title: IP3 accumulation and/or inositol depletion: two downstream lithium's effects that may mediate its behavioral and cellular changes.
abstract: Lithium is the prototype mood stabilizer but its mechanism is still unresolved. Two hypotheses dominate-the consequences of lithium's inhibition of inositol monophosphatase at therapeutically relevant concentrations (the 'inositol depletion' hypothesis), and of glycogen-synthase kinase-3. To further elaborate the inositol depletion hypothesis that did not decisively determine whether inositol depletion per se, or phosphoinositols accumulation induces the beneficial effects, we utilized knockout mice of either of two inositol metabolism-related genes-IMPA1 or SMIT1, both mimic several lithium's behavioral and biochemical effects. We assessed in vivo, under non-agonist-stimulated conditions,3H-inositol incorporation into brain phosphoinositols and phosphoinositides in wild-type, lithium-treated, IMPA1 and SMIT1 knockout mice. Lithium treatment increased frontal cortex and hippocampal phosphoinositols labeling by several fold, but decreased phosphoinositides labeling in the frontal cortex of the wild-type mice of the IMPA1 colony strain by ~50%. Inositol metabolites were differently affected by IMPA1 and SMIT1 knockout. Inositoltrisphosphate administered intracerebroventricularly affected bipolar-related behaviors and autophagy markers in a lithium-like manner. Namely, IP3but not IP1reduced the immobility time of wild-type mice in the forced swim test model of antidepressant action by 30%, an effect that was reversed by an antagonist of all three IP3receptors; amphetamine-induced hyperlocomotion of wild-type mice (distance traveled) was 35% reduced by IP3administration; IP3administration increased hippocampal messenger RNA levels of Beclin-1 (required for autophagy execution) and hippocampal and frontal cortex protein levels ratio of Beclin-1/p62 by about threefold (p62 is degraded by autophagy). To conclude, lithium affects the phosphatidylinositol signaling system in two ways: depleting inositol, consequently decreasing phosphoinositides; elevating inositol monophosphate levels followed by phosphoinositols accumulation. Each or both may mediate lithium-induced behavior.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Mental Health Center, Beer-Sheva, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Sade
authors.affiliation: Department of Psychiatry and Centre for High-Throughput Biology, University of British Columbia Vancouver, BC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Toker
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Tel Aviv, Israel.
authors.forename: N Z
authors.initials: NZ
authors.lastname: Kara
authors.affiliation: School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Tel Aviv, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Einat
authors.affiliation: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rapoport
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Moechars
authors.affiliation: Metabolism Program Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: G T
authors.initials: GT
authors.lastname: Berry
authors.affiliation: Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Mental Health Center, Beer-Sheva, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Bersudsky
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|Mental Health Center, Beer-Sheva, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Agam
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001343:Autophagy / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D007294:Inositol / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010716:Phosphatidylinositols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D027981:Symporters / Q000235:genetics*
chemical_list: D018692:Antimanic Agents; D010716:Phosphatidylinositols; D012333:RNA, Messenger; C508355:SLC5A3 protein, mouse; D027981:Symporters; D007294:Inositol; D015544:Inositol 1,4,5-Trisphosphate; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D018021:Lithium Chloride