MOOD STABILIZERS LAMOTRIGINE BLOCKS NMDA RECEPTOR-INITIATED ARACHIDONIC ACID SIGNALING IN RAT BRAIN: IMPLICATIONS FOR EFFICACY IN BIPOLAR DISORDER. Hyperglutamatergic dysfunction is considered to contribute to bipolar disorder and Alzheimer disease. We showed that lamotrigine (LTG), an a FDA-approved mood stabilizer used for treating bipolar disorder (BD), reduces AA signaling in rat brain coupled to activation of glutamatergic NMDA (N-methyl-D-aspartate) receptors. These receptors allow calcium into the cell, which in turn activates AA-selective cytoplasmic phospholipase A2 (cPLA2) to release AA from membrane phospholipid. NMDA or saline was administered acutely to unanesthetized rats that had been treated p.o. daily for 42 days with vehicle or a therapeutically relevant dose of LTG. Regional brain AA incorporation was measured using quantitative autoradiography after intravenous 1-14CAA infusion, as were other AA cascade markers. Chronic LTG compared to vehicle blocked the AA signal produced by acute NMDA, and also reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA-binding activity of the COX-2 transcription factor, NF-kappaB, within the AA cascade. Since AA cascade and NMDAR signaling markers are upregulated in the BD brain, LTG may be effective in BD by dampening these changes (4) . CHRONIC VALPROATE BLOCKS DOPAMINE D2-LIKE RECEPTOR-MEDIATED BRAIN SIGNALING VIA ARACHIDONIC ACID IN RATS. Lithium and carbamazepine, approved for BD, attenuate brain dopaminergic D2-like receptor signaling involving arachidonic acid (AA) in unanesthetized rats. We showed that chronic valproic acid (VPA), an effective mood-stabilizer , also attenuates the AA signal in unanesthetized rats, which was produced by an acute dose of the D2 receptor agonist, quinpirole, and reduced brain concentrations of the AA metabolites prostaglandin (PG)E2 and thromboxane (TX)B2. These results further support our hypothesis that mood stabilizers effective in BD generally downregulate brain dopaminergic D2-like receptor-signaling involving AA(5). VALPROATE REDUCES RAT BRAIN ARACHIDONIC ACID METABOLISM BY UNCOMPETITIVELYINHIBITING ACYL-COA SYNTHETASE-4. After reporting that chronic valproate (VPA) reduced AA turnover in brain phospholipids of unanesthetized rats, we identified an acyl-CoA synthetase (Acsl4) isoenzyme that converts AA to AA-CoA as VPA's target, using different enzyme flag proteins expressed in E. coli. Inhibition followed Michaelis-Menten kinetics and was uncompetitive and selective for AA compared with other fatty acid, with high catalytic efficiency. Inhibition of Acsl4 may contribute to VPA's efficacy against BD. As a follow up, we are testing other drugs that inhibit Acsl-4 in vitro as potential mood stabilizers(7). GABAPENTIN'S LACK OF EFFECT ON RAT BRAIN ARACHIDONIC ACID METABOLISM AGREES WITH ITS INEFFICACY AGAINST BIPOLAR DISORDER. In rats, FDA-approved mood stabilizers used for BD downregulate brain markers of AA metabolism, which are upregulated in postmortem BD brain. Phase III clinical trials showed that the anticonvulsant gabapentin (GP) is ineffective in treating BD. Using molecular techniques, we confirmed that chronic Gp did not significantly alter rat brain AA metabolic markers, consistent with its lack of clinical efficacy (6) CHRONIC LITHIUM REDUCES INFLAMMATION-RELATED UPREGULATED BRAIN ARACHIDONIC ACID METABOLISM IN HIV-1 TRANSGENIC RAT. HIV-1 transgenic (Tg) rats, a model for human HIV-1 associated neurocognitive disorder (HAND), show upregulated markers of brain arachidonic acid (AA) metabolism and neuroinflammation after 7 months of age. Since lithium decreases brain AA metabolism in control rats and a rat lipopolysaccharide model of neuroinflammation, and appears to do so in HAND, we hypothesized that lithium would dampen upregulated brain AA metabolism in HIV-1 Tg rats. We confirmed this by measuring regional brain AA incorporation using qquantitative autoradiography, after intravenous 1-(14)CAA infusion in unanesthetized 10-month-old HIV-1 Tg and age-matched wildtype that had been fed a control or LiCl diet for 6 weeks. Incorporation was significantly higher in HIV-1 Tg than wildtype rats fed the control diet. Since lithium treatment dampened upregulated brain AA metabolism in HIV-1 Tg rats, it may prove therapeutic in HIV-1 patients with HAND and neuroinflammation through a comparable effect. (3) II. ATYPICAL ANTIPSYCHOTICS OLANZAPINE DECREASES RAT BRAIN ARACHIDONIC ACID METABOLISM BY REDUCING ITS PLASMA AVAILABILITY. Olanzapine, an atypical antipsychotic, is used to treating BD, Alzheimer disease and schizophrenia. We used our in vivo model to show that chronic olanzapine decreased brain AA metabolism (incorporation and turnover in brain phospholipids) in unanesthetized rats, by the plasma concentration of AA, and its availability to brain. This observation supports the hypothesis that drugs effective in BD downregulate the brain AA cascade, and suggests that dietary deprivation of AA (20:4n-6) and its shorter chain precursor, linoleic acid (18:2n-6), could enhance olanzapines antipsychotic action in patients (1). CHRONIC CLOZAPINE DOWNREGULATES MARKERS OF RAT BRAIN ARACHIDONIC ACID CASCADE AND SYNAPTIC INTEGRITY. Clozapine is an atypical antipsychotic used for treating schizophrenia (SZ) and BD. In both diseases brain AA cascade markers are upregulated. Similar to olanzapine, chronic clozapine reduced rat brain AA cascade markers: cyclooxygenase (COX) activity and concentration of proinflammatory PGE2. It also showed neuroprotective action, by increasing brain expression of brain derived neurotrophic factor (BDNF) and of a marker of post-synaptic dendritic spines, drebrin. These effects were associated with increased expression of docosahexaenoic acid (DHA)-selective calcium-independent type VIA iPLA2. These results show overlap with effects of mood stabilizers and olanzapine, and support targeting of the brain AA cascade as a common mechanism of action of both classes of drug. Dietary deprivation of AA and LA could enhance clozapines antipsychotic efficacy(2).

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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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