1. Neuropharmacology of sleep
Flavio Guzmán, MD

2. Outline Neurotransmitters that promote wakefulness
Drug summary
Neurotransmitters that promote sleep

3. Neurotransmitters in wakefulness and sleep
Monoamines
Dopamine (DA)
Norepinephrine
Serotonin (5-HT)
Acetylcholine
Histamine
Orexin/hypocretin
Sleep
Adenosine
GABA
Melatonin
Galanin

4. Dopamine
Antipsychotics
Stimulants

5. Dopamine Substantia nigra Ventral tegmental area
Ventral periaqueductal grey
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34(7), 845.

6. Dopamine Substantia nigra Ventral tegmental area
Wakefulness
Motivation
Reward
Learning
Motor function
Cortex
Substantia nigra
Ventral tegmental area
Ventral periaqueductal grey
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34(7), 845.

7. Antipsychotics can reduce wakefulness
First-generation antipsychotics:
Haloperidol
Chlorpromazine
Second-generation antipsychotics:
Olanzapine, quetiapine, risperidone
Used off-label for insomnia

8. Stimulants enhance DA neurotransmission
Stimulants (Methylphenidate, Amphetamine)
Enhance DA and NE neurotransmission
Insomnia as side effect
Modafinil
Approved for excessive sleepiness associated with:
Narcolepsy
Obstructive sleep apnea (OSA)
Shift work disorder

9. Norepinephrine

10. Norepinephrine Locus coeruleus
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34(7), 845.

11. Norepinephrine Locus coeruleus Cortex Wakefulness Arousal Attention
Task performance
Locus coeruleus
Aston-Jones, G., & Cohen, J. D. (2005). An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance.Annu. Rev. Neurosci., 28,

12. Norepinephrine Noradrenergic effect and insomnia Alpha 1 antagonist
Bupropion
Stimulants
Alpha 1 antagonist
Prazosin for PTSD
Vivid nightmares
Nighttime arousal
Byers, M et al (2010). Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and safety. Journal of clinical psychopharmacology, 30(3),

13. Serotonin

14. Serotonin Dorsal raphe nucleus
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34(7), 845.

15. Serotonin Dorsal raphe nucleus Cortex Preoptic area Basal forebrain
Hypothalamus
Thalamus
Dorsal raphe nucleus
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34(7), 845.

16. SSRIs and sleep SSRIs (Fluoxetine, Citalopram) Increase wakefulness
Reduce REM sleep
Monaca, C., et al (2003). 5-HT 1A/1B receptor-mediated effects of the selective serotonin reuptake inhibitor, citalopram, on sleep: studies in 5-HT 1A and 5-HT 1B knockout mice. Neuropsychopharmacology 28(5),
Vasar, V., et al(1994). The effect of fluoxetine on sleep: a longitudinal double-blind polysomnographic study of health volunteers. International clinical psychopharmacology, 9(3),

17. Acetylcholine

18. Acetylcholine Basal forebrain
Laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT)
Basal forebrain
Monti, J. M. (2013). The neurotransmitters of sleep and wake, a physiological reviews series. Sleep medicine reviews, 17(4),

19. Acetylcholine Basal forebrain Cortex
thalamus, hypothalamus, and brainstem
Laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT)
Basal forebrain
Monti, J. M. (2013). The neurotransmitters of sleep and wake, a physiological reviews series. Sleep medicine reviews, 17(4),

20. Acetylcholine Wakefulness REM sleep Learning Memory Basal forebrain
Laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT)
Basal forebrain
Monti, J. M. (2013). The neurotransmitters of sleep and wake, a physiological reviews series. Sleep medicine reviews, 17(4),

21. Acetylcholine and pharmacological studies
Desynchronized cortical activity and increased wakefulness
ACh
Nicotine
Muscarinic receptor agonists
Davila DG, Hurt RD, Offord KP, Harris CD, Shepard JW Jr. Acute effects of transdermal nicotine on sleep architecture, snoring, and sleepdisordered breathing in nonsmokers. Am J Respir Crit Care Med 1994;150:469-74
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34(7), 845

22. Histamine
Antihistamines
Tricylic antidepressants
Antipsychotics

23. Histamine Tuberomammillary nucleus
Krystal, A. D., et al (2013). Review of the histamine system and the clinical effects of H 1 antagonists: Basis for a new model for understanding the effects of insomnia medications. Sleep medicine reviews,17(4),

24. Histamine Wakefulness REM sleep Learning Memory
Tuberomammillary nucleus
Krystal, A. D., et al (2013). Review of the histamine system and the clinical effects of H 1 antagonists: Basis for a new model for understanding the effects of insomnia medications. Sleep medicine reviews,17(4),

25. Histamine antagonists as insomnia treatments
Antihistamines
Diphenhydramine
Tricyclic antidepressants
Doxepin
Antipsychotics
Chlorpromazine
Quetiapine
Olanzapine

26. Orexin
Suvorexant

27. Lateral and posterior hypothalamus
Orexin
Lateral and posterior hypothalamus
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34(7), 845.

28. Orexin Lateral and posterior hypothalamus
Projections to arousal regions
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34(7), 845.

29. The orexin system System for sustaining wakefulness
Increases arousal in motivating conditions
Patients with narcolepsy with cataplexy:
Severe loss of orexin neurons
Very low CSF levels of orexin-A
Chandra K. Cooper (2014) Orexin receptor antagonists: Novel hypnotic agents. Mental Health Clinician: March 2014-Trends in sedative-hypnotic therapy, Vol. 4, No. 2, pp

30. Orexin A and B bind to OXR
The orexin 1 receptor shows higher affinity for orexin A than orexin B
Orexin 2 receptor binds both orexin A and orexin B with similar affinities
Chandra K. Cooper (2014) Orexin receptor antagonists: Novel hypnotic agents. Mental Health Clinician: March 2014-Trends in sedative-hypnotic therapy, Vol. 4, No. 2, pp

31. Suvorexant: an orexin antagonist
Suvorexant is reversible dual orexin receptor antagonist (DORA)
OX1R
OX2R
Belsomra (Suvorexant) [package insert]. Whitehouse Station, NJ: Merck and CO. Inc; 2015

32. Sleep promoting systems
Melatonin and the circadian rhythm
GABA

33. Melatonin

34. Circadian rhythm and melatonin
Reproduced from:
Circadian sleep–wake rhythm disturbances in end-stage renal disease. Birgit C. P. Koch, J. Elsbeth Nagtegaal, Gerard A. Kerkhof & Piet M. ter Wee. Nature Reviews Nephrology 5, (July 2009)

35. Melatonin effects on sleep
Induces sleep, influenced by the circadian phase
Transition from arousal to high sleep propensity matches the nocturnal rise of melatonin
Melatonin binds to MT1 and MT2 receptors
Szabadi, E. (2015). Neuronal Networks Regulating Sleep and Arousal: Effect of Drugs. In Drug Treatment of Sleep Disorders (pp ). Springer International Publishing.

36. Melatonergic agents Ramelteon Agomelatine Hypnotic MT1, MT2 agonist
Antidepressant
MT1, MT2 agonist, 5HT2C antagonist
Szabadi, E. (2015). Neuronal Networks Regulating Sleep and Arousal: Effect of Drugs. In Drug Treatment of Sleep Disorders (pp ). Springer International Publishing.

37. GABA

38. GABA and GABAA receptor
GABA is a major inhibitory neurotransmitter
Neuronal inhibition by increasing chloride ion conductance
Inhibits brain regions involved in wakefulness
Watson, C. J., Baghdoyan, H. A., & Lydic, R. (2012). Neuropharmacology of sleep and wakefulness: 2012 update. Sleep medicine clinics, 7(3),

39. Benzodiazepine receptor agonists (BzRA)
Benzodiazepines
“Z-drugs”
Zolpidem
Eszopiclone
Zaleplon

40. End of presentation