Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG
- First Online:
- 174 Downloads
Modafinil is a wake-promoting agent that affects hypothalamic structures involved in the homeostatic and circadian regulation of vigilance. Administered during sleep deprivation, it reduces the need for prolonged recovery sleep and decreases the rebound in EEG slow-wave activity. These diachronic effects suggest an action of modafinil on a homeostatic sleep regulatory process.
The aim of this study was to determine whether modafinil, in comparison to the d-amphetamine reference psychostimulant and to placebo, interferes with the vigilance regulatory processes reflected in the EEG during waking.
Thirty-three healthy subjects were investigated during 60 h of sustained wakefulness in a double-blind placebo-controlled parallel-design study. A 4-min maintenance-of-wakefulness test administered hourly allowed the concomitant assessment of alertness and waking EEG activity. The effects of equipotent psychostimulant dosages (modafinil 300 mg and d-amphetamine 20 mg) were evaluated at the beginning of the first sleep deprivation night, at the end of the second sleep deprivation night and in the afternoon preceding the first recovery night.
One hour following ingestion, both psychostimulants increased alertness during 10–12 h, independently of the time of administration. At the level of the waking EEG, d-amphetamine attenuated the natural circadian rhythm of the different frequency bands and suppressed the sleep deprivation-related increase in low frequency (0.5–7 Hz) powers. In contrast, modafinil, which exhibited a transient amphetamine-like effect, had slight effect on circadian rhythms. Its selective action was characterized by maintenance of the α1 (8.5–11.5 Hz) EEG power, which under placebo exhibited a homeostatic decrease paralleling that of alertness with a circadian trough at night.
These findings demonstrate that the alertness-promoting effects of modafinil and d-amphetamine involve distinct EEG activities and do not reside on the same vigilance regulatory processes. While d-amphetamine inhibits the expression of a sleep-related process, probably through a direct cortical activation masking EEG circadian rhythms, modafinil, through a synchronic effect, preferentially disrupts the homeostatic down-regulation of a waking drive.
KeywordsAlertness Circadian rhythm Homeostasis Sleep deprivation Psychostimulant Waking EEG
- Angus RG, Pigeau RA, Heslegrave RJ (1992) Sustained operations studies: from the field to the laboratory. In: Stampi C (ed) Why we nap. Birkhauser, BostonGoogle Scholar
- Broughton RJ, Fleming JA, George CF, Hill JD, Kryger MH, Moldofsky H, Montplaisir JY, Morehouse RL, Moscovitch A, Murphy WF (1997) Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 49:444–451PubMedGoogle Scholar
- Cooley JW, Tuckey JW (1965) An algorithm for the machine calculation of complex Fourier series. Math Comp 19:297–301Google Scholar
- Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K (1996) 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. Neurosci Lett 220:5–8PubMedGoogle Scholar
- Ferraro L, Antonelli T, Tanganelli S, O'Connor WT, Perez de la Mora M, Mendez-Franco J, Rambert F, Fuxe K (1999) 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. Neuropsychopharmacology 20:346–356CrossRefPubMedGoogle Scholar
- Krueger JM, Obal FJ, Fang J (1999) Why we sleep: a theoretical view of sleep function. Sleep Med Rev 3:119–129Google Scholar
- Laboratoire Lafon L (1997) Modiodal, modafinil. Dossier d'information médicale et pharmaceutique. Laboratoire L. Lafon, Maison-Alfort, FranceGoogle Scholar
- Lin JS, Hou Y, Jouvet M (1996) Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci USA 93:14128–14133Google Scholar
- Matejcek M (1982) Vigilance and the EEG: psychological, physiological and pharmacological aspects. Electroencephalography in drug research. Fischer, Stuttgart New York, pp 405–440Google Scholar
- Mitler MM, Gujavarty KS, Browman CP (1982) Maintenance of wakefulness test : a polysomnographic technique for evaluating treatment efficacy in patients with excessive somnolence. Electroencephalogr Clin Neurophysiol 53:658–661Google Scholar
- Nishino S, Mao J, Sampahkumaran R, Shelton J, Mignot E (1998) Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res Online 49:49–61Google Scholar
- Rechtschaffen A, Kales A (1968) A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. US Government Printing Office, Washington D.C., USAGoogle Scholar
- Saletu B, Grunberger J, Linzmayer K, Stohr H (1986) Pharmaco-EEG, psychometric and plasma levels studies with two novel alpha-adrenergic stimulants CRL 40476 and 40028 (adrafinil) in elderlies. In: Pancheri P (ed) News trends in experimental and clinical psychiatry, Rome, p 5631Google Scholar
- Saletu B, Barbanoj MJ, Anderer P, Sieghart W, Grunberger J (1993a) Clinical-pharmacological study with two isomers (d-, l-) of fenfluramine and its comparison with chlorpromazine and d-amphetamine: blood levels, EEG mapping and safety evaluation. Meth Find Exp Clin Pharmacol 15:291–312Google Scholar
- Stampi C, Stone P, Michimori A (1993) The alpha attenuation test: a new quantitative method for assessing sleepiness and its relationship to the MSLT. J Sleep Res 22:115Google Scholar
- Warot D, Corruble E, Payan C, Weil JS, Puech AJ (1993) Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur J Psychiatry 8:201–208Google Scholar
- Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ (2002) Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology 159:238–247Google Scholar