1. Physiological roles and pharmacological effects of melatonin HMS BWH Frank A.J.L. Scheer, Ph.D. Division of Sleep Medicine Harvard Medical School Brigham and Women’s Hospital

2. Overview Melatonin regulation Melatonin influence on SCN Melatonin effects on circadian system Melatonin effects on sleep

3. Overview Melatonin regulation

5. Paraventricular nucleus of the hypothalamus Intermediolateral cell column of the spinal cord melatonin

8. Zeitzer et al., J Physiol 2000;526:695–702 Plasma melatonin (proportion of max) 1.0

9. Zeitzer et al., J Physiol 2000;526:695–702

10. Pinealocyte  -adrenergic receptor  -adrenergic receptor SCG SCNPVN IML EYE Hypothalamus RHT LIGHT ATP cAMP Protein synthesis NA C-kinase CH 2 CH COOH NH 2 NHNH CH 2 CH COOH NH 2 HO CH 2 NH 2 HOCH 2 NHHOCH 2 CH 3 C O 5-Hydroxytryptophan (5HTP) Tryptophan Serotonin (5HT) N-Acetylserotonin Tryptophan-5-hydroxylase 5HTP-decarboxylase NAT HIOMT NHNH NHNH NHNH CH 2 NHCH 2 CH 3 C O CH 3 O Melatonin NHNH CH 2 NHCH 2 CH 3 C O CH 3 O  Melatonin NHNH Adapted from Arendt J. 1995 Melatonin production

11. Salivary melatonin profile after administration of 100 mg atenolol (  ). Deacon et al., Neurosci Lett, 1998 Beta-blockers suppress endogenous melatonin

12. Overview Melatonin regulation Melatonin influence on SCN

13. Although there is melatonin binding in various brain areas depending on the species, the SCN invariably shows strong binding. Melatonin receptors

14. from Weaver, In: Regulation of sleep and circadian rhythms 1999:197–262 Melatonin binding

15. Shifting SCN circadian rhythm Melatonin effects on SCN

16. Melatonin can phase-shift SCN neuronal activity in vitro McArthur et al., Endocrinology, 1997

17. Which receptor is involved in phase-shift by melatonin? … but in absence of Mel1a, Mel1b receptor can mediate shift Siberian hamster Mel1b KO Weaver et al., Mol Endocrinol, 1996Hunt et al., AJP, 2001 … blocking Mel1b receptor suppresses phase shift

18. Shifting SCN circadian rhythm Inhibition SCN-neuronal activity Melatonin effects on SCN

19. van der Top et al., Neuroscience, 2001 Melatonin inhibits SCN neuronal activity

20. Liu et al., Neuron, 1997 … via MT1 (Mel1a) receptor

21. Overview Melatonin regulation Melatonin influence on SCN Melatonin effects on circadian system

22. Melatonin PRC Melatonin effects on circadian rhythms

23. Human melatonin PRC 0.5 mg; 4 days Lewy et al., Chronobiol Int, 1998

24. Melatonin PRC and light PRC compared Shifts by light/10 Lewy et al., Chronobiol Int, 1998 € melatonin  light

25. Melatonin PRC Therapeutic use: Blind Melatonin effects on circadian rhythms

26. Hack et al., J Biol Rhythms 2003 Entrainment in blind with melatonin 0.5 mg at 21:00

27. Entrainment in blind with melatonin 0.5 mg at 21:00 Hack et al., J Biol Rhythms 2003

28. Melatonin PRC Therapeutic use: Blind Jetlag/Shift-work Melatonin effects on circadian rhythms

29. Melatonin use for jet lag/shift work Sharkey and Eastman., AJP, 2001

30. Melatonin use for jet lag/shift work 0.5 mg; 4 days 3 mg; 4 days placebo; 4 days Sharkey and Eastman., AJP, 2001

31. Melatonin use for jet lag/shift work At what dose? Sharkey and Eastman., AJP, 2001

32. Melatonin PRC Therapeutic use: Blind Jetlag/Shift-work Delayed sleep phase syndrome Melatonin effects on circadian rhythms

33. Melatonin use for delayed sleep phase syndrome Dahlitz et al., Lancet, 1991 Randomized placebo-controlled crossover trial in 8 patients 4 week administration; 5 mg melatonin; 1 h before fixed bedtime (23:00) NB Unclear whether due to phase advance or direct effects on sleep

34. Melatonin PRC Therapeutic use Amplification endogenous melatonin rhythm Melatonin effects on circadian rhythms

35. Exogenous melatonin can modulate amplitude of endogenous melatonin rhythm Zaidan et al., Neuroendocrinology, 1994 Human; 2ug/3h; i.v. % of max control night

36. Bothorel et al., Eur J Neurosci 2002 Rat; 1 mg/kg; s.c. Exogenous melatonin can modulate amplitude of endogenous melatonin rhythm

37. Amplification dependent on circadian phase of administration Rat; 1 mg/kg; s.c. Bothorel et al., Eur J Neurosci 2002

38. Rat; 2.5 and 25 uM reversed microdialysis into SCN Amplification mediated via the SCN Bothorel et al., Eur J Neurosci 2002

39. Overview Melatonin regulation Melatonin influence on SCN Melatonin effects on circadian system Melatonin effects on sleep

40. Melatonin effects on Sleep At what circadian phase?

41. Melatonin effects on Sleep At what circadian phase?  During daytime but not during nighttime in young healthy subjects 1.Melatonin 2.SCN

42. Melatonin effects on Sleep At what circadian phase? In whom might it be useful at night?

43. Melatonin effects on Sleep At what circadian phase? In whom might it be useful at night?  in people who are not properly entrained  decreased nocturnal melatonin levels?

44. Melatonin effects on Sleep At what circadian phase? In whom? At what dose?

45. Melatonin effects on Sleep At what circadian phase? In whom? At what dose?  Exogenous melatonin leading to plasma levels at or above physiological nighttime levels (0.3 mg  physiological).  Endogenous melatonin levels?

46. melatonin Paraventricular nucleus of the hypothalamus Intermediolateral cell column of the spinal cord thoracic

47. melatonin Paraventricular nucleus of the hypothalamus Intermediolateral cell column of the spinal cord cervical

48. Scheer et al., submitted

49. Melatonin effects on Sleep At what circadian phase? In whom? At what dose? Acute or repeated administration required?

50. Randomized, double-blind, placebo- controlled, cross-over design Arrows indicate recordings Scheer et al., Hypertension, 2004

51. Scheer et al., submitted

52. - Single capsule: no effect on blood pressure - Prolonged supplementation: Scheer et al., Hypertension, 2004

53. Melatonin effects on Sleep At what circadian phase? In whom? At what dose? Acute or repeated administration required?  During daytime, acute effect  However, during nighttime, repeated administration might be required in some cases

54. Melatonin effects on Sleep At what circadian phase? In whom? At what dose? Acute or repeated administration required? By what mechanism?

55. Melatonin effects on Sleep At what circadian phase? In whom? At what dose? Acute or repeated administration required? By what mechanism?  Temperature decrease?  Acute suppression of wake-promoting drive from the SCN?  Amplification/synchronization of rhythmic output(s) of SCN

56. Melatonin effects on Sleep At what circadian phase? In whom? At what dose? Acute or repeated administration required? By what mechanism? Therapeutic use:  Circadian misaligned (shift workers, jetlag, blind)  Low melatonin levels (elderly, beta- blockers, benzodiazepines)

57. Time for questions