Suppressive effect of paroxetine, a selective serotonin uptake inhibitor, on tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice

Tetrahydrobiopterin (BH4) is a coenzyme of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), which are rate-limiting enzymes of monoamine biosynthesis. According to the monoamine hypothesis of depression, antidepressants will restore the function of the brain monoaminergic system and the BH4 concentration. In the present study, we investigated the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on the 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 (8W) were divided into two housing groups, i.e., group-housing (eight animals per cage; 28 days), and isolation-housing (one per cage; 28 days), being p.o.-administered paroxetine (5 or 10 mg/kg; days 15-28), and exposed to a 20-min novelty stress (day 28). The levels of BH4, DA, homovanilic acid (HVA), 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the prefrontal cortex and midbrain. In both the regions, novelty stress significantly increased BH4 levels under the isolation-housing condition, whereas these levels were decreased under the group-housing condition. Thus, social isolation altered the neurochemical response to novelty stress. Paroxetine significantly decreased BH4 levels under the isolation-housing condition, whereas decreased HVA/DA and 5-HIAA/5-HT ratios were observed under the group-housing condition. Thus, social isolation may have influenced the suppressive effects of paroxetine on BH4 levels as well as exerted an influence on DA and 5-HT turnover. We replicated our recent findings that SSRI, fluvoxamine, suppressed BH4 levels, as well as DA and 5-HT turnover in the mouse mesoprefrontal system.