(1): The ability of lithium chloride treatment to reduce the convulsant threshold to cholinergic muscarinic drugs in rats, was shown to be related to its ability to enhance phospholipase A2 activation by these drugs, with the release of the second messenger and membrane excitant, arachidonic acid, from membrane phospholipids. This was demonstrated in awake rats fed lithium chloride chronically who were then administered subconvulsant doses of the cholinergic muscarinic agonist, arecoline. (2): Sodium valproate, used to treat bipolar disorder, when administered chronically to rats, reduced the brain activity of cyclooxygenase-1 and -2, and the brain concentrations of 11-dehydrothromboxane B2 and prostaglandin E2, metabolites of arachidonic acid produced via these enzymes. mRNA levels of the cyclooxygenase enzymes were unchanged. Comparison with observations following chronic lithium administration suggested that anti-bipolar disorder drugs generally target the conversion of arachidonic acid via cyclooxygenase-2 to prostaglandin E2 and related eicosanoids. (3): The basis for the reported reduction of arachidonic acid turnover in rat brain phospholipids, following the administration of valproic acid, is not understood. We showed in awake rats administered valproic acid that the reduction is not caused by activation of valproate to valproyl-CoA or by its incorporation into brain phospholipids. (4): Using immuno-histochemical techniques, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 were shown to co-localize at the plasma membrane of Purkinje cells in the monkey cerebellum, whereas cyclooxygenase-1 was found within punctate intracellular regions. These findings are consistent with functional coupling of cPLA2 and cyclooxygenase-2 at post-synaptic brain sites involved in receptor-mediated signaling. They suggest that an unesterified brain arachidonate pool released by cPLA2 is the precursor for prostaglandin formation via cyclooxygenase-2. (5): Feeding lithium chloride to rats has been shown to reduce the brain activity of cPLA2. It does this by reducing transcription of the gene for this enzyme, not by reducing the enzyme phosphorylation necessary for its activation.

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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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