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