OBJECTIVE To investigate the possibility of direct transport of melatonin from the nasal cavity into the cerebrospinal fluid (CSF) after nasal administration in rats and to compare the animal results with a human study. METHODS Rats (n = 8) were given melatonin both intranasally in one nostril (40 microg/rat) and intravenously by bolus injection (40 microg/rat) into the jugular vein using a Vascular Access Port. Just before and after drug administration, blood and CSF samples were taken and analyzed by HPLC. RESULTS Melatonin is quickly absorbed in plasma (T(max) = 2.5 min) and shows a delayed uptake into CSF (T(max) = 15 min) after nasal administration. The melatonin concentration-time profiles in plasma and CSF are comparable to those after intravenous delivery. The AUC(CSF)/AUC(plasma) ratio after nasal delivery (32.7 +/- 6.3%) does not differ from the one after intravenous injection (46.0 +/- 10.4%), which indicates that melatonin enters the CSF via the blood circulation across the blood-brain barrier. This demonstrates that there is no additional transport via the nose-CSF pathway. These results resemble the outcome of a human study. CONCLUSIONS The current results in rats show that there is no additional uptake of melatonin in the CSF after nasal delivery compared to intravenous administration. This is in accordance with the results found in humans, indicating that animal experiments could be predictive for the human situation when studying nose-CSF transport.