Fluvoxamine,a selective serotonin reuptake inhibitor,suppresses tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice

Rationale Tetrahydrobiopterin (BH₄) is a coenzyme of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), rate-limiting enzymes of monoamine biosynthesis. According to the monoamine hypothesis of depression, antidepressants will restore the function of the brain monoaminergic system, and BH₄ concentration.Objective To investigate the effects of fluvoxamine on BH₄ levels and dopamine (DA) and serotonin (5-HT) turnover in the mesoprefrontal system, incorporating two risk factors of depression, social isolation and acute environmental change.Methods Male ddY mice (6W) were divided into two housing groups, i.e. group-housing (eight animals per cage; 35 days), and isolation-housing (one per cage; 35 days), SC injected with fluvoxamine (20 or 40 mg/kg; days 29–35), and exposed to 20-min novelty stress (day 35). The levels of BH₄, DA, homovanilic acid (HVA), 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the prefrontal cortex and midbrain.Results Under the group-housing condition, novelty stress significantly increased BH₄ levels in both regions, and the HVA/DA ratio in the midbrain, whereas it did not change any parameters in either region under the isolation-housing condition. In the prefrontal cortex, fluvoxamine significantly decreased the 5-HIAA/5-HT ratio under the group-housing condition, and BH₄ levels and the HVA/DA ratio under the isolation-housing condition. In the midbrain, fluvoxamine significantly decreased all parameters, except for an increasing in the 5-HIAA/5-HT ratio under the isolation-housing condition.Conclusion Isolation-housing suppressed the increase of BH₄ levels and DA turnover elicited by novelty stress. Fluvoxamine suppressed BH₄ levels, and DA and 5-HT turnover. Fluvoxamine may have altered DA turnover by suppressing BH₄ levels.