Biogenic Amines and the States of Sleep
Michel Jouvet
Science 163 (862) pages : 32-41 (1969)


The Four Major Concepts

Biogenic Amines and the Sleep States

Insomnia Following Selective Decrease of Cerebral Serotonin

The Problem of Paradoxical Sleep



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Biogenic Amines and the Sleep States

Due to a lack of adequate techniques, it is only very recently that a neuro pharmacological study of sleep has been successfully carried out. It was not until the technique of making continuous long-term electroencephalographic recordings had been perfected and suitable pharmacological techniques had been developed that this field was adequately explored. The fact that the monoamines themselves (serotonin and noradrenalin) do not cross the mammalian blood brain barrier presented a major technical difflculty. In birds, whose blood brain barrier is permeable, intravenous injection of serotonin or noradrenalin leads to slow-wave sleep, as indicated by hehavior and by electroencephalographic recording (25). Attempts to by pass this barrier in mammals through local application or through injection of serotonin into the brain have led, also, to an increase of cortical synchronization in short-term experiments (26). Injection into the ventricles has given questionable results (27). The use of precursors of these amines which readily cross the blood-brain barrier has been a step forward. The increase of cerebral serotonin (through intravenous or intraperitoneal injection of its precursor 5-hydroxytryptophan (5 HTP)) leads first to a state which resembles slow-wave sleep (28). However, this drug leads to a suppression of paradoxical sleep for 5 to 6 hours; the suppression is followed by a secondary rebound (29) The injection of dihydroxyphenylalanine (DOPA), which is a precursor of both dopamine (DA) and noradrenalin, produces an increase in waking (30, 31), whereas the injection of dihydroxyphenylserine, which is be lieved to be a direct precursor of noradrenalin (32), increases slow-wave sleep and paradoxical sleep (33). More recently it has been demonstrated that numerous drugs known to act on the concentrations of monoamines in the brain act in a rather predictable way on the sleep states. Producing a decrease in serotonin and noradrenalin, reserpine (0.5 milligram per kilogram in the cat), although inducing a "state of tranquility" (34), suppresses the appearance of slow-wave sleep for 12 hours and of paradoxical sleep for about 24 hours, whereas it triggers continuous PGO waves similar to those of paradoxical sleep. Secondary injection of 5-hydroxytryptophan, which restores a normal brain concentration of serotonin, results in the immediate reappearance of electroencephalographic patterns of slow wave sleep, whereas the injection of di hydroxyphenylalanine, which restores the catecholamine concentration following the administration of reserpine, leads to the reappearance of paradoxical sleep. Thus there was an implication that serotonin may be involved in slow wave sleep whereas the catecholamines rnay be involved in paradoxical sleep (30, 35). Monoamine oxidase (MAO) inhibitors (nialamide, iproniazid, phenylisopropylhydrazide), which act upon both brain monoamines by inhibiting their catalolism and by thus increasing their concentration in the brain, were shown to act dramatically upon sleep states. Most of the monoamine oxidase inhibitors utilized have a very specific suppressive effect upon paradoxical sleep and increase slow-wave sleep in the cat. This suppressive effect is so intense that it is even operative when the "need" for paradoxical sleep is greatly enhanced following paradoxical sleep deprivation (30, 36). This suggests that monoamine oxidase is necessary to the passage from slow-wave sleep to paradoxical sleep. These findings were of only limited significance in view of the enormous complexity of the biochemical mechanism of the brain. Most of these drugs were acting upon both indoleamines and catecholamines and therefore might very well be inter fering with the cyclic alteration of the brain's electrical activity.

More recently, however, some drugs that act selectively upon serotonin or catecholamines have been discovered. The most interesting ones for the neurophysiologist are those which inhibit the synthesis of monoamines (p-chlorophenylalanine for serotonin; alpha-methylparatyrosine for dopamine and noradrenalin, or disulfiram for noradrenalin). It is thus possible to alter selectively the metabolism of one monoamine in the study of the sleep states.

Other major steps came at this time, which permitted a more rigorous way of thinking by closing the gap between neuropharmacology, neuroanatomy, and neurophysiology. Indeed, histofluorescence techniques have made possible the precise topographical study of nerve cells containing monoamines (37). It was demonstrated that the serotonin containing neurons were located mostly in the raphe system (37, 38), the noradrenalin-containing neurons in the lateral part of the bulbopontine tegmentum (principally in the locus coeruleus), and the dopamine-containing neurons in the ventral part of the mesencephalon (37).

It was shown that the cell bodies of the monoamine-containing neurons send terminals to widespread regions of the spinal cord and brain, of which the ascending pathways, either mono- or polysynaptic, follow the medial forebrain bundle (37, 39). Moreover, it was shown that sectioning of the axons would suppress specific fluorescence of the corresponding terminals after 8 to 10 days (37). This finding made it possible to attack specific groups of monoamine containing neurons by classical neurophysiological techniques and to correlate such destruction with biochemical analysis, a critical period of time being allowed between destruction of the nerve cells and death of the animal (40).

Thus it was possible to alter the concentrations of monoamines in the brain either by inhibiting their synthesis or by destroying monoamine-containing nerve cells.

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  • 1- G Moruzzi and H. W. Magoun
    Electroencephalog. Clin. Neurophysiol. 1, 445 (1949).
  • 2 - F. Bremer
    in Brain Mechanisms and Consciousness, E. D. Adrian, F. Bremer, H. H. Jasper, Eds. (Blackwell, Oxford, 1954), pp. 137-162; F. Bremer, Schweiz. Arch. Neurol. Neurochir. Psychiat. 86, 34 (1960); N. Kleitman, Sleep and Wakefulness (Univ. of Chicago Press, Chicago, 1963); D. B. Lindsley, in Handbook of Physiology and Neurophysiology, J. Field H. W. Magoun, V. E. Hall, Eds.(American Physiological Society, Washington, 20 D.C., 1960), vol. 1, p. 1553; for the historical development of the passive hypothesis of sleep, see G. Moruzzi, Proc. Amer. Phil. Soc. 108, 19 (1964).
  • 3- See P. L. Parmeggiani
    in Progress in Brain Research, Topics in Basic Neurology, W. Batgmann and J. L. Schadé, Eds. (Elsevier, Amsterdam, 1964), references pp. 180-190.
  • 4 - The mean percentages of slow-wave sleep and paradoxical sleep in the adult cat are, respectively, 53 and 16 percent of a 24-hour day; the mean duration of paradoxical-sleep episodes is 6 minutes. See F. Delorme, P. Vimont, D. Jouvet, Compt. Rend. Soc. Biol. 158, 2128 (1964); M. B. Sterman, T. Knauss, D.Lehmann, C. D. Clemente Electroencephalog. Clin. Neurophysiol. 19, 509 (1965).
  • 5 - C. Batini, G. Moruzzi, M. Palestini, G. F Rossi, A. Zanchetti
    Science 128, 30 (1958); C Batini F Magni, M. Palestini G F. Rossi A. Zanchetti, Arch. Ital. Biol. 97,13 (1959).
  • 6 - M. Bonvallet and V. Bloch
    Science 133, 1133 (1961);G. F Rossi, K. Minobe, O Candia Arch. Ital. Biol. 101, 470 (1963)- A. Camacho Evangelista and F. Reinoso-Suarez, Science 146, 268 (1964); G. Moruzzi, Harvey Lectures Ser. 58, 233 (1963); , Electroencephalog. Clin. Neurophysiol. 16, 2 (1964).
  • 7 - F. Fontana
    Dei moti pell'iride (Giusti, Lucca, 1765); R. Klaue, J. Psychol. Neurol. Leipzig 47, 510 (1937).
  • 8 - E. Aserinsky and N. Kleitman
    J. Appl. Physiol. 8, 1 (1955); W, C. Dement and N. Kleitman, Electroencephalog. Clin. Neurophysiol. 9, 673 (1957); W. C. Dement, ibid. 10, 291 (1958), M. Jouvet, F. Michel, J. Courjon, Compt. Rend. Soc. Biol. 153, 101 (1959).
  • 9 - F. Snyder
    Amer. J. Psychiat. 122, 377 (1965); W. C. Dement, in New Directions in Psychology, T, M. Newcomb, Ed (Holt, Rinehart, and Winston, New York, 1965), vol. 2, p. 135; M. Jouvet Physiol. Rev. 47, 117 (1967); W. P. Koella Sleep (Thomas, Springffeld, ID.,1967 ); E. Hartmann, The Biology of Dreaming (Thomas, Springfield, 111., 1967).
  • 10 - Slow-wave sleep is also called light sleep,deep sleep, synchronized sleep, and non-rapid eye-movement sleep.
  • 11 - Paradoxical sleep is also called activated sleep, deep sleep, desynchronized sleep, rapid eye-moyement or REM sleep, para sleep, and rhombencephalic sleep. Since dreaming occurs almost exclusively during this sleep state, it is also called dreaming sleep or D-state.
  • 12 - M. Jeannerod J. Mouret M. Jouvet
    J. Physiol. Paris 57, 255 (1965); F. Michel, M. Jeannerod, J. Mouret, A. Rechstchaffen, M. Jouvet Compt. Rend. Soc. Biol. 158, 103 (1964;- J. Mouret, M. Jeannerod, M. Jouvet, J. Physiol. Paris 55, 305 (1963); M. Jeannerod, thesis. University of Lyons (1965).
  • 13 - D. C. Brooks and E. Bizzi
    Arch. Ital. Biol. 101, 648 (1963); D. C. Brooks, paper presented before the Association for the Psychophysiological Study of Sleep, Denver, 1968.
  • 14 - D. Peyrethon-Duzan, J. Peyrethon, M. Jouvet
    Comp. Rend. Soc. Biol. 161, 2530 (1967).
  • 15 - E. Bizzi and D, C. Brooks
    Arch. Ital. Biol. 101, 666 (1963), O. Benoit J. Physiol. Paris 56, 259 (1964); O, Pompeiano and A. R. Morrison, Arch. Ital. Biol. 103, 569 (1965); M. Jouvet, M. Jeannerod, J. F. Delorme, Compt. Rend. Soc. Biol. 159, 1599 (1965).
  • 16 - J. L. Valatx, D. Jouvet, M. Jouvet
    Electroencephalog. Clin. Neurophysiol. 17, 218 (1964); J. Cadilhac, T. Passouant-Fontaine, P. Passouant, J. Physiol. Paris 54, 305 (1962); D. Jouvet-Mounier, thesis University of Lyons 1968); and L. Astic, Compt. Rend. Soc. Biol. 156, 1411 (1967); A. Shimizu and H. E. Him wich, Electroencephalog. Clin. Neurophysiol. 24, 307 (1968) H. P. Roffwarg, J. N. Muzio, W. C. Dement Science 152, 604 (1966).
  • 17 - J. Peyrethon and D. Peyrethon-Duzan
    Compt. Rend. Soc. Biol. 161, 2533 (1967).
  • 18 - H. Hermann, M. Jouvet, M. Klein
    Compt. Rend. 258, 2175 (1964); E. S. Tauber, H. P Roffwarg, E. D. Weitzman, Nature 212, 1612 (1966)- A. Rechtschaffen, M. Bassan, S. Ledecky-Tanecek, paper presented before the Association for the Psychophysiological Study of Sleep, Denver, 1968.
  • 19 - M. Klein F. Michel, M. Jouvet
    Compt. Rend. Soc. Biol. 158, 99 (1964); T. Ookawa and J. Gotoh, Poultry Sci., 43, 1603 (1964); V. Tradardi, Arch. Ital. Biol. 104, 516 (1966; M. A. Corner, J. J, Peters, P. Rutgers van der Loeff, Brain Res, 2, 274 (1966).
  • 20 - F Snyder
    Amer. J. Psychiat. 123 121 (1966).
  • 21 - E. Hartmann, J. Bernstein, C. Wilson
    Psychophysiology 4, 389 (1968).
  • 22 - P. Albrecht, M. B. Vissher, J. J. Bittner, F. Halberg
    Proc. Soc. Exp. Biol. 92, 703 (1956); L. E. Scheving, W. H. Harrison, P. Gordon,J. E. Pauly, Amer. J. Physiol. 214, 166 (1968) .
  • 23 - F. O. Schmitt
    in Macro-molecular Specificity and Biological Memory, F. O. Schmitt,Ed. (M.l.T. Press, Cambridge, 1962).
  • 24 - W. Dement
    Science 131, 1705 (1960); D. Jouvet, P. Vimont, F. Delorme, M. Jouvet, Compt. Rend. Soc. Biol. 158, 756 (1964); P. Vimont, D. Jouvet, J. F. Delorme, Electroencephalog. Clin. Neurophysiol. 20, 439 (1966); W. C. Dement, P, Henry, H. Cohen, J. Ferguson, Sleep and Altered States of Consciousness, S. S. Kety E. V. Evarts, H. L. Williams, Eds. (Williams and Wilkins, Baltimore,1967) .
  • 25 - C. E. Spooner and W. D. Winters
    Experientia 21, 256 (1965); In. J. Neuropharmacol. 5, 217 (1966); ibid. 6, 109 (1967).
  • 26 - W. P. Koella C. M. Trunca, J. S. Szicman
    Life Sci. 4, 1;3 (1965); W. P. Koella and J.S. Czicman, Amer. J. Physiol. 211, 926 (1966); I X. Lebedur and R. Tissot, Electroencephalog. Clin. Neurophysiol. 20 (1965).
  • 27 - W. Feldberg and S. L. Sherwood
    J. Physiol. London 123, 148 (1954)- P. B. Bradley and A. J. Hance, ibid. 132, 50 (1956); E. R. John, B. M. Wenzel, R. D. Tschirgi, J. Pharmacol. Exp.Therap. 123, 193 (1958).
  • 28 - D. F. Bogdanski, H. Weissbach, S. Udenfriend
    J. Pharmacol. Exp. Therap. 122, 182 (1958); M. Monnier and R. Tissot, Helv. Physiol. Pharmacol. Acta 16 255 (1958); E. Costa, G. R. Pscheidt, W. G. van Meter, H.E. Himwich, J. Pharmacol. Exp. Therap. 130,81 (1960).
  • 29 - F. Delorme
    thesis, University of Lyons (1966).
  • 30 - M. Jouvet
    in Sleep and Alrered States of Consciousness, S, S. Kety, E. V. Evarts, H. L. Williams, Eds. (Williams and Wilkins, Baltimore, 1967),
  • 31 - B. J. Key and E. Marley
    Electroencephalog. Clin. Neurophysiol. 14, 90 (1962); C. E. Spooner and W. D. Winters, Int. J. Neuropharmacol. 6, 109 (1967); M. Momnier and R. Tissot, Helv. Physiol. Pharmacol. Acta 16,255 (1958).
  • 32 - H. Blaschko, K. H. Burn, H. Langemann
    Brit. J. Pharmacol. 5, 431 (1950).
  • 33 - V. Havlicek
    Int. J. Neuropharmacol. 6, 83 (1967) .
  • 34 - The state of "tranquility" produced by reserpine led to the hypothesis that serotonin could be involved in parasympathetic (trophotropic) mechanisms of sleep; see B. A. Brodie. P. A. Shore, A. Pletscher, Science 123, 993 (1956), B. A. Brodie, K. F. Finger, F.B. Orlans, G. P. Quinn, F. Sulser, J. Pharmacol. Exp. Therap. 129, 250 (1960).
  • 35 - J. Matsumoto and M. Jouvet
    Compt. Rend. Soc. Biol. 158, 2135 (1964) F. Delorme, M. Jeannerod, M. Jouvet, ibid. 159, 900 (1965).
  • 36 - M. Jouvet, P. Vimont, J. F. Delorme
    ibid p. 1595.
  • 37 - B. Falck
    in Progress in Brain Research, H.G. Himwich, Ed. (Elsevier, Amsterdam, 1964), p. 28- B. Falck N. A. Hillarp, G. Thieme, A Torp, J. Histochem. Cytochem. 10, 348 (1962); A. Dahlstrom and K. Fuxe, Acta Physiol. Scand. Suppl. 232, 1 (1964); ibid. 247, 5 (1965); K. Fuxe, Z. Zelforsch.Mikroskop. Anat. Abt. Histochemie 65, 573 ( 1965 ) .
  • 38 - A. Brodal E. Taber, F. Walberg
    J. Comp. Neurol., 239 (1960).
  • 39 - A. Heller and R. Y. Moore
    J. Pharmacol. Exp. Therap. 150 1 (1965), J. A. Harvey, A. Heller, R. Y. Moore, ibid. 140, 103 (1963); A. Heller, J. A. Haney, R. Y. Moore, Biochem. Pharmacol. 11, 859 (1962).
  • 40 - It is not surprising that, if this procedure is not followed, attempts to correlate serotonin concentrations in rostral parts of the brain with the electrical activity of the cortex after eitber midpontine transection (which leads to fast, low-voltage activity) or rostropontine transection (which leads to synchronized acticity) have produced negative results in short term experiments (R. A. Antonelll, G. Bertac cini, P. Mantegazzini, J. Neurochem. 8, 157 (1961))
  • 41 - K. B. Koe and A. Weissman
    J. Pharmacol. Exp. Therap, 154, 499 ( 1967 ) .
  • 42 - F. Delorme, L. Froment, M. Jouvet
    Compt. Rend. Soc. Biol. 160, 2347 (1966); J. Mouret, J. L. Froment, P. Bobillier, M. Jouvet, J. Physiol. Paris 59, 463 (1967). p-Chloromethamphetamin has been shown to produce a selective decrease of serotonin [A. Pletscher, G.Bartholini, H. Bruderer, W. P. Burkard, K. F. Gey, J. Pharmacol. 145, 344 (1964)]. Also, my associates and I found that this drug induces a very marked arousal which coincides with the depletion of brain serotonin. However, a secondary injection of 5-hydroxytryptophan does not restore normal sleep and has always been followed shonly by the death of the animal.
  • 43 - W. P. Koella
    paper presented before the American College of Neuropsychopharmacology, Puerto Rico, 1967.
  • 44 - J. Mouret, P, Bobillier, M. Jouvet
    Compt. Rend. Soc. Biol. 161, 1600 (1967); J. Mouret, P. Bobillier N, Frachon, A. Vilpulla, M. Jouvet European J. Pharmacol., in press; C. Torda Brain Res. 6, 375 (1967).
  • 45 - T. J Crowley, E. Smith, 0. F. Lewis
    paper presented before the Association for Psychophysiological Study of Sleep, Denver, 1968; E. D, Weitzman, M. Rapport, P. McGregor, J. Jacoby, Science 160, 1361 (1968).
  • 46 M. Jouvet and J. Renault
    Compt Rend. Soc. Biol. 160, 1461 (1966); M. Jouvet, P. Bobillier, J F. Pujol, J. Renault, ibid., p. 2343; M. Jouvet, in Advances in Pharmacology, S. Garattini and P. A. Shore, Eds. (Academic Press, New York, 1968 ); J, Renault, thesis, University of Lyons (1967).
  • 47 - These results may explain the relative insomnia following mid-pontine transections (4), since destruction of the raphe system caudal to this plane would produce the same amount of sleep (20 percent). The insomnia that follows surgical splitting of the brain stem may also be explained by these results as this procedure (sagittal transection) inevitably involves the destruction of numerous raphe neurons [F. Michel and M. P. Roffwarg, Experientia 23, 126 (1967); M. Mancia, T. Desiraju, G. S. Chhina, Electroencephalog. Clin. Neurophysiol. 24, 409 (1968)].
  • 48 - E. Hartmann and D. Freedman
    paper presented before the Association for the Psychophysiological Study of Sleep, Gainesvflle,Florida 1966- E. L. Bliss, in Sleep and Altered States of Consciousness, S. S. Kety, E.V. Evarts, H. L. Williams, Eds. (Williams and Wilkins, Baltimore, 1967).
  • 49 - E. Weiss, B. Bordwell, M, Seeger, J. Lee, W. C. Dement, J. Barchas
    paper presented before the Association for Psychophysiological Study of Sleep, Denver, 1968.
  • 50 - M. Jouvet
    Arch. Ital. Biol. 100, 125 (1962).
  • 51 - G Carli and A. Zanchett
    ibid. 103, 751 (1965)- G. Rossi Electroencephalog. Clin. Neurophysiol. 14, 428 (1962).
  • 52 - P. H. Hashimoto, T. Maeda, K, Toru, N.Shimizu
    Med. J. Osaka Univ. 12, 425 (1962).
  • 53 - J. Mouret, N. Frachon, A. Vilpulla, M. Jouvet
    Compt. Rend. Soc. Biol., in press.
  • 54 - M. Jouvet and F. Delorme
    ibid. 159, 895 (1965).
  • 55 - B. Roussel
    thesis, University of Lyons, (1967); A Buguet, P. Bobillier M. Jouvet Compt. Rend. Soc. Biol. 161, 2537 (1967).
  • 56 - It is interesting to note that, through administration for 6 to 12 weeks of synthetic diet free of phenylalanine and tyrosine (the aminoacids that are precursors of dopamine and noradrenalin) to patients with inoperable cancer, a systematic and selective decline of paradoxical sleep was obtained which was immediately reversed when tyrosine was there after added to the diet (H. L. Williams, B. K. Lester, J. D. Coulter, paper read before the Association for Psychophysiological Study of Sleep, Denver, 1968).
  • 57 - E. D. Weitzman, P. McGregor, C. Moore, J. Jacoby
    paper presented before the Association for Psychophysiological Study of Sleep, Denver, 1968; T. J. Crowley, E. S. Smith, O. F. Lewis, ibid.
  • 58 - S. Spector, A. Sjoerdsma, S. Udenfriend
    J. Pharmacol 147, 86 (1965).
  • 59 - J. L. Froment, D. Peyrethon-Duzan, M. Jouvet
    Compt. Rend. Soc. Biol., in press.
  • 60 - M. Goldstein, B. Anagnoste, E. Lauber, M.R. McKereghare
    Life Sci. Oxford 3, 763 (1964) .
  • 61 - A. Carlsson
    in Biogenic Amines, H. E. Himwich and W. A. Himwich Eds. (Elsevier Amsterdam, ]964), pp. 9-2;.
  • 62 - D. Peyrethon-Duzan, J Peyrethon, M. Jouvet
    Compt. Rend. Soc. Biol. IC2, 116 (1968).
  • 63 - J. F. Pujol, J. Mouret, M. Jouvet, J. Glowinski
    Science 159 112 (1968).
  • 64 - T. Tokizane
    in Progress in Brain Research, T. Tokizane and J. P. Schade, Eds. (Elsevier, Amsterdam, 1966).
  • 65 - N. Khazan and C. H. Sawyer
    Psychopharmacologia 5, 457 (1964).
  • 66 - R. George, W. L. Haslett, D. J. Jenden
    Int. J. Neuropharmacol. 3, 541 (1964).
  • 67 - J. H. Burn and M. J. Rand.
    J. Rev. Pharmacol. 5, 163 (1965).
  • 68 - This and our related studies are supported by a grant from the Direction des Recherches et Moyens d'Essais, l'Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, and a grant (E.O.A.R. 62-67) from the European Office of Aerospace Research. I thank B. E. Jones for invaluable assistance in editing the English version of this article.