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Synaptic and behavioral interactions of oseltamivir (Tamiflu) with neurostimulants

Washington University, School of Medicine, Department of Psychiatry, St. Louis, Missouri Izumiy{at}wustl.edu

K Tokuda

Washington University, School of Medicine, Department of Psychiatry, St. Louis, Missouri

KA O’Dell

Washington University, School of Medicine, Department of Psychiatry, St. Louis, Missouri

CF Zorumski

Washington University, School of Medicine, Department of Psychiatry, St. Louis, Missouri

T Narahashi

Northwestern University, Feinberg School of Medicine, Department of Molecular Pharmacology and Biological Chemistry, Chicago, Illinois

Oseltamivir (Tamiflu), a neuraminidase inhibitor, is widely used for treatment of influenza. Because abnormal behaviors have been observed in some Japanese teenagers following oseltamivir use, its safety has been questioned. Oseltamivir is known to alter neuronal function and behavior in animals, particularly when administered in combination with ethanol. Based on this, it has been hypothesized that interactions of oseltamivir with other drugs may result in altered CNS excitability in this study. It has been found that injection of ephedrine and caffeine overcame inactivity induced by oseltamivir and ethanol but did not alter changes in novelty seeking behavior in a Y-maze test. In ex-vivo hippocampal slices, oseltamivir carboxylate (OTC), an active form of oseltamivir, alters excitability in the absence of ethanol. In slices pretreated with OTC, long-term depression (LTD), a form of synaptic plasticity that is correlated with Y-maze performance was not altered if caffeine or ephedrine was administered individually. However, LTD could not be induced in slices pretreated with OTC if caffeine and ephedrine were administered simultaneously. These observations suggest that combination of oseltamivir with other neurostimulants may alter synaptic plasticity and this may contribute to behavioral changes associated with the drug.

Key Words: avian influenza • caffeine • ephedrine • long-term depression • oseltamivir • Tamiflu

Human & Experimental Toxicology, Vol. 27, No. 12, 911-917 (2008)
DOI: 10.1177/0960327109102367


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