Previous immunohistochemical studies have shown that c-Fos proteins induced by DOI, a 5-HT2A/2C agonist, are present in the population of cortical neurons, which are devoid of 5-HT2A receptors. A mechanism of the induction of c-Fos proteins expression by DOI is still unclear. However, the involvement of the 5-HT2A and AMPA, but not 5-HT2C receptors in this process has been reported. In the present study, we investigated whether arachidonic acid, a retrograde messenger, is involved in the above mechanism of c-Fos induction. Phospholipase A2 pathway, which leads to the subsequent generation of arachidonic acid and its metabolites, is known to be coupled to 5-HT2A receptor activation. The inhibition of arachidonic acid cascade both at the level of phospholipase A2 (by dexamethasone, 1.5 mg/kg) or at the level of cyclooxygenases that catalyze arachidonic acid biotransformation (by indomethacin, 3 mg/kg), decreased the number of c-Fos immunopositive cells after induction by DOI (8 mg/kg). Our results suggest that arachidonic acid cascade may be involved in the induction of c-Fos proteins by DOI in the rat parietal cortex.