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

Abstract

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.

Chronic Lithium Administration to Rats Selectively Modifies 5-HT2A/2C Receptor-Mediated Brain Signaling Via Arachidonic Acid

“…This difference is consistent with a dose effect. The increments in k* caused by 2.5 mg/kg DOI could be blocked by preadministration of the 5-HT 2A/2C antagonist, mianserin, further supporting a 5-HT 2A/2C -mediated activation of PLA 2 (Qu et al, 2003).…”

“…DOI to increase k* for AA (Table 1 and Qu et al, 2003), DOI at 2.5 and 50 mg/kg i.p. in unanesthetized rats decreases regional cerebral metabolic rates for glucose, rCMR glc , measured with 2-deoxy-D-glucose (Freo et al, 1991).…”

“…DOI, a hallucinogen (Sadzot et al, 1989), has a high and equal affinity for 5-HT 2A and 5-HT 2C receptors (http://kidb.cwru.edu/pdsp/php, 2003), which can be coupled to PLA 2 (Bayon et al, 1997;Qu et al, 2003). We chose a DOI dose of 1 mg/kg i.p.…”

“…We chose a DOI dose of 1 mg/kg i.p. rather than the 2.5 mg/kg that we used previously (Qu et al, 2003), since the latter dose produced large increments (about 60%) in k* and we wished a more graded response to minimize any interactions between DOI and lower affinity non-5-HT 2A/2C receptors (Abi-Saab et al, 1999;Kuroki et al, 2003;Obata et al, 2003;Ramirez et al, 1997;Scruggs et al, 2000). Furthermore, 1 mg/kg DOI is reported to have significant central effects in rats (Bull et al, 2004;Ichikawa et al, 2002).…”

D-Amphetamine Stimulates D2Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

“…These receptors, like D 2 -like receptors, can be coupled to PLA 2 activation and AA release (Berg et al, 1998;Garcia and Kim, 1997;KurraschOrbaugh et al, 2003;Pavoine et al, 2003;Qu et al, 2003). However, raclopride's ability to block k* increments following 2.5 mg/kg D-amphetamine (Table 2) indicates that the increments did not directly involve serotonin or epinephrine-initiated signaling.…”