Incorporation coefficients k(*) of intravenously injected [(3)H]arachidonic acid from blood into brain reflect the release from phospholipids of arachidonic acid by receptor-initiated activation of phospholipase A(2) (PLA(2)). In unanesthetized adult rats, 2.5 mg/kg intraperitoneally (i.p.) (+/-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), which is a 5-HT(2A/2C) receptor agonist, has been reported to produce the behavioral changes of what is known as the 5-HT(2) syndrome, but only a few small regional decrements in brain glucose metabolism. In this study, 2.5 mg/kg i.p. DOI, when administered to unanesthetized rats, produced widespread and significant increases, of the order of 60%, in k(*) for arachidonate, particularly in neocortical brain regions reported to have high densities of 5-HT(2A) receptors. The increases could be entirely blocked by chronic pretreatment with mianserin, a 5-HT(2) receptor antagonist. The results suggest that the 5-HT(2) syndrome involves widespread brain activation of PLA(2) via 5-HT(2A) receptors, leading to the release of the second messenger, arachidonic acid. Chronic mianserin, a 5-HT(2) antagonist, prevents this activation.