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


CONCLUSIONS
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.
Miura
H
H
Department of Psychiatry, School of Medicine, Nagoya University, Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan. hmiura@med.nagoya-u.ac.jp
Qiao
H
H
Kitagami
T
T
Ohta
T
T
Ozaki
N
N
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000209:etiology; D004298:Dopamine / Q000737:chemistry* / Q000378:metabolism; D016666:Fluvoxamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006799:Housing, Animal; D007279:Injections, Subcutaneous; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D008636:Mesencephalon / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000737:chemistry* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012934:Social Isolation / Q000523:psychology
D001708:Biopterins; D004298:Dopamine; D016666:Fluvoxamine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse; C003402:sapropterin