1. Using our in vivo fatty acid method (AG000134-20 BPMS), we demonstrated that chronic lithium administration to rats enhanced brain cholinergic muscarinic receptor-mediated activation of PLA2, to release the second messenger, AA from membrane phospholipids. Such enhancement is consistent with lithium?s reported ability to reduce the convulsant threshold to cholinomimetics in rodents and the reported therapeutic efficacy of cholinomimetics in human bipolar disorder. 2. With our fatty acid method (AG000134-20 BPMS), we imaged serotonergic (5-HT) signal transduction involving arachidonic acid (AA) in awake rats. Acute administration of the 5-HT2A/2C receptor agonist, (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), or of fluoxetine (Prozac, an antidepressant that increases 5-HT in the synaptic cleft), stimulated brain incorporation of intravenously-injected radiolabeled AA, a marker of phospholipase A2 (PLA2) activation. The effect was blocked by pre-administration of a 5-HT2A/2C receptor antagonist. These results are consistent with fluoxetine being effective in depression by increasing AA release from membrane phospholipids through the 5-HT2A/2C - mediated activation of PLA2.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000145-04
Application #
6968662
Study Section
(BPMS)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Modi, Hiren R; Ma, Kaizong; Chang, Lisa et al. (2017) Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder. Psychiatry Res 254:279-283
Yuan, Zhi-Xin; Rapoport, Stanley I (2015) Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice. Prostaglandins Leukot Essent Fatty Acids 101:9-14
Modi, Hiren R; Basselin, Mireille; Rapoport, Stanley I (2014) Valnoctamide, a non-teratogenic amide derivative of valproic acid, inhibits arachidonic acid activation in vitro by recombinant acyl-CoA synthetase-4. Bipolar Disord 16:875-80
Modi, Hiren R; Taha, Ameer Y; Kim, Hyung-Wook et al. (2013) Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability. J Neurochem 124:376-87
Kim, H-W; Rapoport, S I; Rao, J S (2011) Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol Psychiatry 16:419-28
Cheon, Yewon; Park, Jee-Young; Modi, Hiren R et al. (2011) Chronic olanzapine treatment decreases arachidonic acid turnover and prostaglandin E? concentration in rat brain. J Neurochem 119:364-76
Chang, Yunyoung C; Kim, Hyung-Wook; Rapoport, Stanley I et al. (2008) Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: cross-talk between excitotoxicity and neuroinflammation. Neurochem Res 33:2318-23
Lee, Ho-Joo; Rao, Jagadeesh S; Chang, Lisa et al. (2007) Chronic lamotrigine does not alter the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat: implications for the treatment of bipolar disorder. Psychopharmacology (Berl) 193:467-74
Lee, Ho-Joo; Rao, Jagadeesh S; Rapoport, Stanley I et al. (2007) Antimanic therapies target brain arachidonic acid signaling: lessons learned about the regulation of brain fatty acid metabolism. Prostaglandins Leukot Essent Fatty Acids 77:239-46
Rao, Jagadeesh S; Ertley, Renee N; Rapoport, Stanley I et al. (2007) Chronic NMDA administration to rats up-regulates frontal cortex cytosolic phospholipase A2 and its transcription factor, activator protein-2. J Neurochem 102:1918-27

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