Effect of adenosine system in the action of oseltamivir on behavior in mice

Abnormal behaviors and death associated with the use of oseltamivir (Tamiflu^®) have emerged as a major issue in influenza patients. We have previously reported that the mechanisms underlying the effects of caffeine, a non-selective adenosine A₁/A₂ receptor antagonist, combined with oseltamivir. Oseltamivir is rapidly hydrolyzed to its active form (oseltamivir carboxylate, OCB). In this study, we investigated the effects of an adenosine system and OCB on the action of oseltamivir on mice behavior. Oseltamivir for 1 day (150mg/kg, intraperitoneally (i.p.)) alone did not affect ambulation at 2h post-injection. However, caffeine (10mg/kg, i.p.) in combination with oseltamivir for 1 day increased ambulation. Moreover, caffeine (30mg/kg, i.p.) in combination with oseltamivir for 3 days increased ambulation, but caffeine (10mg/kg, i.p.) in combination with oseltamivir for 3 days did not increase. These enhancements were inhibited by an adenosine A₂ receptor agonist, CGS21680 (0.2mg/kg, subcutaneously (s.c.)). Furthermore, an adenosine A₂ receptor antagonist, SCH58261 (1 and 3mg/kg, i.p.) in combination with oseltamivir for 1 day increased ambulation. Moreover, SCH58261 (3mg/kg, i.p.) in combination with oseltamivir for 3 days increased ambulation, but SCH58261 (1 mg/kg, i.p.) in combination with oseltamivir for 3 days did not. Conversely, in phenobarbital (PB)-treated mice, caffeine (3mg/kg, i.p.) in combination with oseltamivir for 1 day increased ambulation. Moreover, OCB for 1 day (0.3 μg/mouse intracerebroventricular (i.c.v.)) alone increased ambulation. These findings suggest that the actions of oseltamivir may involve the adenosine systems and its metabolism. Our findings suggest an interaction between the central blockade of adenosine A₂ receptors by caffeine and OCB-induced behavioral changes.