Excessive N-methyl-D-aspartate (NMDA) signaling is thought to contribute to bipolar disorder symptoms. Lithium and carbamazepine, effective against bipolar mania, are reported in rats to reduce brain transcription of an arachidonic acid selective calcium-dependent cytosolic phospholipase A 2 (cPLA 2 ), as well as expression of one of its transcription factors, activator protein (AP)-2. In this study, we determined if chronic administration of NMDA (25 mg/kg i.p.) to rats would increase brain cPLA 2 and AP-2 expression, as these antimanic drugs are known to down-regulate excessive NMDA signaling. Administration of a daily subconvulsive dose of NMDA to rats for 21 days decreased frontal cortex NMDA receptor (NR)-1 and NR-3A subunits and increased cPLA 2 activity, phosphorylation, protein, and mRNA levels. The activity and protein levels of secretory phospholipase A 2 or calcium-independent phospholipase A 2 were not changed significantly. Chronic NMDA also increased the DNA-binding activity of AP-2 and the protein levels of its a and b subunits. These changes were absent following acute (3 h earlier) NMDA administration. The changes, opposite to those found following chronic lithium or carbamazepine, are consistent with up-regulated arachidonic acid release due to excessive NR signaling and may be a contributing factor to bipolar mania. Keywords: activator protein-2, brain, cytosolic phospholipase A 2, N-methyl-D-aspartate, NMDA receptor-3A. J. Neurochem. (2007Neurochem. ( ) 102, 1918Neurochem. ( -1927 The excitatory neurotransmitter glutamate plays important roles in physiological and pathological processes within the central nervous system. Glutamate receptors are classified into two major classes, ionotropic receptors and metabotropic receptors (mGluRs). Ionotropic receptors are classified further based on selectivity to a-amino-3 hydroxy-5-methyl-4-isoxazolprorionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA). Whereas mGluRs are classified into three groups, mGluRs I, II, and III and are coupled to G proteins. Activation of glutamate receptors induces signaling cascades involved in learning and memory, synaptogenesis, and nociception (Dingledine et al. 1999). Address correspondence and reprint requests to Jagadeesh S. Rao, PhD, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, 9000 Rockville Pike, Bldg. 9, 1S-126, Bethesda, MD 20892, USA. E-mail: jrao@mail.nih.govAbbreviations used: AMPA, a-amino-3 hydroxy-5-methyl-4-isoxazolprorionic acid; AP-2, activator protein-2; cPLA 2, calcium-dependent cytosolic phospholipase A 2 ; DTT, dithiothreitol; GRE, glucocorticoid response element; iPLA 2, calcium-independent phospholipase A 2 ; mGluRs, metabotropic receptors; NF-jB, nuclear factor kappa B; NMDA, N-methyl-D-aspartate; NR, NMDA receptor; PEA 3, polyoma enhancer element 3; sPLA 2, secretory phospholipase A 2 .

Chronic administration to rats of mood-stabilizers that are effective against mania in bipolar disorder, is reported to downregulate markers of the brain arachidonic acid cascade. We hypothesized that chronic administration of lamotrigine, which is used to treat depression and rapid cycling in bipolar disorder, might do so as well. Male CDF rats were administered a therapeutically relevant dose of lamotrigine (10 mg/kg) or vehicle intragastrically once daily for 42 days. Protein levels of isoforms of phospholipase A(2) (PLA(2)) and of cyclooxygenase (COX), and the mRNA level of COX-2, were quantified in the frontal cortex using immunoblotting and RT-PCR, respectively. Compared to vehicle-treated rats, chronic lamotrigine significantly decreased frontal cortex protein and mRNA levels of COX-2 without altering protein levels of the PLA(2) isoforms. Consistent with the hypothesis, lamotrigine and other mood-stabilizers have a common downregulatory action on COX-2 expression in rat brain, which may account in part for their efficacy in bipolar disorder.