title: Chronic intraperitoneal injection of interferon-alpha reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate.
abstract: Interferon-alpha therapy is associated with a high rate of depression, but the pathophysiological mechanisms remain unclear. The purpose of the present study was to investigate the effects of i.p. administered interferon-alpha on monoaminergic neurotransmission in the brain. The levels of monoamines and associated metabolites were measured in various regions of the rat brain using a high-performance liquid chromatography-electrochemical detection system. The serotonin transporter mRNA levels were also measured using in situ hybridization. After 1 day, dopamine turnover was diminished in the cortex. Norepinephrine turnover was decreased in most regions tested after 4 days. However, these changes were transient. After 14 days, serotonin turnover was increased in the frontal cortex and hippocampus in rats given a dose of 20 000 IU/kg; in the frontal cortex, hippocampus, amygdala, thalamus, hypothalamus and brainstem in those on 200 000 IU/kg; and in the thalamus and hypothalamus in those on 2 000 000 IU/kg (all P < 0.05). However, 14-day treatment did not significantly change serotonin transporter mRNA levels. Next, the question of whether interferon-alpha affects monoamine levels via induction of nitric oxide (NO), was investigated. However, there were no changes in either NO2- or NO3-, as markers of NO production, in any brain regions after 14-day treatment. These results suggest that chronic peripheral administration of interferon-alpha induces metabolic changes in the central serotonin system. Further investigation is needed to determine exactly how this cytokine affects the central serotonin system and to assess whether a central serotonin abnormality is involved in interferon-induced depression.
authors.affiliation: Department of Psychiatry, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Sato
authors.forename: Eiji
authors.initials: E
authors.lastname: Suzuki
authors.forename: Masamoto
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Jun'ichi
authors.initials: J
authors.lastname: Semba
authors.forename: Shigeru
authors.initials: S
authors.lastname: Watanabe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyaoka
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D006801:Humans; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D007370:Interferon Type I / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009566:Nitrates / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis*
chemical_list: D000998:Antiviral Agents; D015306:Biogenic Monoamines; D007370:Interferon Type I; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin