Brain levels of free fatty acids (FFA) and diacylglycerols (DAG) rise rapidly with the onset of seizures, reflecting activation of phospholipases A2 (PLA2) and C (PLC), respectively. However, the ictal/interictal accumulation of FFA attenuates as recurrent seizures continue. To assess the role of neuronal activity in stimulating PLA2 and C, we compared FFA and DAG in rat cerebral cortex during recurrent ictal periods as a function of associated levels of interictal activity. Pentobarbital-anesthetized rats were paralyzed, ventilated with 30% O2 and subjected to periodic pentylenetetrazol seizures at intervals of 5 min. Animals were killed with focused-microwave irradiation during either the 3rd or 15th seizure. The rise in cortical FFA levels during early seizures for 20:4, 22:6, and 18:0 was 3.6-, 2.5-, and 2.2-fold greater, respectively, when adjacent interictal activity was intense as compared to weak activity. During late seizures, this difference dropped to 2.2-fold for 20:4, the only FFA that showed a significantly higher value between robust versus weak interictal activity. In contrast, accumulation of DAG during early and late seizures was observed only when adjacent interictal activity was high. These results indicate that the cortical accumulation of FFA and DAG during ictal periods of similar intensity and duration depends upon the electrocortical activity during adjacent interictal periods.