The NMDA receptor/nitric oxide pathway: a target for the therapeutic and toxic effects of lithium Mehdi Ghasemi 1, 2 and Ahmad Reza Dehpour 2 1 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 2 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran Although lithium has largely met its initial promise as the first drug discovered in the modern era of psycho- pharmacology, 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 monophospha- tase and glycogen synthase kinase-3 (GSK-3). Recently, increasing evidence has suggested that N-methyl-D-as- partate 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. Introduction Lithium has a long history of use for the treatment of mood disorders (Box 1) especially bipolar disorder (BPD). Over the years, multiple molecular actions associated with the therapeutic effects of lithium have been recognized; nev- ertheless, the definitive mechanism of action of lithium has yet to be established. Recently, several studies have demonstrated that glu- tamatergic activation of N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) signaling could be an attrac- tive potential therapeutic target for the treatment of mood disorders. The metabolism of major excitatory neurotrans- mitters and the function or expression of NMDARs is significantly altered in patients and suicidal victims with BPD or major depressive disorder (MDD) [1]. Although NMDAR antagonists [2], NO synthase (NOS) [3] or soluble guanylyl cyclase (sGC) inhibitors (i.e. methylene blue) [4–6] are beneficial in the treatment of mood disorders, NO may have a dual role in the modulation of depression [7,8]. The NO precursor L-arginine and the NOS inhibitor N v -L-arginine methyl ester (L-NAME) exert pro-depres- sant and antidepressant-like effects in animal behavioral tests [7,8]. Some clinical studies have reported a significant reduction in the total amount and density of NOS immu- noreactive neurons in the paraventricular nucleus [9]; a reduction in neuronal NOS (nNOS) immunoreactivity in the locus coeruleus [10]; and a reduction in the activity of endothelial NOS (eNOS) and nNOS in the prefrontal cor- tex in MDD patients. By contrast, other studies reported that plasma nitrate and total nitrite concentrations are higher in MDD patients [11]. However, clinical studies on BPD patients consistently report that NO levels are higher in BPD patients compared with normal subjects [12,13]. Lithium was initially suggested to exert its therapeutic effects by interfering with signal transduction through G- protein-coupled receptor (GPCR) pathways or by direct inhibition of specific targets in signaling systems, including inositol monophosphatase (IMPase) and glycogen synthase kinase-3 (GSK-3). Increasing evidence suggests that NMDAR/NO signaling mediates some lithium-induced responses in the brain [14–18] or other tissues [19,20]. Indeed, several mechanisms have been proposed for the action of lithium, including its effects on the monoaminergic system, GSK-3b, adenylyl cyclase and key proteins involved in neuroprotection (e.g. p53, Bax, Bcl-2, caspase, and cyto- chrome c) [21]. Therefore, it is unlikely that one hypothesis operates in isolation. Accordingly, there is an intimate interaction between NMDA/NO signaling and these path- ways in the central nervous system (CNS). The NMDA/NO pathway modulates monoaminergic transmission in a bidi- rectional manner, and promotes (or even inhibits) the re- lease of these neurotransmitters in specific regions of the brain [22]. These observations could even explain how a disturbance in NO, or targeting NO through drug treat- ment, could affect monoaminergic function and vice versa. For instance, NMDAR/NO/cGMP modulators augment the antidepressant-like effects of conventional antidepressants [23] as well as lithium [24–26]. However, the probable role of this system in mediating the lithium action has not been fully discussed. In this review, we have gathered evidence that supports a role of NMDAR/NO signaling as the thera- peutic target of lithium. Furthermore, we discuss accumu- lating evidence that this signaling system might also contribute to the adverse effects of lithium. NMDAR/NO signaling and lithium In the early 1990 s, accumulating research showed an in- volvement of NMDAR/NO signaling in the pathophysiology Review Corresponding authors: Ghasemi, M. (mghasem2@jhmi.edu); Dehpour, A.R. (dehpour@yahoo.com) 420 0165-6147/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2011.03.006 Trends in Pharmacological Sciences, July 2011, Vol. 32, No. 7