Methylcobalamin amplifies melatonin-induced circadian phase shifts by facilitation of melatonin synthesis in the rat pineal gland.
Effects of methylcobalamin (methyl-B12), a putative drug for treating human circadian rhythm disorders, on the melatonin-induced circadian phase shifts were examined in the rat. An intraperitoneal injection of 1-100 microg/kg melatonin 2-h before the activity onset time (CT 10) induced phase advances of free-running activity rhythms in a dose-dependent manner (ED50=1.3 microg/kg). Injection of methyl-B12 (500 microg/kg) prior to melatonin (1 microg/kg) injection induced larger phase advances than saline preinjected controls, while the injection of methyl-B12 in combination with saline did not induce a phase advance. These results indicate amplification of melatonin-induced phase advances by methyl-B12. Pinealectomy abolished the phase alternating effect of methyl-B12, suggesting a site of action within the pineal gland. In fact, methyl-B12 significantly increased the content of melatonin in the pineal collected 2-h after activity onset (CT 14). In contrast, no difference in melatonin content was found at CT 10, indicating that the effect of methyl-B12 may be gated after the activity onset time when endogenous melatonin synthesis is known to increase. These results suggest that methyl-B12 amplifies melatonin-induced phase advances via an increase in melatonin synthesis during the early subjective night at a point downstream from the clock regulation.
Ikeda
M
M
Advanced Research Center for Human Sciences, Waseda University, Saitama, Japan. msikeda@mn.waseda.ac.jp
Asai
M
M
Moriya
T
T
Sagara
M
M
Inoué
S
S
Shibata
S
S
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D008297:Male; D008550:Melatonin / Q000096:biosynthesis* / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects; D010870:Pineal Gland / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis; D014805:Vitamin B 12 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C019476:mecobalamin; D008550:Melatonin; D014805:Vitamin B 12