1. It has been hypothesized lithium may be effective in treating bipolar disorder by reducing brain dopamine signaling. We used our in vivo fatty acid method in unanesthetized rats, to show that it specifically reduced dopamine D2-like receptor signaling coupled to phospholipase A2 (PLA2) activation and the release the second messenger, arachidonic acid, from brain membrane phospholipid. (Basselin et al 2005a) 2. With regard to dopamine receptor activation (see #1), We used our fatty acid method in unanesthetized rats to demonstrate that brain D2-like but not D1-like receptors are coupled to phospholipase A2 activation and arachidonic acid release. This is consistent with the literature suggested that D1-like receptors are preferentially coupled to adenylate cyclase activation. We now have a pre-clinical basis for imaging disturbed D2-mediated signal transduction using positron emission tomography, in patients with Parkinson disease and attention deficit hyperactivity disorder. (Bhattacharjee et al 2005). 3. We used our fatty acid method to show that chronic administration of lithium to rats modified signal transduction via post-synaptic serotonergic 5-HT2A/2C receptors, coupled to phospholipase A2 activation and arachidonic acid release. This effect may be related to lithium's ability to ameliorate hallucinations in bipolar disorder. (Basselin et al 2005b) 4. We proposed that drugs used to treat the mania of bipolar disorder - lithium, carbamazepine and valproic acid - selectively target arachidonic acid turnover in brain phospholipid. This proposal was supported by three recent papers. (1) Chronically administered carbamazepine in rats selectively downregulated expression of brain cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2. cPLA2 selectively releases arachidonic acid from brain phospholipids, and cyclooxygenase-2 converts released arachidonic acid to prostaglandin E2. (2) Topiramate, suggested for use as a mood stabilizer but since withdrawn, had no effect on these enzymes. (3) Valproic acid, which reduces arachidonic acid turnover in brain phospholipids, did not affect turnover of docosahexaenoic acid, which is susceptible to a non-cPLA2 enzyme. (Ghelardoni et al 2005; Ghelardoni et al 2004) (Bazinet et al 2005) 5. Downregulation of brain cPLA2 expression by chronic lithium administration to rats was associated with decreased expression of the transcription factor AP-2, which regulates cPLA2 transcription. This may represent a primary affect of lithium on the arachidonic acid cascade. (Rao et al In press)

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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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