Chronic carbamazepine administration reduces N-methyl-D-aspartate receptor-initiated signaling via arachidonic acid in rat brain

Abstract

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.

Figure 1. Coronal autoradiographs of brain showing effects of NMDA and carbamazepine on regional AA incorporation coefficients k* in rats

Values of k* (ml/sec/g brain × 10⁻⁴) are given on a color scale from 3 (blue) to 8 (yellow-orange). Abbreviations: Acg, anterior cingulate cortex; Aud, auditory cortex; AV, anteroventral thalamus nucleus; CPu, caudate-putamen; Fr, frontal cortex; Hipp, hippocampus; IPC, interpeduncular nucleus; MG, medial geniculate nucleus; Mot, motor cortex; Pyr, pyriform cortex; Vis, visual cortex.