Chronic carbamazepine administration reduces N-methyl-D-aspartate receptor-initiated signaling via arachidonic acid in rat brain.
BACKGROUND
Lithium and carbamazepine (CBZ) are used to treat mania in bipolar disorder. When given chronically to rats, both agents reduce arachidonic acid (AA) turnover in brain phospholipids and downstream AA metabolism. Lithium in rats also attenuates brain N-methyl-D-aspartic acid receptor (NMDAR) signaling via AA. We hypothesized that, like chronic lithium, chronic CBZ administration to rats would reduce NMDAR-mediated signaling via AA.


METHODS
We used our fatty acid method with quantitative autoradiography to image the regional brain incorporation coefficient k* of AA, a marker of AA signaling, in unanesthetized rats that had been given 25 mg/kg/day I.P. CBZ or vehicle for 30 days, then injected with NMDA (25 mg/kg I.P.) or saline. We also measured brain concentrations of two AA metabolites, prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)).


RESULTS
In chronic vehicle-treated rats, NMDA compared with saline increased k* significantly in 69 of 82 brain regions examined, but did not change k* significantly in any region in CBZ-treated rats. In vehicle- but not CBZ-treated rats, NMDA also increased brain concentrations of PGE(2) and TXB(2).


CONCLUSIONS
Chronic CBZ administration to rats blocks increments in the AA signal k*, and in PGE(2) and TXB(2) concentrations that are produced by NMDA in vehicle-treated rats. The clinical action of antimanic drugs might involve inhibition of brain NMDAR-mediated signaling involving AA and its metabolites.
Basselin
Mireille
M
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. mirvasln@mail.nih.gov
Villacreses
Nelly E
NE
Chen
Mei
M
Bell
Jane M
JM
Rapoport
Stanley I
SI
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002220:Carbamazepine / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004334:Drug Administration Schedule; D005230:Fatty Acids, Nonesterified / Q000097:blood; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D018709:Statistics, Nonparametric; D013929:Thromboxane B2 / Q000378:metabolism
D018692:Antimanic Agents; D005230:Fatty Acids, Nonesterified; D016194:Receptors, N-Methyl-D-Aspartate; D016718:Arachidonic Acid; D002220:Carbamazepine; D013929:Thromboxane B2; D015232:Dinoprostone