The stimulatory effects of caffeine with oseltamivir (Tamiflu) on light-dark behavior and open-field behavior in mice.
Abnormal behaviors and death associated with the use of oseltamivir (Tamiflu) have emerged as a major issue in influenza patients taking the drug. Here, we investigated the mechanisms underlying the effects of oseltamivir on the behavior of mice using light-dark and open-field preference tests. Oseltamivir (75 and 150 mg/kg, intraperitoneally (i.p.)) alone affected neither time spent in the open area in the light-dark preference test nor ambulation in the open-field test at 2h post-injection. However, a non-selective adenosine A(1)/A(2) receptor antagonist, caffeine (10mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased time spent in the open area in the light-dark preference test. This enhancement was not inhibited by a benzodiazepine receptor antagonist, flumazenil (10-20mg/kg, subcutaneously (s.c.)). Enhancement of ambulation in the open-field test was also observed when caffeine (10mg/kg, i.p.) was combined with oseltamivir (150 mg/kg, i.p.). This enhancement was inhibited by a dopamine D(2) receptor antagonist, haloperidol (0.1mg/kg, s.c.). Furthermore, an adenosine A(2) receptor antagonist, SCH58261 (3mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased ambulation in the open-field test, while an adenosine A(1) receptor antagonist, DPCPX (1-3mg/kg, i.p.) did not. These findings suggest that the actions of oseltamivir may involve the dopamine and adenosine systems. Our findings suggest that due to the interaction between central blockade of adenosine A(2) receptors by caffeine, and oseltamivir-induced behavioral changes, patients being treated with oseltamivir should be closely monitored.
Uchiyama
Hidemori
H
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Toda
Akihisa
A
Imoto
Masumi
M
Nishimura
Satoko
S
Kuroki
Hiroaki
H
Soeda
Shinji
S
Shimeno
Hiroshi
H
Watanabe
Shigenori
S
Eyanagi
Reiko
R
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology*; D003624:Darkness; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D005106:Exploratory Behavior / Q000187:drug effects*; D005442:Flumazenil / Q000008:administration & dosage / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D053139:Oseltamivir / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D014970:Xanthines / Q000008:administration & dosage / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000998:Antiviral Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D018377:Neurotransmitter Agents; D011743:Pyrimidines; D014230:Triazoles; D014970:Xanthines; D053139:Oseltamivir; D002110:Caffeine; D005442:Flumazenil; C051360:1,3-dipropyl-8-cyclopentylxanthine; D006220:Haloperidol