The International Journal of Neuropsychopharmacology

Table of Contents - August 2012 - Volume 15, Issue 07  

Research Article

Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder

Epolia Ramadana1 c1, Mireille Basselina1, Jagadeesh S. Raoa1, Lisa Changa1, Mei Chena1, Kaizong Maa1 and Stanley I. Rapoporta1

a1 Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

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.

(Received February 23 2011)

(Reviewed April 29 2011)

(Revised May 20 2011)

(Accepted May 27 2011)

(Online publication June 28 2011)

Key Words:

Correspondence:

c1 Address for correspondence: E. Ramadan, Ph.D., Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bldg 9, Room 1S126, Bethesda, MD 20892, USA. Tel.: 301 496 8994 Fax: 301 402 0074 Email: ramadanir@mail.nih.gov

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