Chronic administration of valproic acid reduces brain NMDA signaling via arachidonic acid in unanesthetized rats.
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-(14)C]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 E(2) (PGE(2)) and thromboxane B(2) (TXB(2)). VPA pretreatment reduced baseline concentrations of PGE(2) and TXB(2), 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.
Basselin
Mireille
M
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. mirvasln@mail.nih.gov
Chang
Lisa
L
Chen
Mei
M
Bell
Jane M
JM
Rapoport
Stanley I
SI
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001345:Autoradiography; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects*; D013929:Thromboxane B2 / Q000378:metabolism; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D016718:Arachidonic Acid; D013929:Thromboxane B2; D014635:Valproic Acid; D016202:N-Methylaspartate; D015232:Dinoprostone