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

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-(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.

Extracellular-derived calcium does not initiate in vivo neurotransmission involving docosahexaenoic acid

“…The baseline values of k* for DHA and AA in this study agree with published data (26)(27)(28)30 ). k* for each PUFA largely refl ects its metabolic loss following its release from membrane phospholipid, as DHA and AA cannot be synthesized de novo in vertebrate tissue and only negligible amounts (< 1%) can be elongated in brain from their circulating precursors ␣ -linolenic (18:3n-3) and linoleic acid (18:2n-6), respectively.…”

“…MK-801 also had no effect on baseline k* for DHA. In contrast, we confi rmed the report that this dose of NMDA signifi cantly increased k* for AA in wide areas of the brain (26)(27)(28).…”

“…Using our imaging method involving the intravenous infusion of [1-14 C]AA ( 24,25 ), we reported that administration of a subconvulsive dose of NMDA (25 mg/kg i.p.) to unanesthetized rats increased AA signaling, measured as increased AA incorporation coeffi cients k*, in wide areas of brain (26)(27)(28). The increases could be blocked by pretreatment with the NMDA receptor antagonist MK-801, which by itself reduced baseline values of k* by 16-49% ( 26 ).…”

Comparative study between the effect of methotrexate and valproic acid on solid Ehrlich tumour

“…Valproic acid (sodium salt; Sigma-Aldrich) was dissolved in saline and administered by intraperitoneal injection at a dose of 200 mg/kg body weight [9].…”

Anticonvulsants in bipolar disorder

“…Inhibition of NMDA-receptor-mediated currents has been reported for CBZ (Lampe & Bigalke, 1990) in animal studies. Chronic administration of both CBZ and VPA reduces brain NMDA signalling via arachidonic acid (Basselin, Villacreses, Chen, Bell, & Rapoport, 2007;Basselin, Chang, Chen, Bell, & Rapoport, 2008). LTG inhibits the release of glutamate and aspartate.…”