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

• Caffeine (10 mg/kg) in combination with oseltamivir for 1 day increased ambulation.
• Caffeine (30 mg/kg) in combination with oseltamivir for 3 days increased ambulation.
• These enhancements were inhibited by an adenosine A2 receptor agonist.
• Oseltamivir carboxylate for 1 day (0.3 μg/mouse) alone increased ambulation.

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 (150 mg/kg, intraperitoneally (i.p.)) alone did not affect ambulation at 2 h post-injection. However, caffeine (10 mg/kg, i.p.) in combination with oseltamivir for 1 day increased ambulation. Moreover, caffeine (30 mg/kg, i.p.) in combination with oseltamivir for 3 days increased ambulation, but caffeine (10 mg/kg, i.p.) in combination with oseltamivir for 3 days did not increase. These enhancements were inhibited by an adenosine A2 receptor agonist, CGS21680 (0.2 mg/kg, subcutaneously (s.c.)). Furthermore, an adenosine A2 receptor antagonist, SCH58261 (1 and 3 mg/kg, i.p.) in combination with oseltamivir for 1 day increased ambulation. Moreover, SCH58261 (3 mg/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 (3 mg/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.