Methylcobalamin amplifies melatonin-induced circadian phase shifts by facilitation of melatonin synthesis in the rat pineal gland

Brain Res. 1998 Jun 8;795(1-2):98-104. doi: 10.1016/s0006-8993(98)00262-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Chemistry / drug effects
  • Chromatography, High Pressure Liquid
  • Circadian Rhythm / drug effects*
  • Dose-Response Relationship, Drug
  • Drinking Behavior / drug effects
  • Hydroxyindoleacetic Acid / analysis
  • Male
  • Melatonin / biosynthesis*
  • Melatonin / physiology*
  • Motor Activity / drug effects
  • Pineal Gland / drug effects
  • Pineal Gland / metabolism*
  • Pineal Gland / surgery
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / analysis
  • Vitamin B 12 / analogs & derivatives*
  • Vitamin B 12 / metabolism
  • Vitamin B 12 / pharmacology


  • Serotonin
  • Hydroxyindoleacetic Acid
  • mecobalamin
  • Melatonin
  • Vitamin B 12