¹Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

Correspondence: Dr M Basselin, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bldg 9, Room 1S126-MSC 0947, Bethesda, MD 20892, USA. Tel:+1 301 594 5522; Fax: +1 301 402 0074; E-mail: mirvasln@mail.nih.gov

Received 13 April 2005; Revised 25 August 2005; Accepted 30 August 2005; Published online 9 November 2005.

Abstract

It has been proposed that lithium is effective in bipolar disorder (BD) by inhibiting glutamatergic neurotransmission, particularly via N-methyl-D-aspartate receptors (NMDARs). To test this hypothesis and to see if the neurotransmission could involve the NMDAR-mediated activation of phospholipase A₂ (PLA₂), to release arachidonic acid (AA) from membrane phospholipid, we administered subconvulsant doses of NMDA to unanesthetized rats fed a chronic control or LiCl diet. We used quantitative autoradiography following the intravenous injection of radiolabeled AA to measure regional brain incorporation coefficients k^* for AA, which reflect receptor-mediated activation of PLA₂. In control diet rats, NMDA (25 and 50 mg/kg i.p.) compared with i.p. saline increased k^* significantly in 49 and 67 regions, respectively, of the 83 brain regions examined. The regions affected were those with reported NMDARs, including the neocortex, hippocampus, caudate-putamen, thalamus, substantia nigra, and nucleus accumbens. The increases could be blocked by pretreatment with the specific noncompetitive NMDA antagonist MK-801 ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate) (0.3 mg/kg i.p.), as well by a 6-week LiCl diet sufficient to produce plasma and brain lithium concentrations known to be effective in BD. MK-801 alone reduced baseline values for k^* in many brain regions. The results show that it is possible to image NMDA signaling via PLA₂ activation and AA release in vivo, and that chronic lithium blocks this signaling, consistent with its suggested mechanism of action in BD.