Fraction is converted to AA-CoA by AA-selective acyl-CoA synthetase (Acsl)-4, then is re-esterified into membrane by lysophospholipid choline acyltransferase (LPCAT)-3. When administered chronically to rats, every of the 4 mood stabilizers interferes with neuroreceptor-mediated activation of cPLA2, reduces COX-2 activity and PGE2 concentration inside the brain. Valproate, lamotrigine, plus the antipsychotics olanzapine and clozapine also every single minimize COX-2 gene transcription inside the nucleus through NF-B. Lithium and carbamazepine each reduce cPLA2 IVA expression by lowering its gene transcription by AP-2, whereas valproate uncompetitively inhibits AA-selective Acsl-4. Both lithium and carbamazepine improve GRK-3, which may well lower G-protein neuroreceptor coupled activation of cPLA2. The figure also illustrates diffusion of circulating unlabeled unesterified AA and radiolabeled AA* into the cellular unesterified AA pool that may be offered for reacylation.18 See text for information.Buy2300099-98-1 Prepared by Dr.BuyN3-PEG4-C2-Pfp ester Chuck T. Chen as adapted from Rao et al.11aphenyl)-as-triazine), have no widespread structure that would recommend a specific popular target.1 Since the discovery of lithium’s efficacy against BD some 65 years ago,five several hypotheses have been recommended to clarify its action,1 a few of that are presented within this volume. Within this Critique, I present evidence for the arachidonic acid (AA) cascade hypothesis, though other actively investigated hypotheses include the following: (1) Myo-inositol depletion (inhibition of inositol monophosphatase (IMPase) within the phosphatidylinositide cycle).6 (two) Inhibition of glycogen synthase kinase-3 (GSK3).7 (3) Inhibition of protein kinase C. This hypothesis has been proposed to explain the action of Tamoxifen against bipolar mania.8 (four) Inhibition of NMDA/AMPA receptors. Thishypothesis is constant with evidence that both the N-methyl(NMDA) receptor antagonist ketamine, plus the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist riluzole, showed efficacy in bipolar depression.9 It overlaps to some extent the AA cascade hypothesis, considering that each of the mood stabilizers blocks an AA signal triggered by injected NMDA in rats (see below).D-aspartate2. THE ARACHIDONIC CASCADE HYPOTHESIS two.1. The AA Cascade. In contrast to lots of in the other hypotheses, the AA cascade hypothesis for lithium’s action will not determine a single enzyme, protein, or receptor target of lithium. Rather, this hypothesis encompasses a technique of ordered metabolic reactionsdx.doi.org/10.1021/cn500058v | ACS Chem. Neurosci. 2014, five, 459-ACS Chemical NeuroscienceReviewTable 1. Effects of Each of 4 Chronically Administered Mood Stabilizers in Unanesthetized Rats on Arachidonic Acid Signaling Provoked by Acute Administration of NMDA, Dopaminergic D2, Cholinergic muscarinic M1,3,five or Serotonergic 5-HT2A/2C agonist, NMDA, Quinpirole, Arecoline, and two,5-Dimethoxy-4-iodoamphetamine (DOI)adrug effects on arachidonic acid signal receptor subtype coupling to cPLA2 agonistb antagonistc mood stabilizers lithium carbamazepine valproate lamotrigine glutamatergic NMDA signal Ca2+ coupled NMDA MK-801 dopaminergic D2 signal quinpirole raclopride or butaclamol -e cholinergic muscarinic M1,three,5 signal G-protein coupled arecoline atropine -e -e -e serotonergic 5-HT2A/2C signal DOI mianserin d -e -e -ea Specificity of a receptor effect was confirmed by blocking the AA signal in independent experiments with pretreatment with MK-801, raclopride or butaclamol, atropin.PMID:24179643