Vol 5 n° 4 - Chronobiology and Mood Disorders
Past issues Contributors How to publish Contributions and comments Home
 
3 9 9 C l i n i c a l   r e s e a r c h Clinical applications of melatonin in circadian disorders Alfred J. Lewy, MD, PhD Keywords:  melatonin;  circadian  phase;  seasonal  affective  disorder;  circadian sleep disorder; the blind; jet lag; shift work Author  affiliations:  Sleep  and  Mood  Disorders  Laboratory,  Oregon  Health Science University, Portland, Ore, USA Address   for   correspondence:   Sleep   and   Mood   Disorders   Laboratory, Oregon  Health  Science  University,  3181  SW  Sam  Jackson  Park  Road, Portland, OR 97239, USA
 (e-mail: lewy@ohsu.edu) Chronobiological disorders and syndromes include sea- sonal affective disorder (SAD), total blindness, advanced and delayed sleep phase syndrome, jet lag, and shift work  maladaptation.  These  disorders  are  treated  by adjusting  circadian  phase,  using  appropriately  timed bright light exposure and melatonin administration (at doses of 0.5 mg or less). In some cases, it may be neces- sary to measure internal circadian phase, using the time when endogenous melatonin levels rise. © 2003, LLS SAS Dialogues Clin Neurosci. 2003;5:399-413. Copyright © 2003 LLS SAS.  All rights reserved www.dialogues-cns.org elatonin appears to be useful in two ways to the field of human chronobiology. One role is as a marker for biological rhythms.The other role is as a circadian phase- shifting agent. Both roles appear to be important. In virtually all organisms, melatonin is produced mainly during nighttime darkness.1,2 In most vertebrates, circu- lating melatonin levels are derived exclusively from the pineal gland.3,4 In most mammals, the changing duration of melatonin production throughout the year is the cue for  seasonal  rhythms.5  In  some  mammals,  such  as humans, a feedback loop exists between melatonin and the endogenous circadian pacemaker.6-13 An approximately 24-h (hence, circadian) rhythm in melatonin is generated by 12 h of (usually daytime) inhi- bition of an otherwise constantly “on” signal from the paraventricular nucleus of the hypothalamus.14 This inhi- bition comes from the endogenous circadian pacemaker, located in the suprachiasmatic nucleus (SCN).15-17 The pineal gland is then stimulated to produce melatonin for about 12 h via a neural pathway that traverses through the intermedullary column and thoracic sympathetic out- flow (Figure 1).18 Preganglionic neurons synapse in the superior cervical ganglion with postganglionic neurons that enter the cranium and innervate pinealocytes.19 The latter release the sympathetic neurotransmitter, norepi- nephrine, which stimulates b 1-adrenergic receptors and results in the synthesis and secretion of melatonin, which is  then  released  into  blood  and  cerebrospinal  fluid (CSF).20 Receptors for melatonin have been identified in a number of sites, including the SCN.21,22 The approximately 24-h rhythm generated by the SCN becomes precisely 24 h via photic input from ganglion cells in the retina.23,24 At least one novel photoreceptor has  been  identified  that  mediates  circadian  entrain- ment.25 The pathway from the retina to the hypothala- mus, the retinohypothalamic tract, is different from that which mediates vision.26 M