Melatonin Counters the 5-fluorouracil-induced Decrease in Brain Serotonin and Dopamine Levels

It has been demonstrated that both 5-fluorouracil and melatonin inhibit rat liver tryptophan-2,3-dioxygenase activity. This study sought to examine the effects that this inhibition has on the levels of various neurotransmitters in the brain. By inhibiting TDO, melatonin increases brain serotonin levels. Melatonin also increases dopamine levels but does not alter norepinephrine levels. 5-Fluorouracil has been found to decrease brain levels of all three neurotransmitters (i.e. serotonin, norepinephrine and dopamine). This could be due to the antineoplastic inhibiting DNA synthesis and gene expression of the enzymes required in the synthesis of these neurotransmitters. The decrease in norepinephrine levels induced by 5-fluorouracil could also be due to decreases in serotonin and dopamine levels. Dopamine can be converted to norepinephrine, whose release can be induced by serotonin. Even though 5-fluorouracil and melatonin alter brain serotonin levels, neither drug alters the conversion of serotonin to the metabolite 5-hydroxy-indole acetic acid. The same is true for the dopamine metabolite 3,4-dihydroxyphenylacetic acid. By decreasing the levels of norepinephrine, serotonin and dopamine, 5-fluorouracil could contribute to the development or exacerbation of depression in cancer patients. Melatonin, if administered together with 5-fluorouracil, could counter this 5-fluorouracil-induced depression by significantly increasing brain serotonin and dopamine levels. The use of melatonin as adjunctive therapy with 5-fluorouracil to improve patients' quality of life needs to be investigated further. doi: 10.5214/ans.0972.7531.2006.130201