ANTIMANIC THERAPIES TARGET BRAIN ARACHIDONIC ACID SIGNALING. ? Evidence from our laboratory, obtained by administering anti-bipolar agents and antidepressants chronically to rats so as to produce therapeutically relevant plasma concentrations, suggested that the common mechanism of action of the effective antimanic antibipolar drugs (lithium, carbamazepine and valproic acid) involves downregulation of the brain arachidonic acid cascade (AA, 20:4n-6) , and that the cascade is upregulated in the disease itself. This work was reviewed in detail, and the AA cascade hypothesis for anti-manic drug action was further elaborated (1).? ? FLUOXETINE UPREGULATES THE BRAIN ARACHIDONIC ACID CASCADE IN RAT BRAIN. ? Some antidepressants, if given during the depressive phase of bipolar disorder, accelerate a switch back to mania. Relevant to these observations, we found that chronic (21 days followed by 3 days of washout) administration to rats of the selective serotonin reuptake inhibitor (SSRI) antidepressant, fluoxetine, upregulated incorporation and turnover of AA in brain phospholipids, as well as mRNA, protein and activity levels of AA-selective cytosolic phospholipase A2 (cPLA2), markers of the brain arachidonic acid cascade (2, 3). These results can be explained if bipolar mania involves an upregulated arachidonic acid cascade, as suggested by our multiple studies with anti-manic drugs (1), and if fluoxetine, in addition to having a selective antidepressant action, also upregulates this cascade. ? ? LAMOTRIGINE, APPROVED FOR TREATING BIPOLAR DEPRESSION, DOES NOT ALTER ARACHIDONIC ACID TURNOVER IN RAT BRAIN PHOSPHOLIPID. ? Lamotrigine is the only FDA-approved monotherapy for bipolar depression, and does not appear to increase switching to bipolar mania (see above). When given chronically to adult rats, unlike fluoxetine, lamotrigine did not change AA turnover in brain phospholipids. These results suggest that only antidepressants that increase the AA cascade promote switching to mania (4). ? ? TWO AGENTS APPROVED FOR TREATING BIPOLAR MANIA INCREASE MEMBRANE GRK3 IN RAT BRAIN.? G-protein receptor kinases (GRKs) are a family of kinases involved in the desensitization of agonist-activated G-protein coupled receptors. We found that chronic administration to rats of lithium and carbamazepine (but not of valproic acid), mood stabilizers effective against bipolar mania, increased GRK3 expression in the membrane but not the cytosolic fraction of brain. This change is consistent with an effect of these agents on neuroreceptor mediated signal transduction (5). ? ? MOOD STABILIZERS DOWNREGULATE TRANSCRIPTION OF ENZYMES OF ARACHIDONIC CASCADE IN RAT BRAIN. ? We reported that chronically administered carbamazepine and valproic acid, to produce therapeutically relevant plasma concentrations, downregulate the brain AA cascade in rat brain. They do this in part by reducing mRNA levels of cyclooxygenase (COX)-2 and AA-selective cytosolic phospholipase A2 (cPLA2), respectively, in brain. In the current studies, we showed that these mRNA effects arose because carbamazepine reduced brain expression of the cPLA2 transcription factor, activator protein (AP)-2 in the first instance, and valproate reduced brain expression of the COX-2 transcription factor, NF-kappaB in the second instance (6, 7).? ? AN ANIMAL MODEL OF AN UPREGULATED BRAIN ARACHIDONIC ACID CASCADE.? Based on our reports that drugs effective against the mania of bipolar disorder downregulate brain AA turnover when given chronically to rats, as well as other markers of the AA cascade, we created an animal with an upregulated brain AA cascade as a potential model for such upregulation in bipolar disorder. Glutamatergic NMDA receptors are known to allow calcium into the cell to stimulate cytosolic cPLA2 and release AA from membrane phospholipid. We injected a subconvulsive dose in rats of N-methyl-D-aspartate (NMDA) daily for 21 days, and measured markers of the AA cascade in brain. Chronically injected rats had elevated expression of cPLA2 and its transcription factor, activator protein (AP)-2, whereas acutely NMDA injected rats did not have these changes. Thus, the chronic NMDA-treated rat is a usable model of an upregulated brain arachidonic acid cascade, which may characterize bipolar disorder as well, because of neuroinflammation, Alzheimer disease (3).

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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
Rao, Jagadeesh S; Bazinet, Richard P; Rapoport, Stanley I et al. (2007) Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-kappaB DNA binding activity and COX-2 mRNA. Bipolar Disord 9:513-20
Lee, Ho-Joo; Rao, Jagadeesh S; Ertley, Renee N et al. (2007) Chronic fluoxetine increases cytosolic phospholipase A(2) activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat. Psychopharmacology (Berl) 190:103-15
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

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