Our studies are confirming in several ways our hypothesis that drugs effective against the mania of bipolar disorder downregulated the brain AA cascade. ? ? Effective antimanic drugs reduce AA but not DHA turnover. Chronic therapeutically-relevant doses of carbamazepine and valproate, like lithium, reduced AA but not DHA turnover in brain phospholipids of awake rats, consistent with a common AA cascade effect (Bazinet et al. 2005b, a).? ? cPLA2 transcription and AP-2 are downregulated by lithium and carbamazepine, whereas valproate inhibits acyl-CoA synthetase. Lithium and carbamazepine in rats downregulated the enzyme that releases AA from brain phospholipid, cPLA2; and the factor AP-2 that regulates the transcription of this enzyme (Rao et al. 2005). Valproate inhibited an AA selective acyl-CoA synthetase as its likely mechanism of action on the brain AA cascade (Bazinet et al. 2006). The three drugs also affected kinases that phosphorylate relevant enzymes in the cascade (Rao et al. 2006a). ? ? Each of the three effective antimanic drugs downregulates rat brain COX-2 expression. Chronic lithium, carbamazepine and valproate each reduced rat brain COX-2 activity, as well as brain PGE2, a preferred AA product formed via COX-2. Valproate also reduced COX-1 protein and COX-2 mRNA (Rao et al. In press). ? ? Topiramate doesn't affect cascade. Topiramate, a suggested antimanic drug later proven ineffective, did not change AA or DHA turnover in rat brain phospholipid, or brain PLA2 or COX-2 expression (Lee et al. 2005)(Ghelardoni et al. 2005). Thus, clinical efficacy in bipolar mania correlates with a mood-stabilizer's ability to downregulate the rat brain AA cascade, and measuring the cascade can be used for screening potential antimanic agents.? ? Lithium can correct the suggested AA neurotransmission imbalance in bipolar mania. In rats fed a therapeutic dose of lithium for 6 weeks, the AA signal in response to a serotonin agonist was altered in visual and auditory regions, the dopamine and NMDA AA signals were blocked, and the cholinergic AA signal was upregulated (Basselin et al. 2005a, 2006b) (Basselin et al. 2005b). These findings suggest that bipolar mania reflects a neurotransmission imbalance consisting of excessive dopaminergic and NMDA, altered serotonergic, and reduced cholinergic transmission. ? ? Chronic lithium increases baseline glucose metabolism in rats. Baseline elevations in AA incorporation in auditory-visual areas in LiCl fed rats corresponded to elevated baseline values for glucose metabolism in these regions, which we measured with radiolabeled 2-deoxy-D-glucose (Basselin et al. 2006a). ? ? Lithium's modulation of neurotransmission patterns may reflect neuroreceptor desensitization. Chronic lithium as well as carbamazepine (but not valproate) increased rat brain membrane g-protein receptor kinase (GRK)-3 (Ertley et al. 2006). This increase may facilitate neuroreceptor desensitization and account for our finding that lithium reduced AA signaling via D2-like and 5-HT2A/2C receptors. ? ? Chronic fluoxetine increases the AA signal cascade. Chronically administered fluoxetine, which is used in depression, upregulated the brain AA signal at 3 days after washout, although the response to a hallucinogen acting at 5-HT2A/2C receptors was unaltered (Qu et al. 2006). Brain cPLA2 activity and AA turnover in phospholipids were both elevated by chronic fluoxetine in the absence of washout, consistent with fluoxetine upregulating activity and protein levels of brain cPLA2 but not sPLA2 or iPLA2. The cPLA2 increase correlated with increased nuclear AUF-1 RNA stabilizing protein, which recognizes a sequence on cPLA2 mRNA to increase its stability (Rao et al. 2006b).

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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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