fluvoxamine and sapropterin

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.. 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.. 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.. 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.. 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.

Topics: Animals; Biopterins; Depressive Disorder; Dopamine; Fluvoxamine; Housing, Animal; Injections, Subcutaneous; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mesencephalon; Mice; Mice, Inbred Strains; Nerve Tissue Proteins; Prefrontal Cortex; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Plasma Membrane Transport Proteins; Social Isolation

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.

Topics: Animals; Biopterins; Dose-Response Relationship, Drug; Fluvoxamine; Hippocampus; Male; Mice; Selective Serotonin Reuptake Inhibitors; Serotonin; Social Isolation; Stress, Physiological