Abstract
The mood stabilizing drugs commonly used to treat bipolar disorder--lithium, valproic acid (VPA), and carbamazepine (CBZ)--limit the frequency of swings to either manic or depressive states. We previously showed that these drugs all have a common action on cultured neurons, which can be reversed by the addition of either inositol or specific inhibitors of the enzyme prolyl oligopeptidase (PO). Inhibition of PO activity is reported to enhance phosphoinositide (PIns) signaling consistent with the suggestion that mood stabilizers inhibit PIns signaling. We now report that VPA directly inhibits recombinant PO activity, which would have the opposite effect on PIns signaling. This unexpected result suggests a model that could explain the dual action of VPA in stabilizing mood: we propose that euthymic mood is dependent on stable PIns signaling and that VPA may limit mood swings to mania by decreasing PIns signaling, and that it may limit mood swings to depression by inhibiting PO and thus increasing PIns signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Antimanic Agents / pharmacology
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Antimanic Agents / therapeutic use
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Bipolar Disorder / drug therapy*
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Bipolar Disorder / metabolism
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Bipolar Disorder / physiopathology
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Brain / drug effects
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Brain / metabolism
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Brain / physiopathology
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Brain Chemistry / drug effects*
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Brain Chemistry / physiology
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Cells, Cultured
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Humans
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Models, Neurological
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Neurons / drug effects
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Neurons / metabolism
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Phosphatidylinositols / metabolism*
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Prolyl Oligopeptidases
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Rats
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Recombinant Fusion Proteins / drug effects
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Serine Endopeptidases / drug effects*
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Up-Regulation / drug effects
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Up-Regulation / physiology
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Valproic Acid / pharmacology*
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Valproic Acid / therapeutic use
Substances
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Antimanic Agents
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Phosphatidylinositols
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Recombinant Fusion Proteins
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Valproic Acid
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Serine Endopeptidases
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PREPL protein, human
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Prolyl Oligopeptidases