We found that substances present in monkey cerebrospinal fluid (CSF) could inhibit [3H]-paroxetine binding in monkey brain preparations. The molecular weight of one of these inhibitory substances was approximately 2000, which is in agreement with earlier studies using human CSF. We also found that the inhibitory effect of the substances present in monkey CSF on [3H]-paroxetine binding decreased after 8 weeks of chronic fluvoxamine (5 mg/kg day, p.o.) treatment. These results suggest that the ability of a drug to decrease the activity of endogenous 5-HT uptake modulators may related to its antidepressive effects.