Responsiveness of norepinephrine (NE)–sensitive cyclic AMP (cAMP)‐generating systems was determined in slices from different areas of the rat cerebral cortex in which FeCl2 solution was injected unilaterally into the sensorimotor cortex to induce epileptic activity. In anterior cortical areas of rats in which the appearance of electrographic isolated spikes was dominant either ipsilaterally or contralaterally to the injection site 8–10 days after the injection, the cAMP accumulations elicited by NE and an NE‐phentolamine combination were greater on the side of dominant spike activity than on the other. In anterior cortical areas of rats showing dominant spike activity on either side of the cortex 31–60 days after the injection, the cAMP accumulation elicited by NE was smaller on the dominant side than on the other. In anterior cortical areas of rats showing nearly equal spike activity on the two sides 31–60 days after the injection, the cAMP accumulations elicited by NE and an NE‐phentolamine combination were greater on the side ipsilateral to the injection site than on the other. In anterior and posterior cortical areas of rats in which the appearance of spike and wave complexes, as well as isolated spikes, was detected 31–60 days after the injection, the cAMP accumulations elicited by NE and combinations of NE and phentolamine or propranolol were greater on the side ipsilateral to the injection site than on the other. The elicitation by an NE‐propranolol combination, but not by an NE‐phentolamine combination, of cAMP accumulation was almost completely inhibited by 8‐phenyltheophylline. These results suggest that alterations in NE‐sensitive cAMP‐generating systems of the cortex involving α‐ and β‐adrenoceptors and adenosine receptors are related to the neurochemical process of iron‐induced epilepsy. Copyright © 1990, Wiley Blackwell. All rights reserved