title: Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder.
abstract: An up-regulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-d-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release AA from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signalling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanaesthetized rats that had been treated p.o. daily for 42 d with vehicle or a therapeutically relevant dose of LTG (10 mg/kg.d). Regional brain AA incorporation coefficients k* and rates J               in, and AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and J               in in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA-binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signalling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signalling are up-regulated in the post-mortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade.
authors: Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. ramadanir@mail.nih.gov
authors: Epolia
authors: E
authors: Ramadan
authors: Mireille
authors: M
authors: Basselin
authors: Jagadeesh S
authors: JS
authors: Rao
authors: Lisa
authors: L
authors: Chang
authors: Mei
authors: M
authors: Chen
authors: Kaizong
authors: K
authors: Ma
authors: Stanley I
authors: SI
authors: Rapoport
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood*; D001345:Autoradiography; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D000077213:Lamotrigine; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013929:Thromboxane B2 / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D015777:Eicosanoids; D018690:Excitatory Amino Acid Agonists; D016328:NF-kappa B; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; D016718:Arachidonic Acid; D013929:Thromboxane B2; D016202:N-Methylaspartate; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D000077213:Lamotrigine