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Chronic Administration of Valproic Acid Reduces Brain NMDA Signaling via Arachidonic Acid in Unanesthetized Rats

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Abstract

Evidence that brain glutamatergic activity is pathologically elevated in bipolar disorder suggests that mood stabilizers are therapeutic in the disease in part by downregulating glutamatergic activity. Such activity can involve the second messenger, arachidonic acid (AA, 20:4n − 6). We tested this hypothesis with regard to valproic acid (VPA), when stimulating glutamatergic N-methyl-d-aspartate (NMDA) receptors in rat brain and measuring AA and related responses. An acute subconvulsant dose of NMDA (25 mg/kg i.p.) or saline was administered to unanesthetized rats that had been treated i.p. daily with VPA (200 mg/kg) or vehicle for 30 days. Quantitative autoradiography following intravenous [1-14C]AA infusion was used to image regional brain AA incorporation coefficients k*, markers of AA signaling. In chronic vehicle-pretreated rats, NMDA compared with saline significantly increased k* in 41 of 82 examined brain regions, many of which have high NMDA receptor densities, and also increased brain concentrations of the AA metabolites, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). VPA pretreatment reduced baseline concentrations of PGE2 and TXB2, and blocked the NMDA induced increases in k* and in eicosanoid concentrations. These results, taken with evidence that carbamazepine and lithium also block k* responses to NMDA in rat brain, suggest that mood stabilizers act in bipolar disorder in part by downregulating glutamatergic signaling involving AA.

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Abbreviations

AA:

Arachidonic acid (20:4n − 6)

PLA2 :

Phospholipase A2

cPLA2 :

Cytosolic PLA2

NMDA:

N-methyl-d-aspartic acid

PGE2 :

Prostaglandin E2

TXB2 :

Thromboxane B2

VPA:

Valproic acid

COX:

Cyclooxygenase

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute on Aging. None of the authors has a financial or other conflict of interest related to this work.

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  1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bldg 9, Room 1S126, MSC 0947, 9 Memorial Drive, Bethesda, MD, 20892, USA

    Mireille Basselin, Lisa Chang, Mei Chen, Jane M. Bell & Stanley I. Rapoport

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  1. Mireille Basselin
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Correspondence to Mireille Basselin.

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Basselin, M., Chang, L., Chen, M. et al. Chronic Administration of Valproic Acid Reduces Brain NMDA Signaling via Arachidonic Acid in Unanesthetized Rats. Neurochem Res 33, 2229–2240 (2008). https://doi.org/10.1007/s11064-008-9700-2

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