Dyken ME, Mark AL & Abboud FM (1993). Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 328, 303-307. Steriade M (2004). Acetylcholine systems and rhythmic activities during the waking--sleep cycle. Prog Brain Res 145, 179-196. Steriade M, McCormick DA & Sejnowski TJ (1993). Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679-685. Stutzmann JM, Piot O, Reibaud M, Doble A & Blanchard JC (1992). Pharmacological properties and mechanism of action of the cyclopyrrolones. Encephale 18, 393-400. Sun MK & Guyenet PG (1986). Hypothalamic glutamatergic input to medullary sympathoexcitatory neurons in rats. Am J Physiol 251, R798-810. Swanson LW & Sawchenko PE (1983). Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6, 269-324. Taniguchi T, Wang JK & Spector S (1982). [3H]Diazepam binding sites on rat heart and kidney. Biochem Pharmacol 31, 589-590. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996). Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93, 1043-1065. Tochikubo O, Ikeda A, Miyajima E & Ishii M (1996). Effects of insufficient sleep on blood pressure monitored by a new multibiomedical recorder. Hypertension 27, 1318-1324. Trinder J, Kleiman J, Carrington M, Smith S, Breen S, Tan N & Kim Y (2001). Autonomic activity during human sleep as a function of time and sleep stage. J Sleep Res 10, 253-264. van Luijtelaar EL & Coenen AM (1984). An EEG averaging technique for automated sleep-wake stage identification in the rat. Physiol Behav 33, 837-841. Vanoli E, Adamson PB, Ba-Lin, Pinna GD, Lazzara R & Orr WC (1995). Heart rate variability during specific sleep stages. A comparison of healthy subjects with patients after myocardial infarction. Circulation 91, 1918-1922. Viola AU, Simon C, Ehrhart J, Geny B, Piquard F, Muzet A & Brandenberger G (2002). Sleep processes exert a predominant influence on the 24-h profile of heart rate variability. J Biol Rhythms 17, 539-547. von Economo C (1930). Sleep as a problem of localization. J Nerv Ment Dis 71, 253-264. Wisden W, Laurie DJ, Monyer H & Seeburg PH (1992). The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci 12, 1040-1062. Wolf MM, Varigos GA, Hunt D & Sloman JG (1978). Sinus arrhythmia in acute myocardial infarction. Med J Aust 2, 52-53. Yamamoto M & Nakahama H (1983). Stochastic properties of spontaneous unit discharges in somatosensory cortex and mesencephalic reticular formation during sleep-waking states. J Neurophysiol 49, 1182-1198. Yang CCH & Kuo TBJ (1999). Assessment of cardiac sympathetic regulation by respiratory-related arterial pressure variability in the rat. J Physiol 515, 887-896. Yang CCH, Kuo TBJ & Chan SHH (1996). Auto- and cross-spectral analysis of cardiovascular fluctuations during pentobarbital anesthesia in the rat. Am J Physiol 270, H575-582. Yang CCH, Lai CW, Lai HY & Kuo TBJ (2002). Relationship between electroencephalogram slow-wave magnitude and heart rate variability during sleep in humans. Neurosci Lett 329, 213-216. Yang CCH, Shaw FZ, Lai CJ, Lai CW & Kuo TBJ (2003). Relationship between electroencephalogram slow-wave magnitude and heart rate variability during sleep in rats. Neurosci Lett 336, 21-24. Yien HW, Hseu SS, Lee LC, Kuo TBJ, Lee TY & Chan SHH (1997). Spectral analysis of systemic arterial pressure and heart rate signals as a prognostic tool for the prediction of patient outcome in the intensive care unit. Crit Care Med 25, 258-266. Yoshimoto M, Higuchi H, Kamata M, Yoshida K, Shimizu T & Hishikawa Y (1999). The effects of benzodiazepine (triazolam), cyclopyrrolone (zopiclone) and imidazopyridine (zolpidem) hypnotics on the frequency of hippocampal theta activity and sleep structure in rats. Eur Neuropsychopharmacol 9, 29-35. 郭博昭 (1999). 心率變異分析心電轉換器; 申請案號: 87200683; 公告號碼: 363404 中華民國專利公報 七月一日 第2803-2806頁.