The anxiogenic-like effect of caffeine in two experimental procedures measuring anxiety in the mouse is not shared by selective A(2A) adenosine receptor antagonists

Rationale: The elevated plus-maze and the light/dark box are two establishe d anxiety tests in rodents, which are useful to screen putative anxiogenic effects of drugs. Objective: Caffeine is well known to promote anxious beha viour in humans and animal models, but the precise site of action of the dr ug 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 ,, receptor. First, the effects induced by the non-selective drug caffeine were compared with those elicited by two selective A(2A) receptor antagonis ts over a wide range of doses in the same experimental conditions. The effe cts of Az, or A, adenosine receptor agonists and of a selective Al adenosin e receptor antagonist were also investigated. Second, wild-type and A,, rec eptor knockout mice offered another approach to delineate the role played b y A(2A) receptor in caffeine's anxiogenic effects. Methods: Mice were expos ed 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 admin istered (50 or 100 mg/kg IP) induced anxiety-like effects in both procedure s. Its chronic administration (50 mg/kg IP twice daily) for 1 week or consu mption in the drinking water (0.3 g/l) for 8 days or 2 months were also anx iogenic in the plus-maze test. The A2A 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 SCH582 61 (3 mg/kg IP) had no effects in the plus-maze test. An antagonist (DPCPX) and an agonist (CPA) at A, receptors had no acute effects on anxiety-relat ed indices, whereas an A(2A) receptor agonist (CGS 21680) displayed non-spe cific 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 t est in A(2A) receptor knockout mice that exhibited higher basal anxiety lev els than wild-type mice. Chronic administration (50 mg/kg IP twice daily) f or 1 week elicited less anxiety-like behaviour in A(2A) receptor knockout t han in wild-type mice. Conclusions. Adaptative mechanisms following mutatio n in A(2A) receptors or their long-term blockade after chronic ingestion of caffeine may be responsible for increase proneness to anxiety. However, th e short-term anxiety-like effect of caffeine in mice might not be related s olely to the blockade of adenosine A(2A) receptors, since it is not shared by A(2A) selective antagonists.