title: Oseltamivir (Tamiflu) increases dopamine levels in the rat medial prefrontal cortex.
abstract: Oseltamivir (Tamiflu), a neuraminidase inhibitor, is effective for treating both seasonal flu and H5N1 influenza A virus infection. Oseltamivir is generally well tolerated, and its most common adverse effects are nausea and vomiting. However, neuropsychiatric behaviors including jumping and falling from balconies by young patients being treated by oseltamivir have been reported from Japan; this has led to warnings against its prescribing by many authorities. The pharmacological mechanism of the neuropsychiatric effects of oseltamivir remains unclear. Many studies reported that changes in neurotransmission and abnormal behaviors are closely related. We investigated the changes in dopamine and serotonin metabolism after systemic administration of oseltamivir in the medial prefrontal cortex (mPFC) of rats by using microdialysis. After systemic administration of oseltamivir (25mg/kg or 100mg/kg; intraperitoneally (i.p.)), extracellular dopamine in the mPFC was significantly increased as compared to the control values; 3,4-dihydroxyphenylacetic acid and homovanillic acid, the metabolites of dopamine, had also increased significantly. Serotonin was unchanged after the administration of oseltamivir. These findings suggest that oseltamivir increased dopamine release in the mPFC; further, they suggest that the increase in dopamine during oseltamivir treatment may have caused abnormal behaviors in young patients. In cases where oseltamivir is prescribed to children, close observation is required.
authors.affiliation: Department of Hospital Pharmacy, Jichi Medical University, Shimotsuke-shi, Tochigi 329-0498, Japan. yoshino@jichi.ac.jp
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Yoshino
authors.forename: Koichi
authors.initials: K
authors.lastname: Nisijima
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Shioda
authors.forename: Kunio
authors.initials: K
authors.lastname: Yui
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kato
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D017551:Microdialysis; D053139:Oseltamivir / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D053139:Oseltamivir; D012701:Serotonin; D004298:Dopamine; D006719:Homovanillic Acid