Physiological roles and pharmacological effects of melatonin

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

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

3. Melatonin regulation Overview

4. Melatonin regulation

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

6. melatonin

7. melatonin

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

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

10. Melatonin production Hypothalamus LIGHT RHT IML EYE SCN PVN NH2 Tryptophan CH2 CH COOH N H SCG Tryptophan-5-hydroxylase b-adrenergic receptor NH2 HO CH2 CH ATP 5-Hydroxytryptophan (5HTP) COOH N H 5HTP-decarboxylase NA cAMP HO CH2 CH2 NH2 Serotonin (5HT) Protein synthesis N H NAT C-kinase NA HO CH2 CH2 NH C CH3 N-Acetylserotonin O N H HIOMT a-adrenergic receptor CH3 O CH2 CH2 NH C CH3 Pinealocyte Melatonin O N H CH3 O CH2 CH2 NH C CH3  Melatonin O N H Adapted from Arendt J. 1995

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

12. Melatonin regulation Melatonin influence on SCN Overview

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

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

15. Melatonin effects on SCN • Shifting SCN circadian rhythm

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 … blocking Mel1b receptor suppresses phase shift Siberian hamster Mel1b KO Hunt et al., AJP, 2001 Weaver et al., Mol Endocrinol, 1996

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

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

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

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

22. Melatonin effects on circadian rhythms • Melatonin PRC

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 • melatonin •  light Lewy et al., Chronobiol Int, 1998

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

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

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

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

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 placebo; 4 days 3 mg; 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 effects on circadian rhythms • Melatonin PRC • Therapeutic use: • Blind • Jetlag/Shift-work • Delayed sleep phase syndrome

33. Melatonin use for delayed sleep phase syndrome 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 Dahlitz et al., Lancet, 1991

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

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

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

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

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

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

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

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

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