Melatonin research in mice: a review

There continues to be considerable interest in the physiological role(s) of the hormone melatonin and its potential as a drug more than 60 years after its discovery. While there is an emphasis on human studies, there is still a need for animal models in biology. Laboratory strains of mice remain at the forefront of much biomedical research for many reasons. However, in the case of melatonin research, mice represent a problem that is often not recognized by researchers entering from other fields of biomedicine. In this review, I have brought together the results of a large number of studies in which melatonin was measured in the pineal gland and blood of different mouse strains. The unequivocal conclusion to be drawn from the review is that the majority of laboratory mouse strains do not produce melatonin, whereas the CBA and C3H strains produce substantial amounts of melatonin during the late dark period. Of course, this has been known from studies conducted more than 30 years ago, but papers continue to be published that report high levels of melatonin in the pineal glands and blood and melatonin metabolites in the urine of melatonin deficient strains. Reasons for these erroneous results are discussed and center around the use of unvalidated, poorly documented immunoassays and inadequate sample preparation (i.e. direct versus extracted assays). Finally, I discuss the validity of using extraordinary high doses (as high as 200 mg/kg) of melatonin administered to melatonin deficient mice in experiments. It is hoped that the presentation of multiple sources of data in one place documenting the actual melatonin deficiency of the various strains will reduce the uncritical use of unreliable results to support the use of melatonin deficient strains in melatonin research.