莫达非尼觉醒作用机制研究进展

摘要/Abstract

摘要： 莫达非尼是强效促觉醒药物,主要用于治疗发作性睡病等原因引起的白天嗜睡。莫达非尼和多巴胺(dopamine, DA)转运体有一定亲和性,可增加脑内DA释放,也影响去甲肾上腺素(noradrenaline, NA)、5-羟色胺(serotonin, 5-HT)、谷氨酸、γ-氨基丁酸(γ-aminobutyric acid, GABA)、orexin和组胺能等神经系统,但觉醒作用机制存有众多争议。行为学研究发现,DA转运体基因敲除(knock-out, KO)动物给予莫达非尼后,不能产生显著的觉醒作用;D₂受体KO)动物对莫达非尼的觉醒作用显著降低,前处理D₁受体拮抗剂,莫达非尼对D₂受体KO小鼠的促觉醒作用消失,提示多巴胺能D₁/D₂ 受体在莫达非尼促觉醒作用中至关重要,其他神经递质的变化可能是觉醒的继发性作用。本文综述莫达非尼觉醒作用机制研究进展。

关键词: 莫达非尼, 觉醒, 多巴胺, D₁受体, D₂受体, DA转运体

Abstract: Modafinil is a potent wake-promoting compound with low abuse potential used in the treatment of narcolepsy and day time sleepiness. The compound is reported to affect multiple neurotransmitter systems such as catecholamines, serotonin, glutamate, GABA, orexin, and histamine, however, the molecular mechanism by which modafinil increases wakefulness is debated. It was previously testified that arousal effects of modafinil were not exhibited in dopamine transporter KO mice; furthermore, treatment of dopamine (DA) D₂ receptor (D₂R)-deficient mice with D₁R-specific antagonists completely abolished arousal effects of modafinil. These findings strongly indicate that dopamine and dopaminergic D₁R and D₂R are essential for the wakefulness caused by modafinil, and its influence on other neurotransmitter systems may result from enhanced dopaminergic activity and wakefulness.This review summarizes the progress on mechanism profile for arousal effects of modafinil.

Key words: Modafinil, Wakefulness, Dopamine, Dopamine D₁ receptor, Dopamine D₂ receptor, DA transporter

中图分类号:

R749

陈长瑞, 曲卫敏, 黄志力. 莫达非尼觉醒作用机制研究进展[J]. 中国临床药理学与治疗学, 2010, 15(12): 1428-1433.

CHEN Chang-rui, QU Wei-min, HUANG Zhi-li. Mechanism profile for arousal effects of modafinil[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(12): 1428-1433.

参考文献

[1] Schwartz JR, Feldman NT, Bogan RK, et al. Dosing regimen effects of modafinil for improving daytime wakefulness in patients with narcolepsy[J]. Clin Neuropharmacol, 2003, 26 (5): 252-257.
[2] Moldofsky H, Broughton RJ, Hill JD. A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy[J]. Sleep Med, 2000, 1 (2): 109-116.
[3] Swanson JM. Role of executive function in ADHD[J]. J Clin Psychiatry, 2003, 64(14): 35-39.
[4] Wong YN, Simcoe D, Hartman LN, et al. A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers[J]. J Clin Pharmacol, 1999, 39 (1): 30-40.
[5] Lin JS, Roussel B, Akaoka H, et al. Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat[J]. Brain Res, 1992, 591 (2): 319-326.
[6] Caldwell JA J, Caldwell JL, Smythe NK, et al. A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study[J]. Psychopharmacology (Berl), 2000, 150 (3): 272-282.
[7] Caldwell JA, Caldwell JL, Smith JK, et al. Modafinil's effects on simulator performance and mood in pilots during 37 h without sleep[J]. Aviat Space Environ Med, 2004, 75 (9): 777-784.
[8] Qu WM, Huang ZL, Xu XH, et al. Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil[J]. J Neurosci, 2008, 28 (34): 8462-8469.
[9] Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat[J]. J Pharmacol Exp Ther, 1997, 283 (2): 757-769.
[10] Lagarde D, Milhaud C. Electroencephalographic effects of modafinil, an alpha-1-adrenergic psychostimulant, on the sleep of rhesus monkeys[J]. Sleep, 1990, 13 (5): 441-448.
[11] Broughton RJ, Fleming JA, George CF, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy[J]. Neurology, 1997, 49 (2): 444-451.
[12] Pack AI, Black JE, Schwartz JR, et al. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea[J]. Am J Respir Crit Care Med, 2001, 164 (9): 1675-1681.
[13] Huang ZL, Urade Y, Hayaishi O. Prostaglandins and adenosine in the regulation of sleep and wakefulness[J]. Curr Opin Pharmacol, 2007,7(1):33-38.
[14] Huang ZL, Urade Y, Osamu H. The Role of Adenosine in the Regulation of Sleep[J]. Curr Top Med Chem, 2011, In press.
[15] 黄志力.睡眠与睡眠障碍[M] //孙凤艳.医学神经生物学.上海:上海科学技术出版社, 2008,317-331.
[16] 黄志力, 曲卫敏, 徐昕红,等.多巴胺神经系统在睡眠觉醒调节中的作用「M」//金国章.脑内多巴胺.上海:上海科学技术出版社, 2010: 印刷中.
[17] Monti JM, Monti D. The involvement of dopamine in the modulation of sleep and waking[J]. Sleep Med Rev, 2007, 11 (2): 113-133.
[18] 许奇,曲卫敏,黄志力.多巴胺D₂受体调控睡眠一觉醒研究进展[J].中国临床药理学与治疗学, 2010, 15 (4): 361-366.
[19] Pawlyk AC, Morrison AR, Ross RJ, et al. Stress-induced changes in sleep in rodents: models and mechanisms[J]. Neurosci Biobehav Rev, 2008, 32 (1): 99-117.
[20] Qu WM, Xu XH, Yan MM, et al. Essential role of dopamine D2 receptor in the maintenance of wakefulness, but not in homeostatic regulation of sleep, in mice[J]. J Neurosci, 2010,30 (12): 4382-4389.
[21] Vernier P, Moret F, Callier S, et al. The degeneration of dopamine neurons in Parkinson's disease: insights from embryology and evolution of the mesostriatocortical system[J]. Ann N Y Acad Sci, 2004, 1035: 231-249.
[22] Heim C, Sova L, Kurz T, et al. Partial loss of dopaminergic neurons in the substantia nigra, ventrotegmental area and the retrorubral area model of the early beginning of Parkinson's symptomatology[J] ? J Neural Transm, 2002, 109 (5/6): 691-709.
[23] Qiu MH, Qu WM, Xu XH, et al. D(1)/D(2) receptor-targeting L-stepholidine, an active ingredient of the Chinese herb Stephonia, induces non-rapid eye movement sleep in mice[J]. Pharmacol Biochem Behav, 2009, 94 (1): 16-23.
[24] Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition[J]. Neuropsychopharmacology, 2008, 33 (7): 1477-1502.
[25] Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation[J]. Cell, 1999, 98 (4): 437-451.
[26] Scammell TE, Estabrooke IV, McCarthy MT, et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulness[J]. J Neurosci, 2000, 20 (22): 8620-8628.
[27] Mignot E, Nishino S, Guilleminault C, et al. Modafinil binds to the dopamine uptake carrier site with low affinity[J]. Sleep, 1994, 17 (5): 436-437.
[28] Jones BE. From waking to sleeping: neuronal and chemical substrates[J]. Trends Pharmacol Sci, 2005, 26 (11): 578-586.
[29] Wisor JP, Nishino S, Sora I, et al. Dopaminergic role in stimulant-induced wakefulness[J]. J Neurosci, 2001, 21 (5): 1787-1794.
[30] Tanganelli S, Fuxe K, Ferraro L, et al. Inhibitory effects of the psychoactive drug modafinil on gamma-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms[J]. Naunyn Schmiedebergs Arch Pharmacol, 1992, 345 (4): 461-465.
[31] Tanganelli S, Perez de la Mora M, Ferraro L, et al. Modafinil and cortical gamma-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins[J]. Eur J Pharmacol, 1995, 273 (1/2): 63-71.
[32] Ferraro L, Tanganelli S, O'Connor WT, et al. The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor[J]. Neurosci Lett, 1996, 220 (1): 5-8.
[33] 徐昕红,黄志力,曲卫敏.莫达非尼促觉醒作用及机制研究[D].上海,复旦大学,2009.
[34] Touret M, Sallanon-Moulin M, Fages C, et al. Effects of modafinil-induced wakefulness on glutamine synthetase regulation in the rat brain [J]. Brain Res Mol Brain Res, 1994, 26 (1/2): 123-128.
[35] Ferraro L, Antonelli T, O'Connor WT, et al. Modafinil: an antinarcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers[J]. Biol Psychiatry, 1997, 42 (12): 1181-1183.
[36] Ferraro L, Antonelli T, Tanganelli S, et al. The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade[J]. Neuropsychopharmacology, 1999, 20 (4): 346-356.
[37] Ferraro L, Antonelli T, O'Connor WT, et al. The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission[J]. Neurosci Lett, 1998, 253 (2): 135-138.
[38] Perez de la Mora M, Aguilar-Garcia A, Ramon-Frias T, et al. Effects of the vigilance promoting drug modafinil on the synthesis of GABA and glutamate in slices of rat hypothalamus[J]. Neurosci Lett, 1999, 259 (3): 181-185.
[39] Madras BK, Xie Z, Lin Z, et al. Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro[J]. J Pharmacol Exp Ther, 2006, 319 (2): 561-569.
[40] Gallopin T, Luppi PH, Rambert FA, et al. Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study[J]. Sleep, 2004, 27 (1): 19-25.
[41] de Saint Hilaire Z, Orosco M, Rouch C, et al. Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats[J]. Neuroreport, 2001, 12 (16): 3533-3537.
[42] Duteil J, Rambert FA, Pessonnier J, et al. Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals[J]. Eur J Pharmacol, 1990, 180 (1): 49-58.
[43] Hermant JF, Rambert FA, Duteil J. Awakening properties of modafinil: effect on nocturnal activity in monkeys (Macaca mulatta) after acute and repeated administration[J]. Psychopharmacology (Berl), 1991, 103 (1): 28-32.
[44] Chen CR, Qu WM, Qiu MH, et al. Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic alpha1 and histaminergic H1 receptors in mice[J]. Neuropharmacology, 2007, 53 (4): 534-541.
[45] Wisor JP, Eriksson KS. Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil[J]. Neuroscience, 2005, 132 (4): 1027-1034.
[46] Estabrooke IV, McCarthy MT, Ko E, et al. Fos expression in orexin neurons varies with behavioral state[J]. J Neurosci, 2001, 21 (5): 1656-1662.
[47] Willie JT, Renthal W, Chemelli RM, et al. Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates[J]. Neuroscience, 2005, 130 (4): 983-995.
[48] Eriksson KS, Sergeeva O, Brown RE, et al. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus[J]. J Neurosci, 2001, 21 (23): 9273-9279.
[49] Chu M, Huang ZL, Qu WM, et al. Extracellular histamine level in the frontal cortex is positively correlated with the amount of wakefulness in rats[J]. Neurosci Res, 2004, 49 (4): 417-420.
[50] Huang ZL, Mochizuki T, Qu WM, et al. Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice[J]. Proc Natl Acad Sci U S A, 2006, 103 (12): 4687-4692.
[51] Ishizuka T, Sakamoto Y, Sakurai T, et al. Modafinil increases histamine release in the anterior hypothalamus of rats[J]. Neurosci Lett, 2003, 339 (2): 143-146.
[52] Parmentier R, Anaclet C, Guhennec C, et al. The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders[J]. Biochem Parmacol, 2007, 73 (8): 1157-1171.