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
Overview
• Melatonin regulation• Melatonin influence on SCN• Melatonin effects on circadian system• Melatonin effects on sleep
Overview
• Melatonin regulation
Melatonin regulation
Paraventricular nucleusof the hypothalamus
Intermediolateral cell columnof the spinal cord
melatonin
melatonin
melatonin
Zeitzer et al., J Physiol 2000;526:695–702
Pla
sm
a m
ela
ton
in(p
rop
ort
ion
of
max)
1.0
Zeitzer et al., J Physiol
2000;526:695–702
Pinealocyte
-adrenergicreceptor
-adrenergicreceptor
SCG
SCN PVN IMLEYE
Hypothalamus
RHTLIGHT
ATP
cAMPProtein
synthesisNA
NA
C-kinase
CH2 CH
COOH
NH2
NH
CH2 CH
COOH
NH2
HO
CH2 NH2HO CH2
CH2 NHHO CH2 CH3C
O
5-Hydroxytryptophan(5HTP)
Tryptophan
Serotonin(5HT)
N-Acetylserotonin
Tryptophan-5-hydroxylase
5HTP-decarboxylase
NAT
HIOMT
NH
NH
NH
CH2 NHCH2 CH3C
O
CH3 O
Melatonin NH
CH2 NHCH2 CH3C
O
CH3 O
Melatonin NH
Adapted from Arendt J. 1995
Melatonin production
Salivary melatonin profile after administration of 100 mg atenolol ( ).
Deacon et al., Neurosci Lett, 1998
Beta-blockers suppress endogenous melatonin
Overview
• Melatonin regulation• Melatonin influence on SCN
• Although there is melatonin binding in various brain areas depending on the species, the SCN invariably shows strong binding.
Melatonin receptors
from Weaver, In: Regulation of sleep and circadian rhythms 1999:197–262
Melatonin binding
• Shifting SCN circadian rhythm
Melatonin effects on SCN
Melatonin can phase-shift SCN neuronal activity in vitro
McArthur et al., Endocrinology, 1997
Which receptor is involvedin 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 receptorsuppresses phase shift
• Shifting SCN circadian rhythm
• Inhibition SCN-neuronal activity
Melatonin effects on SCN
van der Top et al., Neuroscience, 2001
Melatonin inhibits SCN neuronal activity
Liu et al., Neuron, 1997
… via MT1 (Mel1a) receptor
Overview
• Melatonin regulation• Melatonin influence on SCN• Melatonin effects on circadian system
• Melatonin PRC
Melatonin effects on circadian rhythms
Human melatonin PRC
0.5 mg; 4 days
Lewy et al., Chronobiol Int, 1998
Melatonin PRC and light PRC compared
Shifts by light/10
Lewy et al., Chronobiol Int, 1998
melatonin light
• Melatonin PRC
• Therapeutic use:
• Blind
Melatonin effects on circadian rhythms
Hack et al., J Biol Rhythms 2003
Entrainment in blind with melatonin
0.5 mg at 21:00
Entrainment in blind with melatonin
0.5 mg at 21:00
Hack et al., J Biol Rhythms 2003
• Melatonin PRC
• Therapeutic use:
• Blind
• Jetlag/Shift-work
Melatonin effects on circadian rhythms
Melatonin use for jet lag/shift work
Sharkey and Eastman., AJP, 2001
Melatonin use for jet lag/shift work
0.5 mg; 4 days
3 mg; 4 days
placebo; 4 days
Sharkey and Eastman., AJP, 2001
Melatonin use for jet lag/shift workAt what dose?
Sharkey and Eastman., AJP, 2001
• Melatonin PRC
• Therapeutic use:
• Blind
• Jetlag/Shift-work
• Delayed sleep phase syndrome
Melatonin effects on circadian rhythms
Melatonin use for delayed sleep phase syndrome
Dahlitz et al., Lancet, 1991
Randomized placebo-controlled crossover trial in 8 patients4 week administration; 5 mg melatonin; 1 h before fixed bedtime (23:00)
NB Unclear whether due to phase advance or direct effects on sleep
• Melatonin PRC
• Therapeutic use
• Amplification endogenous melatonin rhythm
Melatonin effects on circadian rhythms
Exogenous melatonin can modulateamplitude of endogenous melatonin rhythm
Zaidan et al., Neuroendocrinology, 1994Human; 2ug/3h; i.v.
% o
f m
ax c
ontr
ol n
igh
t
Bothorel et al., Eur J Neurosci 2002
Rat; 1 mg/kg; s.c.
Exogenous melatonin can modulateamplitude of endogenous melatonin rhythm
Amplification dependent on circadian phaseof administration
Rat; 1 mg/kg; s.c.
Bothorel et al., Eur J Neurosci 2002
Rat; 2.5 and 25 uM
reversed microdialysis
into SCN
Amplification mediated via the SCN
Bothorel et al., Eur J Neurosci 2002
Overview
• Melatonin regulation• Melatonin influence on SCN• Melatonin effects on circadian system• Melatonin effects on sleep
Melatonin effects on Sleep
• At what circadian phase?
Melatonin effects on Sleep
• At what circadian phase?
During daytime but not during nighttime in young healthy subjects1. Melatonin2. SCN
Melatonin effects on Sleep
• At what circadian phase?• In whom might it be useful at night?
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?
Melatonin effects on Sleep
• At what circadian phase?• In whom?• At what dose?
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?
melatonin
Paraventricular nucleusof the hypothalamus
Intermediolateral cell columnof the spinal cord
thoracic
melatonin
Paraventricular nucleusof the hypothalamus
Intermediolateral cell columnof the spinal cord
cervical
Scheer et al., submitted
Melatonin effects on Sleep
• At what circadian phase?• In whom?• At what dose?• Acute or repeated administration
required?
Randomized, double-blind, placebo-controlled, cross-over design
Arrows indicate recordings Scheer et al., Hypertension, 2004
Scheer et al., submitted
- Single capsule: no effect on blood pressure
- Prolonged supplementation:
Scheer et al., Hypertension, 2004
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
Melatonin effects on Sleep
• At what circadian phase?• In whom?• At what dose?• Acute or repeated administration
required?• By what mechanism?
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
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)
Time for questions
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