Melatonin from cerebrospinal fluid but not from blood reaches sheep cerebral tissues under physiological conditions.

The pineal glandsecretes melatoninthat circulates in the blood and cerebrospinal fluid. We provide data that support the hypothesis that, in sheep and maybe in human, only the cerebrospinal fluid melatonin, and not the blood melatonin, can provide most of melatoninto the cerebral tissue in high concentrations, particularly in the periventricular area. The melatonincontent of sheep brain, our chosen animal model, was found in significant concentration gradients oriented from the ventricle(close to the cerebrospinal fluid) to the cerebral tissue, with concentrations varying by a factor of 1 to 125. The highest concentrations were observed close to the ventriclewall, whereas the lowest concentrations were furthest from the ventricles(407.0 ± 71.5 pg/ml compared to 84.7 ± 5.2 pg/ml around the third ventricle). This concentration gradient was measured in brain tissue collected at mid-day and at the end of the night. Nocturnal concentrations were higher than daytime concentrations, reflecting the diurnal variation in the pineal gland. The concentration gradient was not detected when melatoninwas delivered to the brain via the bloodstream. The diffusion of melatoninto cerebral tissues via cerebrospinal fluidwas supported by in vivo scintigraphy and autoradiography. 2-[(123) I]- melatonininfused into the cerebrospinal fluidquickly and efficiently diffused into the brain tissues, whereas [(123) I]-iodine (control) was mostly washed away by the cerebrospinal fluidflow and [(123) I]-BSA remained mostly in the cerebrospinal fluid. Taken together, these data support a critical role of cerebrospinal fluidin providing the brain with melatonin.