Ischaemia rapidly increases the concentration of cAMP in the brain by mechanism(s) which still remain undefined. In the present study significant enhancement of cAMP generation was found in vitro after brain ischaemia induced by decapitation or cardiac arrest. The particulate fraction from ischaemic brain accumulated considerably more cAMP and responded more effectively to stimulation by noradrenaline (NE), histamine (Hi) and adenosine than that prepared from normoxic controls. The most pronounced effect was observed immediately after ischaemic insult and proceeded to normalize during 24 hours of postischaemic recovery. The activation of cAMP production by NE and Hi, but not 2-chloradenosine (2-CA), was totally dependent on the presence of endogenous adenosine and calcium. The synergism of 2-CA with NE or Hi on cAMP accumulation was observed. Its disappearance after adenosine deaminase treatment indicates that the postischaemic activation of adenosine A2 receptors may be positively modulated by NE and Hi. These results strongly suggest that primary functional changes in the cell-membrane signalling system had been induced by the ischaemic insult.