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.
BACKGROUND
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 A(1 )adenosine receptor agonists and of a selective A(1) 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 A(1) 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.
El Yacoubi
M
M
UPRESA 6036 CNRS, U.F.R. de Médecine & Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.
Ledent
C
C
Parmentier
M
M
Costentin
J
J
Vaugeois
J M
JM
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000284:Administration, Oral; D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D002110:Caffeine / Q000008:administration & dosage*; D003624:Darkness; D004334:Drug Administration Schedule; D007274:Injections, Intraperitoneal; D008027:Light; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000008:administration & dosage; D010627:Phenethylamines / Q000008:administration & dosage; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000008:administration & dosage; D011930:Reaction Time / Q000187:drug effects; D043705:Receptor, Adenosine A2A; D014227:Triazines / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage; D014970:Xanthines / Q000008:administration & dosage
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D018696:Neuroprotective Agents; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D002110:Caffeine; C048599:N(6)-cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine