Although lithium has largely met its initial promise as the first drug discovered in the modern era of psychopharmacology, to date no definitive mechanism for its effects has been established. It has been proposed that lithium exerts its therapeutic effects by interfering with signal transduction through G-protein-coupled receptor (GPCR) pathways or direct inhibition of specific targets in signaling systems, including inositol monophosphatase and glycogen synthase kinase-3 (GSK-3). Recently, increasing evidence has suggested that N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) signaling could mediate some lithium-induced responses in the brain and peripheral tissues. However, the probable role of the NMDAR/NO system in the action of lithium has not been fully elucidated. In this review, we discuss biochemical, preclinical/behavioral and physiological evidence that implicates NMDAR/NO signaling in the therapeutic effect of lithium. NMDAR/NO signaling could also explain some of side effects of lithium.
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