Brain Arachidonic Acid Incorporation and Precursor Pool Specific Activity During Intravenous Infusion of Unesterified [<sup>3</sup>H]Arachidonate in the Anesthetized Rat

Klaff

et al. 2002

Neuropsychopharmacol

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.

Section: Discussionmentioning

confidence: 99%

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

Klaff

et al. 2002

Neuropsychopharmacol

“…Unesterified AA in plasma rapidly replaces the quantity lost, as AA is nutritionally essential and cannot be synthesized de novo in vertebrate tissue or elongated significantly from its precursor, linoleic acid (18 : 2 n-6) (DeMar et al, 2004b;Holman, 1986;Washizaki et al, 1994). Replacement is proportional to PLA 2 activation and can be imaged by injecting radiolabeled AA intravenously, then measuring regional brain radioactivity by quantitative autoradiography.…”

Section: Introductionmentioning

confidence: 99%

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

Basselin

Bell

et al. 2005

Neuropsychopharmacol

106

132

It has been proposed that lithium is effective in bipolar disorder (BD) by inhibiting glutamatergic neurotransmission, particularly via N-methyl-D-aspartate receptors (NMDARs). To test this hypothesis and to see if the neurotransmission could involve the NMDARmediated activation of phospholipase A 2 (PLA 2 ), to release arachidonic acid (AA) from membrane phospholipid, we administered subconvulsant doses of NMDA to unanesthetized rats fed a chronic control or LiCl diet. We used quantitative autoradiography following the intravenous injection of radiolabeled AA to measure regional brain incorporation coefficients k* for AA, which reflect receptormediated activation of PLA 2 . In control diet rats, NMDA (25 and 50 mg/kg i.p.) compared with i.p. saline increased k* significantly in 49 and 67 regions, respectively, of the 83 brain regions examined. The regions affected were those with reported NMDARs, including the neocortex, hippocampus, caudate-putamen, thalamus, substantia nigra, and nucleus accumbens. The increases could be blocked by pretreatment with the specific noncompetitive NMDA antagonist MK-801 ((5R,10S)-( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate) (0.3 mg/kg i.p.), as well by a 6-week LiCl diet sufficient to produce plasma and brain lithium concentrations known to be effective in BD. MK-801 alone reduced baseline values for k* in many brain regions. The results show that it is possible to image NMDA signaling via PLA 2 activation and AA release in vivo, and that chronic lithium blocks this signaling, consistent with its suggested mechanism of action in BD.

“…Incorporation of AA into neural membranes was found to be very rapid; in awake rats, more than 90% of brain radioactivity was esterified within 1 minute, mostly in the sn-2 position of phospholipids (Washizaki et al, 1994). Radioactivity in neural membrane lipids did not significantly decrease for up to 4 hours after injection (DeGeorge et al, 1989;Rapoport, 1999).…”

mentioning

confidence: 99%

Brain Incorporation of [¹¹C]Arachidonic Acid in Young Healthy Humans Measured with Positron Emission Tomography

Giovacchini

J Cereb Blood Flow Metab

Channing³

et al. 2002

Self Cite

Summary: Arachidonic acid (AA) is an important second messenger involved in signal transduction mediated by phospholipase A 2 . The goal of this study was to establish an in vivo quantitative method to examine the role of AA in this signaling process in the human brain. A simple irreversible uptake model was derived from rat studies and modified for positron emission tomography (PET) to quantify the incorporation rate K* of [ 11 C]AA into brain. Dynamic 60-minute three-dimensional scans and arterial input functions were acquired in 8 young healthy adults studied at rest. Brain radioactivity was corrected for uptake of the metabolite [ 11 C]CO 2 . K* and cerebral blood volume (V b ) were estimated pixel-by-pixel and were calculated in regions of interest. K* equaled 5.6 ± 1.2 and 2.6 ± 0.5 L · min −1 · mL −1 in gray and white matter, respectively. K* and V b values were found to be unchanged with data analysis periods from 20 to 60 minutes. Thus, PET can be used to obtain quantitative images of the incorporation rate K* of [ 11 C]AA in the human brain. As brain incorporation of labeled AA has been shown in awake rats to be increased by pharmacological activation associated with phospholipase A 2 -signaling, PET and [ 11 C]AA may be useful to measure signal transduction in the human brain.