Skip to main content

Neurotransmitters, Neurochemistry, and the Clinical Pharmacology of Sleep

  • Chapter
  • First Online:
Sleep Disorders Medicine

Abstract

Neurotransmitter systems form the organizational backbone for this chapter. We briefly summarize the central nervous system (CNS) excitatory and inhibitory neurotransmitters. The excitatory systems mediate CNS arousal, alertness, activity, and responsiveness to environment, and may also heighten autonomic nervous system (ANS) activation. We end our chapter briefly discussing brain chemistry orchestrating sleep–wake regulation including rapid eye movement (REM) and non-REM cycling.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Moore KE (1971) Biochemical correlates of the behavioral effects of drugs. In: Rech RH, Moore KE (eds) An introduction to psychopharmacology. Raven Press, New York, pp 79–136

    Google Scholar 

  2. Stahl SM (2000) Essential psychopharmacology, 2nd edn. Cambridge University Press, New York

    Google Scholar 

  3. Swerdlow NR, Koob GF (1987) Lesions of the dorsomedial nucleus of the thalamus, medial prefrontal cortex and pedunculopontine nucleus: effects on locomotor activity mediated by nucleus accumbens-ventral pallidal circuitry. Brain Res 412(2):233–243

    Article  CAS  PubMed  Google Scholar 

  4. Szabo ST, Gould TD, Manji HK (2004) Neurotransmitters, receptors, signal transduction, and second messengers in psychiatric disorders. In: Schatzberg AF, Nemeroff CB (eds) Textbook of psychopharmacology, 3rd edn. American Psychiatric Publishing, Washington, D.C.

    Google Scholar 

  5. Espana RA, Scammell TE (2004) Sleep neurobiology for the clinician. Sleep 27:811–820

    PubMed  Google Scholar 

  6. Grilly DM (2006) Chapter 5: neuroactive ligands and the nervous system. In: Drugs and human behavior. Boston, Pearson, pp 79–101

    Google Scholar 

  7. Grilly DM (2006) Antidepressants and mood stabilizers. In: Grilly DM (ed) Drugs and human behavior. Pearson, Boston, pp 317–347

    Google Scholar 

  8. Sangal RB, Owens J, Allen AJ, Sutton V, Schuh K, Kelsey D (2006) Effects of atomoxetine and methylphenidate on sleep in children with ADHD. Sleep 29(12):1573–1585

    Article  PubMed  Google Scholar 

  9. Mendelson WB (1987) Pharmacology and neurotransmitters in sleep. In: Mendelson WB (ed) Human sleep: research and clinical care. Plenum Medical Book Company, New York, pp 33–79

    Chapter  Google Scholar 

  10. Jasinski DR, Krishnan S (2009) Abuse liability of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse. J Psychopharmacol 4:419–427

    Article  Google Scholar 

  11. Hirshkowitz M (2006) Therapy for excessive sleepiness. In: Lee-Chiong T (ed) Sleep: a comprehensive handbook. Wiley-Liss, New Jersey, pp 191–196

    Google Scholar 

  12. Aviden AY (2006) Motor disorders of sleep and parasomnias. In: Avidan AY, Zee PC (eds) Handbook of sleep medicine. Lippincott, Williams and Wilkins, Philadelphia, pp 98–136

    Google Scholar 

  13. Oertel WH, Benes H, Garcia-Borreguero D, Geisler P, Högl B, Trenkwalder C, Tacken I, Schollmayer E, Kohnen R, Stiasny-Kolster K (2008) Rotigotine SP710 study group: one year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome. Sleep Med 9(8):865–873

    Article  PubMed  Google Scholar 

  14. Ondo W (2004) Secondary restless legs syndrome. In: Chaudhuri KR, Odin P, Olanow CW (eds) Restless legs syndrome. Taylor and Francis, London, pp 57–84

    Google Scholar 

  15. Yang CK, Winkelman JW (2005) Antidepressant and antipsychotic drugs and sleep. In: Sleep research society. SRS basics of sleep guide. Sleep Research Society, Westchester, Illinois, pp 167–173

    Google Scholar 

  16. Vogel GW, Traub AC, Ben-Horin P, Meyers GM (1968) REM deprivation. II. The effects on depressed patients. Arch Gen Psychiatry 18(3):301–311

    Google Scholar 

  17. Schweitzer PK (2000) Drugs that disturb sleep and wakefulness. In: Kryger MH, Roth T, Dement WC (eds) Principles and practice of sleep medicine, 3rd edn. WB Saunders, Philadelphia, pp 441–461

    Google Scholar 

  18. Becker PM (2005) Pharmacologic and nonpharmacologic treatments of insomnia. Neurol Clin 23(4):1149–1163

    Article  PubMed  Google Scholar 

  19. Ishizuka T, Murakami M, Yamatodani A (2008) Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats. Eur J Pharmacol 578(2–3):209–215

    Article  CAS  PubMed  Google Scholar 

  20. Lin J, 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 14128–14133

    Google Scholar 

  21. U.S. (1998) Modafinil in narcolepsy multicenter study group: randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 43:88–97

    Google Scholar 

  22. Czeisler CA, Walsh JK, Roth T, Hughes RJ, Wright KP, Kingsbury L, Arora S, Schwartz JR, Niebler GE, Dinges DF (2005) Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med 353(5):476–486

    Article  CAS  PubMed  Google Scholar 

  23. Mitler MM, Harsh J, Hirshkowitz M (2000) Treatment of excessive daytime sleepiness associated with narcolepsy: a post-hoc analysis of clinical response to 200-Mg and 400-Mg doses of modafinil (Provigil®). Sleep 23:a292–a293

    Google Scholar 

  24. Bittencourt LR, Lucchesi LM, Rueda AD, Garbuio SA, Palombini LO, Guilleminault C, Tufik S (2008) Placebo and modafinil effect on sleepiness in obstructive sleep apnea. Prog Neuropsychopharmacol Biol Psychiatry 32(2):552–559

    Article  CAS  PubMed  Google Scholar 

  25. Schwartz JR, Nelson MT, Schwartz ER, Hughes R (2004) Effects of modafinil on wakefulness and executive function in patients with narcolepsy experiencing late-day sleepiness. Clin Neuropharmacol 27(2):74–79

    Article  CAS  PubMed  Google Scholar 

  26. Black JE, Hirshkowitz M (2005) Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. Sleep 28(4):464–471

    Article  PubMed  Google Scholar 

  27. Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, Boehlecke B, Chesson AL Jr, Friedman L, Maganti R, Owens J, Pancer J, Zak R (2007) Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 30(12):1705–1711

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hart CL, Haney M, Vosburg SK, Comer SD, Gunderson E, Foltin RW (2006) Modafinil attenuates disruptions in cognitive performance during simulated night-shift work. Neuropsychopharmacology 31:1526–1536

    Article  CAS  PubMed  Google Scholar 

  29. Chemelli RM, Willie JT, Sinton CM et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451

    Article  CAS  PubMed  Google Scholar 

  30. Lin L, Faraco J, Li R et al (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365–366

    Article  CAS  PubMed  Google Scholar 

  31. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distruibution of orexin neurons in the adult rat brain. Brain Res 827:243–260

    Article  CAS  PubMed  Google Scholar 

  32. Nishino S, Ripley B, Overeem S et al (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40

    Article  CAS  PubMed  Google Scholar 

  33. Deadwyler SA, Porrino L, Siegel JM, Hampson RE (2007) Systemic and nasal delivery of orexin-A (Hypocretin-1)reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 27:4239–4247

    Article  Google Scholar 

  34. Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ, Garson SL, Fox SV (2011) Promotion of sleep by suvorexant—A novel dual orexin receptor antagonist. J Neurogenet 25(1–2):52–61

    Article  CAS  PubMed  Google Scholar 

  35. Hoever P, Dorffner G, Benes H, Penzel T, Danker-Hopfe H, Barbanoj MJ, Pillar G, Saletu B, Polo O, Kunz D, Zeithofer J, Berg S, Partinen M, Basseti CL, Hogl B, Ebrahim IO, Holsboer-Trachsler E, Bengsstom H, Peker Y, Hemmeter UM, Chiossi E, Hajak G, Dingemanse J (2012) Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. Clin Pharmacol Ther 91(6):975–985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. López-Muñoz F, Ucha-Udabe R, Alamo C (2005) The history of barbiturates a century after their clinical introduction. Neuropsychiatry Dis Treat 1(4):329–343

    Google Scholar 

  37. Kay DC, Blackburn AB, Buckingham JA, Karacan I (1976) Human pharmacology of sleep. In: Williams RL, Karacan I (eds) Pharmacology of sleep. John Wiley and Sons, New York, pp 83–210

    Google Scholar 

  38. Freemon FR (1973) Clinical pharmacology of sleep: a critical review of all-night electroencephalographic studies. Behav Neuropsychiatry 4–5(11–12, 1–6):49–60

    Google Scholar 

  39. Karacan I, Orr W, Roth T, Kramer M, Thornby J, Bingham S, Kay D (1981) Dose-related effects of phenobarbitone on human sleep-waking patterns. Br J Clin Pharmacol 12(3):303–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Griffiths RR, Johnson MW (2005) Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry 66(suppl 9):31–41

    CAS  PubMed  Google Scholar 

  41. Ballenger JC (2005) Benzodiazepines. In: Schatzberg AF, Nemeroff CB (eds) Textbook of psychopharmacology. American Pychiatric Press, Washington, D.C., pp 215–230

    Google Scholar 

  42. Mendelson WB (1992) Neuropharmacology of sleep induction by benzodiazepines. Crit Rev Neurobiol 6:221–232

    CAS  PubMed  Google Scholar 

  43. Kagen F, Harwood T, Rickels K, Rudzik AD, Sorer H (eds) (1975) Hypnotics. Spectrum Publications, New York

    Google Scholar 

  44. Monti JM, Monti D (2006) Overview of currently available benzodiazepine and nonbenzodiazepine hypnotics. In: Pandi-Perumal SR, Monti JM (eds) Clinical pharmacology of sleep. Birkhausser Verlag, Switzerland, pp 207–223

    Chapter  Google Scholar 

  45. Roth T (2005) Sedative hypnotics. In: Sleep research society. SRS basics of sleep guide. Sleep Research Society, Westchester, Illinois, pp 143–149

    Google Scholar 

  46. Morris HH 3rd, Estes ML. Traveler’s amnesia. Transient global amnesia secondary to triazolam. JAMA 258(7):945–946

    Google Scholar 

  47. Charney DS, Mihic SJ, Harris RA (2001) Hypnotics and sedatives. In: Hardman JG, Limbird LE (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 10th edn. McGraw-Hill, New York, pp 399–427

    Google Scholar 

  48. Hindmarch IE (1990) Zopiclone monograph. Adis Press International, Manchester

    Google Scholar 

  49. Griebel G, Perrault G, Letang V, Granger P, Avenet P, Schoemaker H, Sanger DJ (1999) New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (omega) receptor subtypes. Psychopharmacology 146(2):205–213

    Article  CAS  PubMed  Google Scholar 

  50. Kralic JE, O’Buckley TK, Khisti RT, Hodge CW, Homanics GE, Morrow AL (2002) GABA(A) receptor alpha-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43(4):685–694

    Article  CAS  PubMed  Google Scholar 

  51. Huang Q, Liu R, Zhang P, He X, McKernan R, Gan T, Bennett DW, Cook JM (1998) Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines at five recombinant GABAA/benzodiazepine receptor subtypes [alpha × beta3gamma2 (x = 1–3,5, and 6)] via comparative molecular field analysis. J Med Chem 41(21):4130–4142

    Article  CAS  PubMed  Google Scholar 

  52. Kleitman N (1987) Sleep and wakefulness. University of Chicago Press, Chicago

    Google Scholar 

  53. Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, Basheer R, Haas HL, Zilles K, Bauer A (2007) Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study. J Neurosci 27(9):2410–2415

    Article  CAS  PubMed  Google Scholar 

  54. Thakkar MM, Delgiacco RA, Strecker RE, McCarley RW (2003) Adenosinergic inhibition of basal forebrain wakefulness-active neurons: a simultaneous unit recording and microdialysis study in freely behaving cats. Neuroscience 122(4):1107–1113

    Article  CAS  PubMed  Google Scholar 

  55. Listos J, Malec D, Fidecka S (2006) Adenosine receptor antagonists intensify the benzodiazepine withdrawal signs in mice. Pharmacol Rep 58(5):643–651

    CAS  PubMed  Google Scholar 

  56. Roehrs T, Roth T (2008) Caffeine: sleep and daytime sleepiness. Sleep Med Rev 12(2):153–162

    Article  PubMed  Google Scholar 

  57. Pendergrast M (1999) Uncommon grounds. Basic Books, New York

    Google Scholar 

  58. McNeil CL (2007) Chocolate in Mesoamerica: a cultural history of cacao. University Press of Florida, Gainesville

    Google Scholar 

  59. Brooks PL, Peever JH (2008) Glycinergic and GABA(A)-mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia. J Neurosci 28(14):3535–3545

    Article  CAS  PubMed  Google Scholar 

  60. McCarley RW (2007) Neurobiology of REM and NREM sleep. Sleep Med 8(4):302–330

    Article  PubMed  Google Scholar 

  61. Sleep Research Society (1993) Chemical and neuronal mechanisms of sleep and wakefulness. UCLA and SRS, Los Angeles, pp 41–44

    Google Scholar 

  62. Aldrich MS (1999) Neurobiology of sleep. In: Aldrich MS sleep medicine. Oxford University Press, New York, pp 27–38

    Google Scholar 

  63. Riemann D, Hohagen F, Bahro M, Lis S, Stadmüller G, Gann H, Berger M (1994) Cholinergic neurotransmission, REM sleep and depression. J Psychosom Res 38(Suppl 1):15–25

    Article  PubMed  Google Scholar 

  64. Gillin JC, Sutton L, Ruiz C, Kelsoe J, Dupont RM, Darko D, Risch SC, Golshan S, Janowsky D (1991) The cholinergic rapid eye movement induction test with arecoline in depression. Arch Gen Psychiatry 48(3):264–270

    Article  CAS  PubMed  Google Scholar 

  65. Baghdoyan HA, McCarley RW, Hobson JA (1985) Cholinergic manipulation of brainstem reticular systems: effect on desynchronized sleep generation. In: Wauquier A, Monti JM, Gaillard JM, Radulovacki M (eds) Sleep: neurotransmitters and neuromodulators. Raven Press, New York, pp 15–27

    Google Scholar 

  66. Poland RE, McCracken JT, Lutchmansingh P, Lesser IM, Tondo L, Edwards C, Boone KB, Lin KM (1997) Differential response of rapid eye movement sleep to cholinergic blockade by scopolamine in currently depressed, remitted, and normal control subjects. Biol Psychiatry 41(9):929–938

    Article  CAS  PubMed  Google Scholar 

  67. Siegel JM (2005) REM Sleep. In: Kryger MH, Roth T, Dement WC (eds) Principles and practice of sleep medicine. Elsevier Saunders, Philadelphia, pp 120–135

    Chapter  Google Scholar 

  68. Halberstadt AL, Balaban CD (2006) Serotonergic and nonserotonergic neurons in the dorsal raphe nucleus send collateralized projections to both the vestibular nuclei and the central amygdaloid nucleus. Neuroscience 140(3):1067–1077

    Article  CAS  PubMed  Google Scholar 

  69. Cooper JR, Bloom FE, Roth RH (2002) Biochemical basis of neuropharmacology. Serotonin, histamine, and adenosine. In: Cooper JR, Bloom FE, Roth RH (eds) The biochemical basis of neuropharmacology, 8th edn. Oxford University Press, Oxford, pp 271–304

    Google Scholar 

  70. Winkelman JW, James L (2004) Serotonergic antidepressants are associated with REM sleep without atonia. Sleep 27(2):317–321

    Article  PubMed  Google Scholar 

  71. Schenck CH, Mahowald MW, Kim SW, O’Connor KA, Hurwitz TD (1992) Prominent eye movements during NREM sleep and REM sleep behavior disorder associated with fluoxetine treatment of depression and obsessive-compulsive disorder. Sleep 15(3):226–235

    Article  CAS  PubMed  Google Scholar 

  72. Pace-Schott EF, Gersh T, Silvestri R, Stickgold R, Salzman C, Hobson JA (2001) SSRI treatment suppresses dream recall frequency but increases subjective dream intensity in normal subjects. J Sleep Res 10(2):129–142

    Article  CAS  PubMed  Google Scholar 

  73. Mahowald MW, Schenck CH, Bornemann MA (2007) Pathophysiologic mechanisms in REM sleep behavior disorder. Curr Neurol Neurosci Rep 7(2):167–172

    Article  PubMed  Google Scholar 

  74. Lesage S, Hening WA (2004) The restless legs syndrome and periodic limb movement disorder. Semin Neurol 24(3):249–259

    Article  PubMed  Google Scholar 

  75. Kupfer DJ, Foster FG (1978) EEG sleep and depression. In: Williams RL, Karacan I (eds) Sleep disorders. Wiley, New York, pp 163–204

    Google Scholar 

  76. Arendt J (2006) Chapter 15. The pineal gland and pineal tumors. www.endotext.org

  77. Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP (2008) Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol 85(3):335–353

    Article  CAS  PubMed  Google Scholar 

  78. Borbély AA, Achermann P (1999) Sleep homeostasis and models of sleep regulation. J Biol Rhythms 14(6):557–568

    PubMed  Google Scholar 

  79. Lewy AJ, Emens J, Sack RL, Hasler BP, Bernert RA (2003) Zeitgeber hierarchy in humans: resetting the circadian phase positions of blind people using melatonin. Chronobiol Int 20(5):837–852

    Article  CAS  PubMed  Google Scholar 

  80. Sack RL, Hughes RJ, Edgar DM, Lewy AJ (1997) Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms? Sleep 20:908–915

    Article  CAS  PubMed  Google Scholar 

  81. Zhdanova IV, Wurtman RJ, Morabito C et al (1996) Effects of low oral doses of melatonin, given 2–4 hours before habitual bedtime, on sleep in normal young humans. Sleep 19:423–431

    Article  CAS  PubMed  Google Scholar 

  82. Roth T, Stubbs C, Walsh JW (2005) (TAK-375), A selective Mt1/Mt2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to novel sleep environment. Sleep 28(3):303–307

    PubMed  Google Scholar 

  83. Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T (2007) Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med 3(5):495–504

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Max Hirshkowitz .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this chapter

Cite this chapter

Hirshkowitz, M., Bhandari, H. (2017). Neurotransmitters, Neurochemistry, and the Clinical Pharmacology of Sleep. In: Chokroverty, S. (eds) Sleep Disorders Medicine. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6578-6_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-6578-6_7

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-6576-2

  • Online ISBN: 978-1-4939-6578-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics