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.