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.) ( 7 )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.

Fluoxetine, a selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, is used widely to treat depression and related disorders. By inhibiting presynaptic 5-HT reuptake, fluoxetine is thought to act by increasing 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT 2A/2C receptors. These receptors can be coupled via a G-protein to phospholipase A 2 (PLA 2 ), which when activated releases the second messenger arachidonic acid from synaptic membrane phospholipids. To image this activation, fluoxetine (10 mg/kg) or saline vehicle was administered i.p. to unanesthetized rats, and regional brain incorporation coefficients k* of intravenously injected radiolabeled arachidonic acid were measured after 30 min. Compared with vehicle, fluoxetine significantly increased k* in prefrontal, motor, somatosensory, and olfactory cortex, as well as in the basal ganglia, hippocampus, and thalamus. Many of these regions demonstrate high densities of the serotonin reuptake transporter and of 5-HT 2A/2C receptors. Brain stem, spinal cord, and cerebellum, which showed no significant response to fluoxetine, have low densities of the transporters and receptors. The results show that it is possible to image quantitatively PLA 2 -mediated signal transduction in vivo in response to fluoxetine.