LITHIUM AND OTHER MOOD STABILIZERS EFFECTIVE IN BIPOLAR DISORDER TARGET THE RAT BRAIN ARACHIDONIC ACID CASCADE. A critical review evaluated the arachidonic acid (AA, 20:4n-6) cascade hypothesis for actions of lithium and other FDA-approved mood stabilizers in bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered lithium, carbamazepine, valproate, or lamotrigine each downregulated brain AA metabolism, and is consistent with upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain phospholipids, cyclooxygenase-2 expression, and prostaglandin E2 concentration. Lithium and carbamazepine also reduced expression of cytosolic phospholipase A2 (cPLA2) IVA, which releases AA from membrane phospholipids, whereas valproate uncompetitively inhibited in vitro acyl-CoA synthetase-4, which recycles AA into phospholipid. Topiramate and gabapentin, which are ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical antipsychotics olanzapine and clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic NMDA and dopaminergic D2 receptor activation, while lithium enhanced the signal during cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the antidepressants fluoxetine and imipramine, which switch BD depression to mania, increased AA turnover and cPLA2 IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD mania than depression. The AA hypothesis for mood stabilizer action is consistent with our reports that low-dose aspirin reduced morbidity in patients taking lithium, and that high n-3 and/or low n-6 polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD patients. IP3 ACCUMULATION AND/OR INOSITOL DEPLETION ARE SEPARATE DOWNSTREAM EFFECTS OF LITHIUM. The inositol depletion hypothesis for lithium (Li)'s mood stabilization in bipolar disorder (BD) suggests that the drug modulates brain inositol metabolism. With Dr. Galila Agam, we compared frontal cortex and hippocampal phosphoinositol and phosphoinositide labeling following intracerebroventricular 3H-inositol in wildtype (WT), WT Li-treated, IMPA1 KO and SMIT1 KO mice, to elucidate Li's interaction with inositol metabolic pathways. Our findings suggest that Li's inhibition of inositol monophosphatase-1 (IMPA1) affects the phosphatidylinositol signaling system by depleting inositol followed by decreasing phosphoinositide levels and by elevating inositol monophosphate levels followed by accumulation of phosphoinositols. VALNOCTAMIDE, A NON-TERATOGENIC AMIDE DERIVATIVE OF VALPROIC ACID, INHIBITS ARACHIDONIC ACID ACTIVATION IN VITRO BY RECOMBINANT ACYL-COA SYNTHETASE-4. Valproic acid (VPA), a mood stabilizer used in bipolar disorder (BD), uncompetitively inhibits acylation of arachidonic acid (AA) by recombinant AA-selective acyl-CoA synthetase 4 (Acsl4) at an enzyme inhibition constant (Ki ) of 25 mM. Inhibition may account for VPA's therapeutic effect against BD. However, VPA is teratogenic. We tested whether valnoctamide (VCD), a non-teratogenic amide derivative of a VPA chiral isomer, which had antimanic potency in a phase III BD trial, also inhibits recombinant Acsl4. Rat Acsl4-flag protein was expressed in E coli. Using Michaelis-Menten kinetics, activation of AA to AA-CoA by Acsl4 was inhibited uncompetitively by VCD, with a Ki of 6.38 mM. at a lower Ki than VPA, VCD and other non-teratogenic Acsl4 inhibitors might be considered further for treating BD. We are now evaluating data on whether VCD inhibits brain AA turnover in unanaesthetized rats. TRANSIENT POSTNATAL FLUOXETINE REDUCES CYTOCHROME P450 4A METABOLITES Of ARACHIDONIC ACID IN ADULT MICE. Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine, an antidepressant, alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and the protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). We hypothesized that 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, would be reduced in adult mice treated transiently and postnatally with fluoxetine. Male mice pups were injected i.p. daily with a therapeutically relevant dose fluoxetine (10 mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Transient postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) during adulthood, but did not change other eicosanoid concentrations. Transient postnatal administration of fluoxetine to mice results in reduced brain ARA metabolism involving CYP4A and 20-HETE formation during their adulthood. This animal model may be relevant to effects of pregnant women and children treated with SSRI, which has been reported in some studies to lead to disturbed behavior and even suicide in early life. BRAIN ARACHIDONIC ACID TURNOVER IS NOT ALTERED IN FLINDERS SENSITIVE LINE RAT MODEL OF HUMAN DEPRESSION. Brain serotonergic signaling is coupled to arachidonic acid (AA) releasing calcium-dependent phospholipase A2. Increased brain serotonin concentrations and disturbed serotonergic neurotransmission have been reported in the Flinders sensitive line (FLS) rat model of depression, suggesting that brain AA metabolism is altered in this line. To test this hypothesis, 14C-AA was intravenously infused for 5 min in FSL and control unanaesthetized rats and labeled and unlabeled brain lipids were measured to derive the rate of brain AA turnover using my established kinetic model. Turnover did not differ significantly between controls and FSL rats. These results are consistent with clinical evidence, based on drug responsiveness, that bipolar depression is not associated with upregulated brain AA metabolism, and that serotonin levels in rats can influence brain AA metabolism in multiple ways. MITOCHONDRIAL DYSFUNCTION AND LIPID PEROXIDATION IN RAT FRONTAL CORTEX BY CHRONIC NMDA ADMINISTRATION CAN BE PARTIALLY PREVENTED BY LITHIUM TREATMENT. Chronic N-methyl-d-aspartate (NMDA) administration to rats may help to investigate excitotoxicity mediated by glutamatergic hyperactivity. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's neuroprotective efficacy.

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Kim, Helena K; Isaacs-Trepanier, Cameron; Elmi, Nika et al. (2016) Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment. J Psychiatr Res 76:59-65
Blanchard, Helene C; Taha, Ameer Y; Rapoport, Stanley I et al. (2015) Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders. Prostaglandins Leukot Essent Fatty Acids 96:25-30
Blanchard, Helene; Chang, Lisa; Rezvani, Amir H et al. (2015) Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression. Neurochem Res 40:2293-303
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
Rapoport, Stanley I (2014) Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. ACS Chem Neurosci 5:459-67
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
Ramadan, Epolia; Blanchard, Helene; Cheon, Yewon et al. (2014) Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice. Prostaglandins Leukot Essent Fatty Acids 90:191-7
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
Modi, Hiren R; Basselin, Mireille; Taha, Ameer Y et al. (2013) Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: a potential drug for bipolar disorder. Biochim Biophys Acta 1831:880-6
Kim, Hyung-Wook; Cheon, Yewon; Modi, Hiren R et al. (2012) Effects of chronic clozapine administration on markers of arachidonic acid cascade and synaptic integrity in rat brain. Psychopharmacology (Berl) 222:663-74

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