Chronic NMDA administration to rats up-regulates frontal cortex cytosolic phospholipase A2 and its transcription factor, activator protein-2.
Excessive N-methyl-D-aspartate (NMDA) signaling is thought to contribute to bipolar disorder symptoms. Lithium and carbamazepine, effective against bipolar mania, are reported in rats to reduce brain transcription of an arachidonic acid selective calcium-dependent cytosolic phospholipase A(2) (cPLA(2)), as well as expression of one of its transcription factors, activator protein (AP)-2. In this study, we determined if chronic administration of NMDA (25 mg/kg i.p.) to rats would increase brain cPLA(2) and AP-2 expression, as these antimanic drugs are known to down-regulate excessive NMDA signaling. Administration of a daily subconvulsive dose of NMDA to rats for 21 days decreased frontal cortex NMDA receptor (NR)-1 and NR-3A subunits and increased cPLA(2) activity, phosphorylation, protein, and mRNA levels. The activity and protein levels of secretory phospholipase A(2) or calcium-independent phospholipase A(2) were not changed significantly. Chronic NMDA also increased the DNA-binding activity of AP-2 and the protein levels of its alpha and beta subunits. These changes were absent following acute (3 h earlier) NMDA administration. The changes, opposite to those found following chronic lithium or carbamazepine, are consistent with up-regulated arachidonic acid release due to excessive NR signaling and may be a contributing factor to bipolar mania.
Rao
Jagadeesh S
JS
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USADepartment of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Ertley
Renee N
RN
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USADepartment of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Rapoport
Stanley I
SI
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USADepartment of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Bazinet
Richard P
RP
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USADepartment of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Lee
Ho-Joo
HJ
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USADepartment of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D054513:Group IV Phospholipases A2; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D010741:Phospholipases A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2; D010766:Phosphorylation; D021122:Protein Subunits / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013347:Subcellular Fractions; D050656:Transcription Factor AP-2 / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018692:Antimanic Agents; D004268:DNA-Binding Proteins; D018690:Excitatory Amino Acid Agonists; C409466:NR1 NMDA receptor; C464437:NR3A NMDA receptor; D021122:Protein Subunits; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D050656:Transcription Factor AP-2; D016718:Arachidonic Acid; D016202:N-Methylaspartate; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2