Imaging Brain Phospholipase A2 Activation in Awake Rats in Response to the 5-HT2A/2C Agonist (±)2,5-Dimethoxy-4-Iodophenyl-2-Aminopropane (DOI)

In unanesthetized adult rats, an injection of the 5-HT2A/2C receptor agonist DOI (2.5 mg/kg intraperitoneally) caused widespread increases of about 60% in the incorporation coefficient of arachidonic acid from blood into brain, particularly in neocortical regions with high densities of 5-HT2A receptors. These increases were entirely blocked by chronic pretreatment with the 5-HT2 receptor antagonist mianserin. The findings suggest that the 5-HT2 syndrome involves widespread activation of phospholipase A2 via 5-HT2A receptors, leading to release of the second messenger arachidonic acid, and that chronic mianserin prevents this activation.

Study at a glance

Abstract

Incorporation coefficients k* of intravenously injected [3H]arachidonic acid from blood into brain reflect the release from phospholipids of arachidonic acid by receptor-initiated activation of phospholipase A2 (PLA2). In unanesthetized adult rats, 2.5 mg/kg intraperitoneally (i.p.) (±)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), which is a 5-HT2A/2C receptor agonist, has been reported to produce the behavioral changes of what is known as the 5-HT2 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-HT2A receptors. The increases could be entirely blocked by chronic pretreatment with mianserin, a 5-HT2 receptor antagonist. The results suggest that the 5-HT2 syndrome involves widespread brain activation of PLA2 via 5-HT2A receptors, leading to the release of the second messenger, arachidonic acid. Chronic mianserin, a 5-HT2 antagonist, prevents this activation.