physiological roles and pharmacological effects of melatonin hms bwh frank a.j.l. scheer, ph.d....
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![Page 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](https://reader036.vdocuments.mx/reader036/viewer/2022062421/56649d275503460f949fdd05/html5/thumbnails/1.jpg)
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
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Overview
• Melatonin regulation• Melatonin influence on SCN• Melatonin effects on circadian system• Melatonin effects on sleep
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Overview
• Melatonin regulation
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Melatonin regulation
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Paraventricular nucleusof the hypothalamus
Intermediolateral cell columnof the spinal cord
melatonin
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melatonin
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melatonin
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Zeitzer et al., J Physiol 2000;526:695–702
Pla
sm
a m
ela
ton
in(p
rop
ort
ion
of
max)
1.0
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Zeitzer et al., J Physiol
2000;526:695–702
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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
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Salivary melatonin profile after administration of 100 mg atenolol ( ).
Deacon et al., Neurosci Lett, 1998
Beta-blockers suppress endogenous melatonin
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Overview
• Melatonin regulation• Melatonin influence on SCN
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• Although there is melatonin binding in various brain areas depending on the species, the SCN invariably shows strong binding.
Melatonin receptors
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from Weaver, In: Regulation of sleep and circadian rhythms 1999:197–262
Melatonin binding
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• Shifting SCN circadian rhythm
Melatonin effects on SCN
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Melatonin can phase-shift SCN neuronal activity in vitro
McArthur et al., Endocrinology, 1997
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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
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• Shifting SCN circadian rhythm
• Inhibition SCN-neuronal activity
Melatonin effects on SCN
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van der Top et al., Neuroscience, 2001
Melatonin inhibits SCN neuronal activity
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Liu et al., Neuron, 1997
… via MT1 (Mel1a) receptor
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Overview
• Melatonin regulation• Melatonin influence on SCN• Melatonin effects on circadian system
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• Melatonin PRC
Melatonin effects on circadian rhythms
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Human melatonin PRC
0.5 mg; 4 days
Lewy et al., Chronobiol Int, 1998
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Melatonin PRC and light PRC compared
Shifts by light/10
Lewy et al., Chronobiol Int, 1998
melatonin light
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• Melatonin PRC
• Therapeutic use:
• Blind
Melatonin effects on circadian rhythms
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Hack et al., J Biol Rhythms 2003
Entrainment in blind with melatonin
0.5 mg at 21:00
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Entrainment in blind with melatonin
0.5 mg at 21:00
Hack et al., J Biol Rhythms 2003
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• Melatonin PRC
• Therapeutic use:
• Blind
• Jetlag/Shift-work
Melatonin effects on circadian rhythms
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Melatonin use for jet lag/shift work
Sharkey and Eastman., AJP, 2001
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Melatonin use for jet lag/shift work
0.5 mg; 4 days
3 mg; 4 days
placebo; 4 days
Sharkey and Eastman., AJP, 2001
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Melatonin use for jet lag/shift workAt what dose?
Sharkey and Eastman., AJP, 2001
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• Melatonin PRC
• Therapeutic use:
• Blind
• Jetlag/Shift-work
• Delayed sleep phase syndrome
Melatonin effects on circadian rhythms
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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
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• Melatonin PRC
• Therapeutic use
• Amplification endogenous melatonin rhythm
Melatonin effects on circadian rhythms
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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
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Bothorel et al., Eur J Neurosci 2002
Rat; 1 mg/kg; s.c.
Exogenous melatonin can modulateamplitude of endogenous melatonin rhythm
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Amplification dependent on circadian phaseof administration
Rat; 1 mg/kg; s.c.
Bothorel et al., Eur J Neurosci 2002
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Rat; 2.5 and 25 uM
reversed microdialysis
into SCN
Amplification mediated via the SCN
Bothorel et al., Eur J Neurosci 2002
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Overview
• Melatonin regulation• Melatonin influence on SCN• Melatonin effects on circadian system• Melatonin effects on sleep
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Melatonin effects on Sleep
• At what circadian phase?
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Melatonin effects on Sleep
• At what circadian phase?
During daytime but not during nighttime in young healthy subjects1. Melatonin2. SCN
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Melatonin effects on Sleep
• At what circadian phase?• In whom might it be useful at night?
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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?
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Melatonin effects on Sleep
• At what circadian phase?• In whom?• At what dose?
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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?
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melatonin
Paraventricular nucleusof the hypothalamus
Intermediolateral cell columnof the spinal cord
thoracic
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melatonin
Paraventricular nucleusof the hypothalamus
Intermediolateral cell columnof the spinal cord
cervical
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Scheer et al., submitted
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Melatonin effects on Sleep
• At what circadian phase?• In whom?• At what dose?• Acute or repeated administration
required?
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Randomized, double-blind, placebo-controlled, cross-over design
Arrows indicate recordings Scheer et al., Hypertension, 2004
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Scheer et al., submitted
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- Single capsule: no effect on blood pressure
- Prolonged supplementation:
Scheer et al., Hypertension, 2004
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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
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Melatonin effects on Sleep
• At what circadian phase?• In whom?• At what dose?• Acute or repeated administration
required?• By what mechanism?
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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
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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)
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Time for questions