Fluvoxamine, a selective serotonin reuptake inhibitor, suppresses tetrahydrobiopterin in the mouse hippocampus

In the present study, we investigated the effects of fluvoxamine, a selective serotonin reuptake inhibitor, on brain tetrahydrobiopterin (BH4) levels. We directly measured levels of BH4 by Tani and Ohno's direct method as well as the serotonin (5-HT) turnover ratio, i.e. 5-hydroxyindoleacetic acid (5-HIAA)/5-HT, after sub-acute s.c. injection of fluvoxamine in the hippocampus of mice. Our animal model incorporated two risk factors of depression, social isolation and acute environmental change. Male ddY mice (6W) were housed in isolation (1 per cage; 35 days), injected with fluvoxamine (20 or 40 mg/kg; days 29-35), and exposed to novelty stress (20 min; day 35). In the stress session, behavioral parameters, i.e. total distance and rearing behavior, were measured. Isolation housing increased both behaviors. Fluvoxamine attenuated rearing behavior, but did not influence total distance. Isolation housing increased BH4 levels. Novelty stress increased BH4 levels in group housing, although it did not change them in isolation housing. Fluvoxamine suppressed BH4 levels. In isolation housing, fluvoxamine increased 5-HT turnover ratios, while it decreased them in group housing. In conclusion, fluvoxamine, housing condition, and novelty stress regulated BH4 levels. Fluvoxamine may have changed behavior and 5-HT turnover by suppressing BH4 levels as well as by inhibiting 5-HT reuptake.