The anxiogenic-like effect of caffeine in two experimental procedures measuring anxiety in the mouse is not shared by selective A2A adenosine receptor antagonists

Rationale: The elevated plus-maze and the light/dark box are two established anxiety tests in rodents, which are useful to screen putative anxiogenic effects of drugs. Objective: Caffeine is well known to promote anxious behaviour in humans and animal models, but the precise site of action of the drug is still a matter of debate. The present study investigated whether the anxiogenic effects of caffeine observed in mice depend on the blockade of A_2A receptor. First, the effects induced by the non-selective drug caffeine were compared with those elicited by two selective A_2A receptor antagonists over a wide range of doses in the same experimental conditions. The effects of A_2A or A₁ adenosine receptor agonists and of a selective A₁ adenosine receptor antagonist were also investigated. Second, wild-type and A_2A receptor knockout mice offered another approach to delineate the role played by A_2A receptor in caffeine’s anxiogenic effects. Methods: Mice were exposed to the elevated plus-maze or to the light/dark box for 5 min after acute or chronic administration of tested drugs. Results: Caffeine acutely administered (50 or 100 mg/kg IP) induced anxiety-like effects in both procedures. Its chronic administration (50 mg/kg IP twice daily) for 1 week or consumption in the drinking water (0.3 g/l) for 8 days or 2 months were also anxiogenic in the plus-maze test. The A_2A receptor antagonists ZM241385 (up to 60 mg/kg IP) and SCH58261 (up to 10 mg/kg IP) were devoid of acute effects in both tests. One week administration of ZM241385 (30 mg/kg IP) or SCH58261 (3 mg/kg IP) had no effects in the plus-maze test. An antagonist (DPCPX) and an agonist (CPA) at A₁ receptors had no acute effects on anxiety-related indices, whereas an A_2A receptor agonist (CGS 21680) displayed non-specific motor effects in the plus-maze test. Acute administration of caffeine (50 mg/kg IP) induced no clear-cut anxiety-like effects in the plus-maze test in A_2A receptor knockout mice that exhibited higher basal anxiety levels than wild-type mice. Chronic administration (50 mg/kg IP twice daily) for 1 week elicited less anxiety-like behaviour in A_2A receptor knockout than in wild-type mice. Conclusions: Adaptative mechanisms following mutation in A_2A receptors or their long-term blockade after chronic ingestion of caffeine may be responsible for increase proneness to anxiety. However, the short-term anxiety-like effect of caffeine in mice might not be related solely to the blockade of adenosine A_2A receptors, since it is not shared by A_2A selective antagonists. Received: 21 March 1999 / Final version: 24 June 1999