Neuropharmacology of sleep Flavio Guzmán, MD

Outline Neurotransmitters that promote wakefulness Drug summary Neurotransmitters that promote sleep

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

Dopamine Antipsychotics Stimulants

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.

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.

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

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

Norepinephrine

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

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, 403-450.

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), 225-229

Serotonin

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

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.

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), 850-856. 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), 203-206.

Acetylcholine

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), 313-315.

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), 313-315.

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), 313-315.

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

Histamine Antihistamines Tricylic antidepressants Antipsychotics

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), 263-272.

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), 263-272.

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

Orexin Suvorexant

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.

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.

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. 73-77

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. 73-77

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

Sleep promoting systems Melatonin and the circadian rhythm GABA

Melatonin

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, 407-416 (July 2009)

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. 25-70). Springer International Publishing.

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. 25-70). Springer International Publishing.

GABA

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), 469-486.

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

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