The Neuropharmacology of Serotonin and Sleep: an Evaluation

  • John D. Fernstrom
  • Ross H. Pastel


Depression is often associated with disruption of the normal sleep cycle. In particular, though patients frequently show disturbances in sleep continuity and a reduction in slow wave sleep, the most commonly observed effects are a shortened latency to the first episode of rapid eye movement (REM) sleep after sleep onset (i.e., a reduced REM latency), and an increase in REM density in the first REM periods during the night (Kupfer, 1982). The administration of antidepressant drugs typically suppresses most measures of REM sleep (see Kupfer, 1982), and it is an issue of general interest whether there is a connection between the pharmacologies of REM suppression and of antidepressant treatment. Several of the antidepressants in past, current, and experimental use are active at serotonin (5HT) synapses. The antidepressant action of such drugs is commonly thought to be associated with their ability to enhance transmission across 5HT synapses (see Willner, 1985). If this is the case and if there is a connection between a drug’s effects on sleep and depression, then these agents should have predictable actions on sleep, as should other drugs that affect 5HT synaptic function. The purpose of this review is to evaluate this latter proposition. To this end, a discussion is presented of the effects that each of several classes of agents that modify 5HT transmission has on sleep in mammals. These are broadly classed as agents that decrease or increase synaptic transmission.


NREM Sleep NREM Sleep Time Cortical Slow Wave 
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Further Reading

  1. Aghajanian GK, Asher IH (1971): Histochemical fluorescence of raphe neurons: selective enhancement by tryptophan. Science 172:1159–1161PubMedCrossRefGoogle Scholar
  2. Aghajanian GK, Wang RY (1978): Physiology and pharmacology of central serotonergic neurons. In: Psychopharmacology: A Generation of Progress, Lipton MA, DiMascio A, Killam KF, eds. New York: Raven Press, pp. 171–183Google Scholar
  3. Arnold MA, Fernstrom JD (1981): L-tryptophan injection enhances pulsatile growth hormone secretion in the rat. Endocrinology 108:331–335PubMedCrossRefGoogle Scholar
  4. Autret A, Minz M, Bussel B, Cathala HP, Castaigne P (1976): Human sleep and 5-HTP. Effects of repeated high doses and of association with benserazide (RO.04.4602). Electroencephalogr Clin Neurophysiol 41:408–413PubMedCrossRefGoogle Scholar
  5. Bjorklund A, Baumgarten HG, Nobin A (1974): Chemical lesioning of central monoamine axons by means of 5,6-dihydroxytryptamine and 5,7-dihydroxytryptamine. In: Advances in Biochemical Psychopharmacology, Volume 10, Costa E, Gessa GL, Sandler M, eds. New York: Raven Press, pp. 13–33Google Scholar
  6. Borbely AA, Steigrad P, Tobler I (1980): Effect of sleep deprivation on brain serotonin in the rat. Behav Brain Res 1:205–210PubMedCrossRefGoogle Scholar
  7. Brown CC, Horrom NJ, Wagman AM (1979): Effects of L-tryptophan on sleep onset insomniacs. Waking Sleeping 3:101–108PubMedGoogle Scholar
  8. Dement WC, Mitler MM, Henriksen SJ (1972): Sleep changes during chronic administration of parachlorophenylalanine. Rev Can Biol 31:239–246PubMedGoogle Scholar
  9. Fernstrom JD (1983): The role of precursor availability in the control of monoamine biosynthesis in the brain. Physiol Rev 63:484–546PubMedGoogle Scholar
  10. Fornai C, Radulovacki M (1981): Sleep suppressant action of quipazine: relation to central serotonergic stimulation. Pharmacol Biochem Behav 15:937–944CrossRefGoogle Scholar
  11. Fornai C, Radulovacki M (1982): Methysergide blocks the sleep suppressant action of quipazine in rats. Psychopharmacology 76:255–259CrossRefGoogle Scholar
  12. Fornai C, Radulovacki M (1983a): Sleep suppressant action of fenfluramine in rats. I. Relation to postsynaptic serotonergic stimulation. J Pharmacol Exp Ther 225:667–674Google Scholar
  13. Fornai C, Radulovacki M (1983b): Sleep suppressant action of fenfluramine in rats. H. Evidence against the involvement of presynaptic serotonergic mechanism. J Pharmacol Exp Ther 225:675–681Google Scholar
  14. Fuxe K, Kiianmaa K (1978): 5-hydroxytryptamine neurons and the sleepwakefulness cycle. Effects of metergoline and zimelidine. Neurosci Lett 8:55–58Google Scholar
  15. Gallager DW, Aghajanian GK (1976): Inhibition of firing of raphe neurones by tryptophan and 5-hydroxytryptophan: blockade by inhibiting serotonin synthesis with RO4–4602. Neuropharmacology 15:149–156PubMedCrossRefGoogle Scholar
  16. Griffiths WJ, Lester BK, Coulter JD, Williams HL (1972): Tryptophan and sleep in young adults. Psychophysiobgy 9:345–356CrossRefGoogle Scholar
  17. Hartmann E (1982/83): Effects of L-tryptophan on sleepiness and on sleep. J Psychiatr Res 17:107–113PubMedCrossRefGoogle Scholar
  18. Hartmann E, Chung R (1972): Sleep-inducing effects of L-tryptophan. J Pharm Pharmacol 24:252–253PubMedCrossRefGoogle Scholar
  19. Hartmann E, Chung R, Chien CP (1971): L-Tryptophane and sleep. Psychopharmacologia 19:114–127PubMedCrossRefGoogle Scholar
  20. Hartmann E, Spinweber CL (1979): Sleep induced by L-tryptophan. Effect of dosages within the normal dietary intake. J Nerve Ment Dis 167:497–499CrossRefGoogle Scholar
  21. Heel RC, Morley PA, Brogden RN, Carmine AA, Speight TM, Avery GS (1982): Zimelidine: a review of its pharmacological properties and therapeutic efficacy in depressive illness. Drugs 24:169–206PubMedCrossRefGoogle Scholar
  22. Hery F, Pujol JF, Lopez M, Macon J, Glowinski J (1970): Increased synthesis and utilization of serotonin in the central nervous system of the rat during paradoxical sleep deprivation. Brain Res 21:391–403PubMedCrossRefGoogle Scholar
  23. Hill SY, Reyes RB (1978): Effects of L-tryptophan and ethanol on sleep parameters in the rat. Psychopharmacoiogy 58:229–233CrossRefGoogle Scholar
  24. Hyttel J (1982): Citalopram-pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuropsychopharmacol Biol Psychiatry 6:277–295PubMedCrossRefGoogle Scholar
  25. Johnson DN, Funderburk WH, Ward JW (1971): Effects of fenfluramine on sleepwakefulness in cats. Psychopharmacologia 20:1–9PubMedCrossRefGoogle Scholar
  26. Johnson DN, Funderburk WH, Ruckart RT, Ward JW (1972): Contrasting effects of two 5-hydroxytryptamine-depleting drugs on sleep patterns in cats. Eur J Pharmacol 20:80–84PubMedCrossRefGoogle Scholar
  27. Jouvet M (1969): Biogenic amines and the states of sleep. Science 163:32–41PubMedCrossRefGoogle Scholar
  28. Jouvet M (1972): The role of monoamines and acetylcholine-containing neurons in the regulation of the sleep-waking cycle. Ergebn Physiol 64:166–307PubMedGoogle Scholar
  29. Kafide St Hilaire S, Merica H, Gaillard JM (1984): The effects of indalpine — a selective inhibitor of 5-HT uptake — on rat paradoxical sleep. Eur J Pharmacol 98:413–418CrossRefGoogle Scholar
  30. Kaufman LS (1983): Parachlorophenylalanine does not affect pontinegeniculateoccipital waves in rats despite significant effects on other sleep-waking parameters. Exp Neurol 80:410–417PubMedCrossRefGoogle Scholar
  31. Kiianmaa K, Fuxe K (1977): The effects of 5,7-dihydroxytryptamine-induced lesions of the ascending 5-hydroxytryptamine pathways on the sleep-wakefulness cycle. Brain Res 131:287–301PubMedCrossRefGoogle Scholar
  32. Koe BK, Weissman A (1966): p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–516Google Scholar
  33. Koella WP, Feldstein A, Czicman JS (1968): The effect of para-chlorophenylalanine on the sleep of cats. Electroencephalogr Clin Neurophysiol 25:481–490PubMedCrossRefGoogle Scholar
  34. Kupfer D (1982): Interaction of EEG sleep, antidepressants, and affective disease. J Clin Psychiatry 43:30–35PubMedGoogle Scholar
  35. Laguzzi RF (1982): Effects of serotonin synthesis inhibition on sleep in hippocampectomized rats. Brain Res 240:175–177PubMedCrossRefGoogle Scholar
  36. Lewis SA, Oswald I, Dunleavy DLF (1971): Chronic fenfluramine administration: some cerbral effects. Br Med J 3:67–70PubMedCrossRefGoogle Scholar
  37. Lipton MA, Gordon R, Guroff G, Udenfriend S (1967): p-Chlorophenylalanineinduced chemical manifestations of phenylketonuria in rats. Science 156:248–250Google Scholar
  38. Lovenberg W, Jequier E, Sjoerdsma A (1968): Tryptophan hydroxylation in mammalian systems. In: Advances in Pharmacology, volume 6A, Garattini S, Shore PA, eds. New York: Academic Press, pp. 21–36Google Scholar
  39. Lovenberg W, Weissbach H, Udenfriend S (1962): Aromatic L-amino acid decarboxylase. J Biol Chem 237:89–92PubMedGoogle Scholar
  40. Matthews WD, Smith CD (1980): Pharmacological profile of a model for central serotonin receptor activation. Life Sci 26:1397–1403PubMedCrossRefGoogle Scholar
  41. McCarley RW (1980): Mechanisms and models of behavioral state control. In: The Reticular Formation Revisited, Hobson JA, Brazier MAB, eds. New York: Raven Press, pp. 375–403Google Scholar
  42. McGinty DJ, Harper RM (1976): Dorsal raphe neurons: depression of firing during sleep in cats. Brain Res 101:569–575PubMedCrossRefGoogle Scholar
  43. Mendelson WB, Reichman J, Othmer E (1975): Serotonin inhibition and sleep. Biol Psychiatry 10:459–464PubMedGoogle Scholar
  44. Mogilnicka E (1981): REM sleep deprivation changes behavioral response to catecholaminergic and serotonergic receptor activation in rats. Pharmacol Biochem Behav 15:149–151PubMedCrossRefGoogle Scholar
  45. Moir ATB, Eccleston D (1968): The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J Neurochem 15:1093–1108PubMedCrossRefGoogle Scholar
  46. Mouret J, Bobillier P, Jouvet M (1968): Insomnia following parachlorophenylalanine in the rat. Eur J Pharmacol 5:17–22PubMedCrossRefGoogle Scholar
  47. Nakazawa Y, Hasuzawa H, Kotorii T, Ohkawa T, Sakurada H, Nonaka K, Dainoson K (1980): Study on the effects of L-5HTP on the stages of sleep in man as evaluated by using sleep deprivation. Folia Psychiatr Neurol Jpn 34:83–87PubMedGoogle Scholar
  48. Ng LKY, Chase TN, Colburn RW, Kopin LF (1972): Release of [3H]Dopamine by L-5-hydroxytryptophan. Brain Res 45:499–505PubMedCrossRefGoogle Scholar
  49. Nicholson AN, Stone BM (1979): L-tryptophan and sleep in healthy man. Electroencephabgr Clin Neurophysiol 47:539–545CrossRefGoogle Scholar
  50. Pastel RH, Fernstrom JD (1987): Short-term effects of fluoxetine and trifluoromethylphenylpiperazine on electroencephalographic sleep in the rat. Brain Res 436:92–102PubMedCrossRefGoogle Scholar
  51. Polc P, Schneeberger J, Haefely W (1979): Effects of several centrally active drugs on the sleep-wakefulness cycle of cats. Neuropharmacology 18:259–267PubMedCrossRefGoogle Scholar
  52. Pujol JF, Buguet A, Froment JL, Jones B, Jouvet M (1971): The central metabolism of serotonin in the cat during insomnia. A neurophysiological and biochemical study after administration of p-chlorophenylalanine or destruction of the raphe system. Brain Res 29:195–212PubMedCrossRefGoogle Scholar
  53. Pujol JF, Keane P, Bobillier P, Renaud B, Jouvet M (1978): 5,6-dihydroxytryptamine as a tool for studying sleep mechanisms and interactions between monoaminergic systems. Ann NY Acad Sci 305:576–589Google Scholar
  54. Radulovacki M (1982): L-Tryptophan’s effects on brain chemistry and sleep in cats and rats: a review. Neurosci Biobehav Rev 6:421–427PubMedCrossRefGoogle Scholar
  55. Rechtschaffen A, Lovell RA, Freedman DX, Whitehead WE, Aldrich M (1973): The effect of parachlorophenylalanine on sleep in the rat: some implications for the serotonin-sleep hypothesis. In: Serotonin and Behavior, Barchas J, Usdin E, eds. New York, Academic PressGoogle Scholar
  56. Reuter CJ (1975): A review of the CNS effects of fenfluramine, 780SE and norfenfluramine on animals and man. Postgrad Med J 51(suppl 1): 18–27PubMedCrossRefGoogle Scholar
  57. Reyes RB, Hill SY, Kupfer DJ (1983): Effects of acute doses of zimelidine on REM sleep in rats. Psychopharmacology 80:214–216PubMedCrossRefGoogle Scholar
  58. Reyes RB, Hill SY, Kupfer DJ (1986): Effects of repeated zimelidine administration on sleep parameters in the rat. Psychopharmacology 88:54–57.PubMedCrossRefGoogle Scholar
  59. Rodriguez R, Rojas-Ramirez JA, Drucker-Colin RR (1973): Serotonin-like actions of quipazine on the central nervous system. Eur J Pharmacol 24:164–171PubMedCrossRefGoogle Scholar
  60. Ross CA, Trulson ME, Jacobs BL (1976): Depletion of brain serotonin following intraventricular 5,7-dihydroxytryptamine fails to disrupt sleep in the rat. Brain Res 114:517–523PubMedCrossRefGoogle Scholar
  61. Sallanon M, Buda C, Janin M, Jouvet M (1982): 5-HT antagonists suppress sleep and delay its restoration after 5-HTP in p-chlorophenylalanine-pretreated cats. Eur J Pharmacol 82:29–35Google Scholar
  62. Sallanon M, Janin M, Buda C, Jouvet M (1983): Serotonergic mechanisms and sleep rebound. Brain Res 268:95–104PubMedCrossRefGoogle Scholar
  63. Shipley JE, Kupfer DJ, Dealy RS, Griffin SJ, Coble PA, McEachran AB, Grochocinski VJ (1984): Differential effects of amitriptyline and of zimelidine on the sleep electroencephalogram of depressed patients. Clin Pharmacol Ther 36:251–259PubMedCrossRefGoogle Scholar
  64. Slater IH, Jones GT, Moore RA (1978): Inhibition of REM sleep by fluoxetine, a specific inhibitor of serotonin uptake. Neuropharmacology 17:383–389PubMedCrossRefGoogle Scholar
  65. Sved AF, Van Itallie CM, Fernstrom JD (1982): Studies of the antihypertensive action of L-tryptophan. J Pharmacol Exp Ther 221:329–333PubMedGoogle Scholar
  66. Tabushi K, Himwich HE (1971). Electroencephalographic study of the effects of methysergide on sleep in the rabbit. Electroencephalogr Clin Neurophysiol 31:491–497PubMedCrossRefGoogle Scholar
  67. Tobler I, Borbely AA (1982): Sleep regulation after reduction of brain serotonin: effect of p-chlorophenylalanine combined with sleep deprivation in the rat. Sleep 5:145–153PubMedGoogle Scholar
  68. Toru M, Mitsushio H, Mataga N, Takashima M, Arito H (1984): Increased brain serotonin metabolism during rebound sleep in sleep-deprived rats. Pharmacol Biochem Behav 20:757–761PubMedCrossRefGoogle Scholar
  69. Trulson ME, Jacobs BL (1976): Dose-response relationships between systemically administered L-tryptophan or 5-hydroxytryptophan and raphe unit firing activity in the rat. Neuropharmacology 15:339–344PubMedCrossRefGoogle Scholar
  70. Trulson ME, Jacobs BL (1979): Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Res 163:135–150PubMedCrossRefGoogle Scholar
  71. Ursin R (1972): Differential effect of para-chlorophenylalanine on the two slow wave sleep stages in the cat. Acta Physiol Scand 86:278–285PubMedCrossRefGoogle Scholar
  72. Ursin R (1976): The effects of 5-hydroxytryptophan and L-tryptophan on wakefulness and sleep patterns in the cat. Brain Res 106:105–115PubMedCrossRefGoogle Scholar
  73. Ursin R (1980): Does para-chlorophenylalanine produce disturbed waking, disturbed sleep or activation by ponto-geniculo-occipital waves in cats? Waking Sleeping 4:211–221PubMedGoogle Scholar
  74. Weitzman ED, Rapport MM, McGregor P, Jacoby J (1968): Sleep patterns of the monkey and brain serotonin concentration: effect of p-chlorophenylalanine. Science 160:1361–1363PubMedCrossRefGoogle Scholar
  75. Willner P (1985): Antidepressants and serotonergic neurotransmission: an integrative review. Psychopharmacology 85:387–404PubMedCrossRefGoogle Scholar
  76. Wojcik WJ, Fornai C, Radulovacki M (1980): Effect of tryptophan on sleep in the rat. Neuropharmacology 19:163–167PubMedCrossRefGoogle Scholar
  77. Wyatt RJ, Engelman K, Kupfer DJ, Scott J, Sjoerdsma A, Snyder F (1969): Effects of para-chlorophenylalanine on sleep in man. Electroencephalogr Clin Neurophysiol 27:529–532PubMedCrossRefGoogle Scholar
  78. Wyatt RJ, Engelman K, Kupfer DJ, Fram DH, Sjoerdsma A, Snyder F (1970): Effects of L-tryptophan (a natural sedative) on human sleep. Lancet ii:842–846CrossRefGoogle Scholar
  79. Wyatt RJ, Zarcone V, Engelman K, Dement WC, Snyder F, Sjoerdsma A (1971): Effects of 5-hydroxytryptophan on the sleep of normal human subjects. Electroencephalogr Clin Neurophysiol 30:505–509PubMedCrossRefGoogle Scholar
  80. Zolovick AJ, Stern WC, Panskepp J, Jalowiec JE, Morgane PJ (1973): Sleep-waking patterns in cats after administration of fenfluramine and other monoaminergic modulating drugs. Pharmacol Biochem Behav 1:41–46PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston 1989

Authors and Affiliations

  • John D. Fernstrom
  • Ross H. Pastel

There are no affiliations available

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