Evidence for the involvement of the adenosine A2A receptor in the lowered susceptibility to pentylenetetrazol-induced seizures produced in mice by long-term treatment with caffeine

Long-term caffeine intake has been reported to decrease the susceptibility to convulsants in mice. Occurrence of seizures following long-term oral administration of caffeine (0.3 g/l) was investigated using adenosine A2A receptor knockout (A2AR KO) and control (A2AR WT) mice. Clonic seizures induced by acute pentylenetetrazol (PTZ, 50 mg/kg i.p.) were significantly attenuated in adenosine A2AR KO mice drinking only water and reduced by a 14-day caffeine treatment in adenosine A2AR WT mice. In addition we showed a protecting effect of a 21-day caffeine treatment in A2AR WT mice against kindled seizures induced by PTZ in an increasing dose schedule. Summing up, these protective effects against PTZ-induced seizures occurring when adenosine A2AR is absent or chronically blocked by a relevant dose of caffeine may be related to a decreased neuronal excitability.