nitric oxide pathway: a target for the therapeutic and toxic effects of lithium

Review

The NMDA receptor/nitric oxide pathway: a target for the therapeutic and toxic effects of lithium Mehdi Ghasemi1,2 and Ahmad Reza Dehpour2 1 2

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 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 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. 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; nevertheless, the definitive mechanism of action of lithium has yet to be established. Recently, several studies have demonstrated that glutamatergic activation of N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) signaling could be an attractive potential therapeutic target for the treatment of mood disorders. The metabolism of major excitatory neurotransmitters 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 Nv-L-arginine methyl ester (L-NAME) exert pro-depressant and antidepressant-like effects in animal behavioral tests [7,8]. Some clinical studies have reported a significant Corresponding authors: Ghasemi, M. ([email protected])

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([email protected]); Dehpour, A.R.

reduction in the total amount and density of NOS immunoreactive 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 cortex 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 Gprotein-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 cytochrome c) [21]. Therefore, it is unlikely that one hypothesis operates in isolation. Accordingly, there is an intimate interaction between NMDA/NO signaling and these pathways in the central nervous system (CNS). The NMDA/NO pathway modulates monoaminergic transmission in a bidirectional manner, and promotes (or even inhibits) the release 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 treatment, 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 therapeutic target of lithium. Furthermore, we discuss accumulating 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 involvement of NMDAR/NO signaling in the pathophysiology

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Review Box 1. Lithium: the 190-year-old revolutionary molecule. The story of lithium began in 1818 when this chemical element was isolated from the mineral petalite by Johan August Arfwedson by the Berzelius research team. Its name was derived from the Greek word ‘lithos’ for stone, to reflect its discovery in a mineral. Scientists in the nineteenth century hypothesized that manic disorders could be due to the excess uric acid. There was also evidence that lithium could dissolve crystals of uric acid. This fact led two investigators, Carl Lange in Denmark and William A. Hammond in the USA, to use lithium for treating mania from the 1870 s onwards. However, the use of lithium for this condition was seemingly forgotten by the turn of the twentieth century. In 1949, the Australian psychiatrist John Cade made an accidental observation of a sedative-like action of lithium in guinea pigs. Cade then administered lithium to 10 manic inpatients and its tranquilizing effect was so robust that he speculated that bipolar disorder (BPD) was a ‘‘lithium-deficiency disease’’. Nonetheless, the international psychiatric community was slow to adopt this revolutionary treatment, mainly owing to the reported deaths that resulted from an overdose of lithium chloride when the salt was used as a taste substitute for sodium chloride in patients with cardiac diseases. The general acceptance of lithium as an effective treatment for BPD was largely due to the determined research efforts of the young psychiatrist Mogens Schou and his coworker Poul Christian Baastrup in Europe [225–232] and efforts of Samuel Gershon in the USA [233–236]. The US FDA finally approved lithium application for manic illness in 1970. Although the use of lithium for the treatment of BPD has declined in recent years due to its narrow therapeutic range and to the availability of alternative medications, this drug is a mainstay in the treatment of BPD. Initially lithium was assumed to have a weak antidepressant effect, but several controlled studies later supported its antidepressant efficacy. The antidepressant effects of lithium have been more clearly demonstrated in depressed bipolar than in unipolar patients. However, initial open trials and double-blind controlled studies found that lithium is also effective for unipolar depression.

of mood disorders [27,28]. In conjunction with this finding, some investigators also suggested a possible role for glutamatergic transmission in the therapeutic effects of lithium [29–31]. Lithium was reported to elevate glutamate release and inositol 1,4,5-triphosphate (IP3) accumulation in synaptic clefts in cerebral cortex slices from monkeys and mice [29]. NMDAR blockers and the glutamate release inhibitor carbetapentane inhibited lithium-induced IP3 accumulation in the same tissues [31], suggesting that lithium acutely stimulates glutamate availability in the synaptic cleft. Acute lithium treatment inhibited glutamate uptake by presynaptic nerve endings in the mouse cerebral cortex with maximal effect at 20–25 mM and shortly after 2 hours, and therefore seems to be irrelevant for the therapeutic action of lithium, which occurs at lower concentration and after 1–2 weeks of treatment [30]. However, chronic treatment with lithium for 2 weeks (lithium blood levels, 0.7 mM) significantly increased glutamate uptake by mice cerebrocortical synaptosomes [30]. Lithium also narrowed the range of glutamate uptake (reduced the variance from 0.42 to 0.18), an effect interpreted as stabilization of the uptake [30]. It was hypothesized that upregulation and stabilization of glutamate reuptake is a mechanism underlying the antimanic and mood-stabilizing effects of lithium in BPD, respectively [30] (Figure 1). Using in-vivo microdialysis, other investigators demonstrated that acute and short-term treatment with lithium significantly decreased glutamate levels in the frontal cortex of awake rats [32], confirming that lithium regulates cortical glutamatergic transmission in vivo. Lithium also decreases concentrations of glutamate

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in the gray matter of bipolar patients, with a positive correlation between lithium serum levels and glutamate decrease [33]. Besides effects on glutamate release, lithium affects inhibitory neurotransmitters, especially g-aminobutyric acid (GABA), in the CNS [34,35]. Lithium decreases GABA turnover in animals [36], increases regional cerebral GABA levels in rats [37,38] and GABAergic inputs to granule cells in the rat hippocampal dentate gyrus [39]. Chronic (but not acute) lithium increases rat hippocampal (but not frontal, thalamic or striatal) GABAB (but not GABAA) receptors [40,41], whereas it reduces rat frontal (but not occipitoparietal or hippocampal) GABAA receptors as assessed by benzodiazepine binding [42]. It also decreases striatal and hypothalamic mixed GABAA and GABAB receptors [43]. GABA plays a major part in the release and function of glutamate in the CNS [44,45]. Therefore, it could be speculated that the effects of lithium on glutamate release might be due to its effect on GABAergic neurotransmission in the CNS. However, this assumption warrants further investigation. The first evidence of the inhibitory effects of lithium on NMDAR function was reported in 1998 [15]. Lithium pretreatment (0–7 days) significantly prevented the glutamate-induced, NMDA-mediated excitation in cultured rat cerebellar granule, cerebral cortical, and hippocampal neurons. This protection was suggested to be due to its inhibitory effects on the NMDA-mediated calcium influx via attenuation of constitutive tyrosine phosphorylation of the NR2B subunit of the NMDAR and Src tyrosine kinase [15,21,46,47]. Moreover, other investigators demonstrated that this effect can be partly explained by a reduction in the NR2A tyrosine phosphorylation by lithium and by lithium’s interaction with PyK2 and post-synaptic density (PSD-95) [48,49]. Six-week treatment with lithium also attenuated NMDA-induced signaling in different brain areas [50]. Chronic treatment with lithium at therapeutically relevant concentrations decreased NMDA-mediated cytoplasmic vacuolization in primary rat hippocampal neurons [51]. Substitution of sodium with lithium in the extracellular solution resulted in subtype-specific changes in the inward and outward currents of glutamate receptors, and significantly decreased the currents of NMDARs [52]. Seven-day treatment with lithium also attenuated NMDA- and glutamate-induced calcium influx into the rat primary hippocampal neurons [53]. Lithium could also affect the mRNA expression of NMDARs. Seven-day treatment with lithium (1 mM) had no influence on the cell-surface expression of the NR1 subunit in primary cultures of rat hippocampal neurons [53], whereas lithium at 10 mM decreased NR1 expression gradually and specifically after 48 hours in mice cortical cultures [54]. Twenty four- and 48-hour lithium treatment also reduced the expression of the NR1 subunit mRNA in mice hippocampal cultures [54]. Neurotrophic factors (especially brain-derived neurotraphic factor (BDNF)) may also be involved in the pathophysiology of mood disorders [55]. BDNF prevents neuronal death and glial activation after global ischemia in rats [56], and NMDAR/NO-mediated glutamate toxicity in primary cultures of cerebellar granule cells [57] and 421

Review

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Lithium

GABAergic transmission

Inhibition of α2 autoreceptors

Decrease in β2adrenergic stimulation of adenylyl cyclase

Glutamate level in synapse

α-Adrenergic transmission

nNOS Activity

Key: Increase

Glutmate reuptake channel

Tyrosine phosphorylation of NMDA R

Neurotrophic factor (BDNF) Dopamine transmission (e.g. adenylyl cyclase)

Upregulation & stabilization of gluamate reuptake

Inhibition of 5-HT1A autoreceptors Enhancement of 5-HT1A & 5-HT2 receptor

Glutamate/NMDAInduced Calcium Influx

Neurotoxicity Induced by glutamate/NMDAR signaling

5-HT Transmission

nNOS Activity

mRNA Expression of NMDA R

? Lithium

iNOS Activity

Decrease NO Toxicity

Cytokines & LPS TRENDS in Pharmacological Sciences

Figure 1. Different suggested mechanisms underlying the effects of lithium on glutamtaregic/N-methyl-D-aspartate receptor (NMDAR) signaling in the central nervous system. Lithium modulates this system at several steps, including: (i) increase in glutamate reuptake via glutamate reuptake channels in the presynaptic nerves; (ii) decrease in NMDAR activity via reducing tyrosine phosphorylation of NR1A and NR2B subunits; and thereby (iii) inhibition of Ca2+ influx in the post-synaptic neurons; (iv) decrease in NMDAR mRNA expression; and (v) possible direct inhibition of the nNOS activity. These effects protect neuronal cells against the toxicity induced by hyperactivation of NMDAR/NO signaling. Lithium could also indirectly modulate NMDAR/NO signaling via affecting several other pathways such as adrenergic, serotonergic and dopaminergic transmission, enhancing neurotrophic factors (especially brain-derived neurotrophic factor (BDNF)), and enhancing GABAergic transmission.

cortical and hippocampal neurons [58]. Prevention of nNOS expression by BDNF or inhibition of NO production (as well as increased scavenging of intracellular superoxide ions) prevents motor neuron death [59]. Chronic lithium administration increases the level of BDNF in rodents [60,61]. Inhibition of the BDNF receptor or application of a BDNF neutralizing antibody suppresses the neuroprotective effect of lithium against glutamate toxicity in rat cerebral cortical neurons [61]. These observations suggest that lithium could protect against NMDAR/NO-mediated neurotoxicity via increasing the BDNF levels in the CNS. It seems probable that lithium alters glutamatergic/ NMDAR functioning via several mechanisms that include perturbation to glutamate reuptake, regulation of NMDAR phosphorylation, NMDAR mRNA level, or indirectly via regulating GABAergic transmission or BDNF levels in the CNS (Figure 1). Nitrergic system There are several differences in the methodologies and results of studies that have investigated the effects of lithium on NO synthase (Table 1). In 1993, Bagetta et al. [62] reported that 24-hour lithium treatment (12 mEq/kg, i.p.) increased the nNOS mRNA expression in the rat hippocampus. However, this might be due to the 422

toxic effects of lithium because they used a high dose of lithium. Studies had shown that lithium inhibited the synthesis of cyclic GMP (cGMP) in an identical concentration-dependent manner (IC50 values of 12 mM) [63,64]. Veratridine, an alkaloid that increases lithium entry into cells, augmented lithium-induced inhibition of neurotensin-stimulated cGMP formation (IC50 = 7 mM) [63]. Similarly, lithium could inhibit cGMP synthesis induced by activation of muscarinic receptors in mouse neuroblastoma clones, which appeared to be at the level of sGC, but not NOS [65]. However, Harvey et al. reported that L-NAME inhibited the increase in accumulation of cGMP levels in rat cortex induced by chronic lithium treatment, suggesting a role for the NOS enzyme in mediating this effect of lithium [66]. They found a positive correlation between NOx (nitrite plus nitrate) and cGMP, which confirms an association between NO and its subsequent activation of sGC (and the observed increase in cGMP) in cortical neurons. A synergistic response was also observed when lithium was combined with the glutamatergic agonist kainic acid, thus confirming a glutamatergic basis to the effects of lithium on NO/cGMP signaling [66]. They further described a Yin–Yang relationship between cGMP and cyclic adenosine monophosphate (cAMP) after chronic lithium treatment [67]. Lithium increased cortical cGMP but

Review

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Table 1. Effects of lithium on the NO synthase (NOS) protein, activity and expression in the central nerves system. CM, cytokine mixture (TNF-a, IL1-b and IFN-g); IFN-g, interferon-g; iNOS, inducible nitric oxide synthase; LPS, lipopolysacharide; nNOS, neuronal nitric oxide synthase; SNP, sodium nitroprusside. Region/Cells Rat Hippocampus Rat Cortex Mouse Neuroblastoma Clone, N1E-115

Lithium Treatment Concentration / Dose 12 mEq/kg, i.p. 0.3% m/m, orally -

Duration 24 h 3 weeks -

12 mEq/kg, i.p. 5-20 mM

24 h 24 h

Measurements

Results Reference

nNOS mRNA Expression Accumulation of cGMP & NO2 Levels Muscarinic-induced Elevation of Nitrite/Nitrate Levels

" " $ # " " $ " $ " $ " $ "

[72]

[62] [66] [65]

5 mM

24 h

5 mM

24 h

Rat Paraventricular & Supraoptic Nuclei

60 mM/kg, orally

4 weeks

Muscarinic- or SNP-induced Elevation of cGMP Levels L-Citrulline Level Nitrite Accumulation Induced by LPS plus IFN-g Basal Nitrite Nitrite Accumulation Induced by LPS+CM Basal Nitrite Conversion of L-Arginine to L-Citrulline Induced by LPS+CM Basal L-Citrulline iNOS mRNA Expression After Incubation with LPS+CM Basal Expression NADPH-diaohorase Staining

Rat Frontal Cortex, Hippocampus, & Cerebellum Rat Hippocampus Rat Amygdala Murine Microglial 6-3 Cells BV-2 Microglia

60 mM/kg chow pellet, orally

5 days

nNOS mRNA Expression L-Citrulline Level

" $

[78]

5-10 mM 50 mg/kg, i.p. 0.1-10 mM

Acutely 60 & 90 min 24 h prior IFN-g & 48 h thereafter 30 min prior LPS & 24 h thereafter

L-Citrulline Level NO3 & NOx Levels Accumulation of NO2

# # #

[18] [14]

Nitrite Accumulation Induced by LPS

#

[88]

iNOS mRNA Expression After Incubation with LPS Conversion of L-Arginine to L-Citrulline Induced by Aluminium

# #

[238]

Rat Brain C6 Glioma Cells

Primary Rat Astrocytes 5-20 mM

Rat Cerebrum and Cerebellum

20 mM

1100 mg/Kg, orally

24 h

8 weeks

decreased cAMP; this response might involve lithium-induced hydrolysis of cAMP via activation of cGMP-dependent phosphodiestrase (PDE). Indeed, recent evidence has shown the important role of cGMP-specific PDEs in psychotropic actions (e.g. sildenafil) [68–70]. However, there was no effect of clinically relevant lithium plasma levels on plasma NO metabolites after chronic lithium therapy [71]. Further investigation reported that chronic lithium treatment was associated with an increase in nNOS activity in the brain and induced nNOS gene expression in the hypothalamus [72]. Although the results reported in the 1990 s supported a lithium-induced increase in central NOS activity and expression, more recent studies reported different results (Table 1). Differences in the dose and duration of treatment are important considerations. Although the studies described in Table 1 are all based on in vivo or in vitro treatment with lithium, some investigators [66,67,71] examined these effects in animals treated chronically (e.g. 3 weeks) with the drug. These differences in the protocol and treatment duration might explain the diverse effects of lithium on NO/cGMP signaling. Importantly, similar discrepancies are also observed in clinical studies; both increased [11,73,74] and decreased [10,75– 77] levels of NO have been reported in patients with mood disorders (especially those with MDD). Similar

[237] [87]

discrepancies are also evident in animal studies examining the antidepressant response to NO inhibitors [7,8]. Chronic lithium treatment might provide a more accurate reflection of the clinical situation because it allows for the assessment of plasma lithium levels [66,71]. It is also important to consider whether the actions of lithium on NO signaling can be related to the therapeutic or toxic effects of the ion. Accordingly, lithium was reported to inhibit rat hippocampal NOS activity in a concentrationdependent manner [78], although only the highest dose (>5 mM), which is markedly higher than the concentrations used clinically, was significantly lower than the control [78]. Because neurotoxic elevations of nitrergic and/or glutamatergic activity might underlie the reduced hippocampal volume documented in depressed patients [79], the actions of lithium on NOS might be realized only under pathological conditions. Accordingly, Wegener et al. [80] found that a chronic mild stressor does not activate the hippocampal NMDA/NOS signaling pathway in normal animals, whereas such a stressor has a profound activating effect on this pathway in animals with a high depression-like phenotype. It is plausible, therefore, that a pathological state characterized by hyperactivation of the NO system is more amenable to modulation by psychotropic drugs such as antidepressants and lithium. 423

Review Although the constitutive nNOS enzyme is implicated in mood disorders, some evidence has shown that inducible NOS (iNOS) could be another source of NO in the CNS and might play a part in this condition. The iNOS enzyme is induced by proinflammatory stimuli such as bacterial lipopolysacharides (LPS) or cytokines (e.g. tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IFN-g) [81]. iNOS can negatively affect the activity and expression of constitutive NOS [82], which will have implications for how these NOS isoforms are involved in the development and expression of a mood disorder. Indeed, several studies have suggested a pathophysiologic role for inflammatory processes in mood disorders [83] and there is evidence that iNOS inhibitors have antidepressant activity [84]. Lithium was also reported to have anti-inflammatory properties and to protect cells against cytokine toxicity [85,86]. An initial study by Feinstein [87] demonstrated that lithium increases astroglial iNOS gene expression, suggesting that chronic lithium treatment may modify the inflammatory response. Twenty four-hour lithium pretreatment inhibited NO production by IFN-g-activated microglia [14]. In another study, BV-2 microglia were pre-incubated with lithium for 30 minutes before stimulation with LPS for 24 hours followed by measuring NO metabolites [88]. Lithium attenuated NO production by 68% in response to LPS stimulation, and significantly attenuated LPS-induced iNOS expression by 52% [88]. Interaction with other neurotransmission systems Although studies suggest that lithium could directly affect the central NMDA/NO pathway, these results could be secondary to the effects of lithium on other neurotransmitters, including serotonin (5-hydroxytryptamine (5HT)), noradrenaline and dopamine, which play a major part in the pathophysiology of mood disorders [89] and also interact with NMDA/NO signaling. Lithium facilitates central serotonergic neurotransmission [90,91] via inhibition of presynaptic 5-HT1A and 5HT1B autoreceptors [92–95]. The enhanced 5-HT neurotransmission which develops during chronic lithium treatment could also be related to the alteration of postsynaptic 5-HT1A and 5-HT2 receptors in the frontal cortex and hippocampus [96]. 5-HT1A receptor activation, which is considered a functional antagonist of NMDARs in the CNS [97–100], counteracts NMDAR-evoked NO-mediated cGMP accumulation [101] and downregulates nNOS expression in rat hippocampus, whereas its inhibition upregulates hippocampal nNOS expression [102]. 5-HTlB/lD receptor agonists also abolish NMDAR-induced NOS/ cGMP activity in the brain cortex [103]. Long-term lithium treatment decreases presynaptic a2adrenergic inhibition of noradrenaline release [104] while enhancing potassium-evoked noradrenaline release [105]. Inhibition of a2-autoreceptors facilitates NMDA-evoked [3H]noradrenaline overflow in the rat cortex [106]. Modulation by noradrenaline of glutamate release has an important physiological role in the genesis of long-term potentiation (LTP) in the dentate gyrus [107,108]. Lithium also decreases b-adrenoceptor-mediated stimulation of adenylyl cyclase [109], which has been linked to its antidepressant effects [110]. Activation of a2-adrenoceptor 424

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decreases NOS-mediated cGMP levels [111,112], whereas activation of a1- or b-adrenoceptor stimulates cGMP accumulation in some regions of the brain [113–115]. Lithium has been shown to alter dopamine levels in various regions of the brain [43,116,117], although some reports indicate no alterations [118,119]. Lithium increases the levels of dopamine receptor D2 mRNA coding, but not protein, in the rat striatum and nucleus accumbens septi [120,121], whereas it inhibits dopamine receptor binding [122] and the dopamine-related signaling pathway (including adenylyl cyclase) [123]. Dopamine D1 receptor gene polymorphism is also associated with prophylactic lithium response in BPD [124]. D1 receptor activation enhances NMDA currents [125] and plays a pivotal part in the formation of NMDA-mediated LTP at corticostriatal synapses [125], whereas D2 receptor activation attenuates NMDAR-mediated currents [126]. The D1 receptor interacts with NR1 and NR2A, but not NR2B, subunits [127,128]. nNOS is activated in vivo by burst firing of nigrostriatal dopamine cells through a D1 and D5 receptor-dependent mechanism [129], and stimulation of these receptors leads to NO release from striatal interneurons, and seems to crucially influence the induction phase of long-term depression [130]. Striatal NMDAR co-activation is necessary for D1/5 receptor stimulation of nNOS activity [131]. These observations raise the possibility that monoaminergic transmission may mediate the effect of lithium on NMDAR/NO signaling (Figure 1). Preclinical/behavioral evidence In addition to biochemical reports on the interaction between NMDAR/NO signaling and lithium, some animal experiments have demonstrated that NMDAR/NO signaling (directly or indirectly) could play a part in the behavioral effects of lithium. Animal behavioral tests in mood disorders Although objective modeling of mood disorders in rodents seems inherently problematic, several behavioral experiments representing endophenotypes associated with these disorders have been investigated widely. Indeed, some of the behavioral experiments, such as the forced swimming test (FST) and the tail suspension test (TST), are screening tools to measure the effect of antidepressant drugs on the behavior of laboratory animals. Acute and chronic lithium treatment have antidepressant-like effects in several animal behavioral studies, including the FST and TST [132,133]. We have recently demonstrated that acute injection of combined sub-effective doses of lithium with nNOS/guanylyl cyclase inhibitors or NMDAR antagonists exerted a robust antidepressant-like effect in the mouse FST [24,25]. Pre-treatment with NMDA, L-arginine or the PDE 5 inhibitor sildenafil prevented the antidepressant-like effects of lithium [24,25]. Antidepressant-like effects of 3-week lithium treatment (600 mg/l in drinking water; blood level of 0.6 mM/l) was prevented with acute or 7-day co-administration of L-arginine [26]. Although 3-week lithium treatment with 300 mg/l in drinking water (blood level of 0.2 mM/l) had no effect, acute injection of a non-effective

Review

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dose of L-NAME in this group of mice exerted a significant antidepressant-like effect. Lithium effects in the FST were parallel to its decreasing effects on the serum NOx levels in lithium-treated mice [26]. Although there is consensus among scientists that NMDAR/NOS/cGMP inhibitors exert antidepressant-like effects in various animal behavioral studies in addition to the FST, the modulating effects of these agents on the antidepressant-like effects of lithium in these paradigms have not been fully demonstrated. Several putative animal models of BPD have been reported. In these models, objective parameters such as hyperactivity or psychomotor retardation, increased or decreased social interaction, insomnia, and appetite loss, can be used for assessment. They are mainly classified into four categories (Table 2): nutritional, environmental, genetic, and pharmacological (for review see [134]). Nutritional models are based on two hypotheses of increased homocysteine [135] and decreased omega-3 fatty acids [136] in BPD patients. Long-term administration of homocysteine to mice causes abnormality in the Morris water maze test [135]. Deprivation of omega-3 fatty acids in rats causes an increase in depression-like behavior and aggression [136]. In environmental models, changes in environmental conditions such as sleep deprivation could cause some behavioral changes in rats (including insomnia, hyperactivity, irritability, aggressiveness, hypersexuality, and stereotypy). Another environmental model has focused on social dominance and submissiveness, which are observed after food restriction in rats and mice. Lithium treatment prevents such behaviors in these mod els [137,138]. In genetic models (Table 2), specific transgenic mice (including Clock mutant mice, disrupted in schizophrenia 1 (DISC1) transgenic mice, GSK-3b transgenic mice, glucose transport transgenic mice) [134] show

several behavioral abnormalities, such as hyperactivity, deficits in sensorimotor gating, and impaired sociality. In pharmacological models, hyperactivity or other behavioral changes such as stress resistance and oscillation are evaluated after single or repeated administration of several drugs (including psychostimulants, dopamine agonists, cocaine, opioids, ouabain, pharmacological disruption of noradrenergic systems by 6-hydroxydopamine) alone or combined with each other. Lithium has efficacy in many of these models (for review see [134]). In one pharmacological model, sub-convulsant doses of muscarinic agonists (e.g. pilocarpine) normally induce limbic seizures in lithiumpretreated rats [139]. NMDAR antagonists have an anticonvulsant and neuroprotective effect against lithium-pilocarpine induced status epilepticus and neuronal damage [140–142]. Tonic facilitation of glutamate release by presynaptic NR2B containing NMDARs is increased in the entorhinal cortex of lithium-pilocarpine epileptic rats [143]. Tyrosine phosphorylation of NMDARs is also gradually increased after the onset of lithium-pilocarpine-induced status epilepticus [144]. These observations suggest that NMDAR function is altered in the lithium-pilocarpine model of seizure, indicating a further role for this signaling pathway in the effects of lithium. In another pharmacological model, administration of ouabain (which selectively inhibits sodium pumps) to rats triggers a short period of hyperlocomotion. This effect is prevented by 2-week lithium pretreatment [145], which might be due to the possible stabilizing effects of lithium on the ion current and sodium-pump function in neurons [146,147]. Additionally, ouabain evokes the release of glutamate or other endogenous NMDAR modulators (i.e. spermidine and spermine) in some brain regions [148– 150] which are partially sensitive to NMDAR antagonists

Table 2. Animal models of bipolar disorder (for review see [134]). Animal Models Environmental Models Genetic Models

Nutritional Models Pharmacological Models

Categories Dominance-submission Sleep deprivation Clock knockout mice 22q11 deletion DISC1 transgenic mice mutDISC1 transgenic mice mutPOLG transgenic mice GR transgenic mice GSK-3b over expression GSK-3b transgenic mice Strain difference WFS1 knock out mice Homocysteine administration n-3 polyunsaturated fatty acids deprivation Single drug/Single administration

Repeated administration of a drug

Combination

Amphetamine Metamphetamine Quinpirole 6-OH-dopamine Amphetamine Cocaine Metamphetamine Morphine Amphetamine+chlordiazepoxide Lithium+pilocarpine Morphine+b endorphine

425

Review [149,150]. Inhibition of the sodium pump potentiates glutamate-induced neurotoxicity [151]. Ouabain given via the intracerebroventricular (i.c.v.) route also led to a differential regulation in the expression of NMDAR subunits [152]. These data indicate that ouabain might have a modulatory action on glutamatergic/NMDAR signaling, suggesting that this signaling pathway may mediate the modulating effects of lithium on ouabain. Learning and memory One of the most remarkable neurocognitive impairments in patients with euthymic BPD is disturbances in verbal learning/memory [153,154], the underlying mechanism of which is elusive. For example, mice expressing the phosphorylation-defective mutant GSK-3b (GSK-3b[S9A] mice) represent endophenotypes of BPD [155] with pronounced defective long-term memory [156]. Lithium affects learning, memory and the speed of information processing in patients and in preclinical tests (such as an inhibitory avoidance task in mice) [157]. Passive avoidance learning tests often involve specific brain areas such as the hippocampus. NO also contributes to the inhibitory avoidance of learning and memory [158]. Zarrindast et al. examined the involvement of NO in this effect of lithium [157]. They first demonstrated that post-training lithium administration impaired memory retrieval in a one-trial, step-down inhibitory avoidance task when tested 24 hours later, whereas pre-test treatment with lithium reversed memory impairment induced by its post-training administration. Next, they found that pre-test administration of L-arginine and L-NAME alleviated memory impairment induced by post-training lithium [157]. L-arginine and L-NAME increased the effects of lithium on retrieval of memory impaired by post-training lithium [157]. Moreover, pretest injection of NMDA (i.c.v.) as well as lithium reversed the decrease of the step-down latency induced by posttraining lithium [159]. Pre-test co-administration of low doses of NMDA and lithium synergistically reversed the decrease of the step-down latency. Pre-test injections of a NMDAR antagonist, however, disrupted lithium-induced state-dependent learning [159]. These results further support an interaction between lithium and NMDA/NO signaling in the retrieval of inhibitory avoidance memory. Another task used for preclinical assessment of memory is conditioned taste aversion (CTA), which occurs when the subject associates the taste of a certain food with symptoms caused by a toxic or a spoiled substance. Anatomical and pharmacological data highlight the involvement of several brain structures (e.g. parabrachial nucleus, amygdala, insular cortex, but not hippocampal and striatal regions) in CTA learning [160,161]. Lithium is conventionally used as an unconditioned stimulus in CTA. Lithium at doses sufficient to mediate CTA induces c-Fos expression (which correlates with CTA learning) in the hypothalamic paraventricular nucleus (PVN), nucleus tractus of solitarius (NTS) and central nucleus of amygdale (CeA) [162]. Large populations of nNOS-containing cells and fibers are also distributed in the PVN, parabrachial nucleus, NTS, and ventrolateral medulla, and NO plays an important part in CTA learning [163–166]. NADPH-diaphorase/c-Fos double staining demonstrated that 75% of NADPH-diaphorase 426

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stained cells in the PVN showed c-Fos immunoreactivity 1 hour after lithium injection compared with the salineinjected rats (32%). In lithium-treated rats, NADPH-diaphorase stained cells and fibers were located close to the neurons expressing c-Fos in intermediate NTS and CeA [162]. L-NAME pre-treatment attenuated the lithium-induced c-Fos expression in all three regions. Combined noneffective doses of lithium and L-NAME produced a significant CTA [162], whereas L-arginine counteracted the effect of lithium [167]. These results indicate that the nitrergic pathway contributes to the lithium-induced formation of CTA. Alternative pathways might involve NO as a ‘secondary partner’ in CTA. Indeed, CTA has been shown to strongly involve central cholinergic neurotransmission. Frontal cortical and hippocampal muscarinic receptor changes might underlie CTA in rats exposed to stress and re-stress [168]. Moreover, lithium could facilitate cholinergic transmission via increasing the release of acetylcholine [169–174]. Because NO strongly modulates acetylcholine release [22,175], it could modulate the effects of lithium on the cholinergic system and thereby CTA. Prepulse inhibition (PPI) of the acoustic startle response PPI is the normal inhibition of a startle response to an intense, abrupt stimulus if it is preceded by a weak ‘prepulse’. PPI is thought to provide an operational measure of sensorimotor gating. Adult patients with BPD have significantly lower PPI compared with control subjects [176]. Lowered PPI can be induced by several NMDAR antagonists as well as dopamine agonists [177]. Although mood stabilizers (including lithium) have no effect on PPI by themselves, they reverse the apomorphine-induced disruption of PPI of the acoustic startle response in ddY mice [178]. However, lithium pre-treatment exacerbates disruption of PPI induced by an NMDAR antagonist, but not by valproate and carbamazepine [178]. These data might reflect the inhibitory effects of lithium on the NMDAR in this model. Drugs that are effective treatments for schizophrenia can reverse the disrupted PPI in rodents. Several antipsychotics also inhibit NOS activity within several brain regions [179– 181]. Moreover, the NO/cGMP pathway is involved in the PPI induced by agents such as phencyclidine in rodents [182–186]. The effect of NOS inhibitors on PPI could be due to the possible mediating role of NO in the dopaminergic modulation of sensorimotor gating, probably by a presynaptic mechanism [184], because NO can modulate the release of central dopamine [187]. The NMDA/NO/cGMP signaling pathway seems to be directly or indirectly (e.g. via interaction with dopaminergic neurotransmission) involved in the effects of antipsychotics as well as lithium on PPI. Although antipsychotics are often used for the acute management of mania in BPD, their combination with lithium has been associated with severe neurotoxicity [188–192], which suggests a commonality of action. A combination of neuroleptics and lithium may cause neuromuscular and extrapyramidal signs, hyperthermia, delirium, impairment of consciousness, and encephalopathy [191,193]. Although the underlying mechanisms are incompletely understood, it has been reported that lithium-neuroleptic treatment causes

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neurotoxicity by increasing dopamine receptor blockade [117,189]. Additionally, because the NO system is implicated in the action of lithium and neuroleptics, a combined action on the NO system in certain brain regions and systems could possibly explain this extreme reaction. However, this hypothesis warrants further investigation. Seizure threshold Lithium has been shown to have an anti-epileptic activity in clinical [194,195] and preclinical studies [196–198]. Because NMDAR/NO signaling plays a major part in modulation of the seizure threshold [199,200], we evaluated the possible involvement of this pathway in the effects of lithium on the pentylenetetrazole (PTZ)-induced clonic seizures in mice. Low doses of NMDAR antagonists and NOS inhibitors combined with low-doses of lithium exerted an anticonvulsant effect [201–203]. L-Arginine pretreatment inhibited the anticonvulsant effect of lithium [202], indicating that the NMDAR/NO/cGMP pathway is involved in the anticonvulsant effects of lithium in this model of seizure. The nitrergic system could have a role in the inhibitory effects of lithium on the biphasic effects of morphine on seizure susceptibility in mice [197]. Acute and 21-day lithium treatment inhibited anti- and pro-convulsant effects of morphine on PTZ-induced clonic seizures in mice. L-NAME potentiated this effect of lithium, whereas Larginine reversed it [197]. Lithium, similar to NMDAR/ NOS inhibitors, inhibited tolerance to the anticonvulsant effects of morphine on the same seizure model [204,205]. The mechanisms by which NO mediates the effect of lithium on the opioidergic system have not been elucidated. It appears that disruptions in the signaling pathways of opioid receptors (including the possible blockade of NOS) could be responsible for the effect of lithium. The role of NO in mediating the adverse effects of lithium Diabetes insipidus A total of 20–40% of patients taking lithium have symptoms of diabetes, and 12% have frank nephrogenic diabetes insipidus [206]. Excessive thirst and urination occur in about one-third of patients, reflecting an impaired renalconcentrating ability due to the inhibitory effect of lithium

on intracellular cAMP formation in renal tubules [207,208]. Some investigators have suggested that lithium also increases arginine vasopressin (AVP). Hypothalamic NO modulates the release of AVP and preferentially inhibits secretion of oxytocin in dehydrated rats [209]. Fourweek lithium treatment elevated the hypothalamic nNOS transcript and mRNA expression [72]. NADPH-diaphorase staining showed that the medial parvocellular part of the PVN was densely stained, and the dorsal part of the supraopitc nucleus (which mainly consists of oxytocin-producing neurons) was also predominantly stained [72]. However, acute lithium administration decreased L-citrulline levels in the rat hippocampus, whereas 5-day oral treatment had no effect [78]. The possible interaction between upregulation of nNOS gene expression, decreased NOS activity, and elevation of plasma AVP warrants further investigation. Gastrointestinal system Gastrointestinal motility Lithium affects gastrointestinal motility and gastric function, especially during early treatment, which involves a rapid increase in lithium dosing. Lithium decreases NO-mediated non-adrenergic non-cholinergic (NANC) neurogenic relaxation of the rat gastric fundus in vitro [210]. Pre-incubation with L-NAME significantly augmented this effect of lithium, whereas Larginine prevented it. It seems that lithium impairs the relaxation of the rat gastric fundus probably by interfering with the L-arginine/NO pathway in nitrergic nerves [210]. Similarly, acute in vitro and chronic 30-day ex vivo lithium administration decreased NO-mediated NANC relaxation of rat anococcygeus muscles, which was prevented by Larginine and potentiated by L-NAME (Table 3) [19]. After chronic treatment, the lithium blood level was 0.35 mM, suggesting that this adverse effect of lithium could be observed at therapeutic levels of lithium [19]. Damage to the gastrointestinal mucosa Although lithium disturbs gastrointestinal motility, we have recently demonstrated that chronic lithium administration has a protective effect against gastrointestinal mucosal damage in a rat model of irritable bowel syndrome [211]. Lithium attenuated the visceral hypersensitivity, increased the nociceptive threshold, and decreased stool frequency.

Table 3. Effects of lithium on the nitric oxide synthase (NOS) protein, expression and activity in the periphery. iNOS, inducible nitric oxide synthase; nNOS, neuronal nitric oxide synthase Region/Cells

Lithium Treatment

Mouse RAW 264.7 Macrophages

Concentration / Dose 1 & 50 mM

Duration 24 h

Primary Human Hepatocytes

20 mM

1-24 h

1-24 h Human Hepatoblastoma Cell Line 20 mM HepG2; Colorectal Cancer Cell Lines DLD1; HuH7 & SW480 Cells 12.9 mg/kg, Twice Daily, i.v. 2 Days Rat Liver Rat Mesenteric Vascular Beds Rat Corpus Cavernosum Rat Anococcyegeus Muscle Mouse Blood

600 600 600 600

mg/L mg/L mg/L mg/L

in in in in

Drinking Drinking Drinking Drinking

Water Water Water Water

4 4 4 3

weeks weeks weeks weeks

Measurements

Results

Reference

Nitrite Accumulation Induced by LPS Basal Nitrite iNOS Protein (Western Blotting) Nitrite Level

$" $ "

[87]

Cytoplasmic iNOS Protein (Immunofluorescence) NADPH-diaphorase Staining NADPH-diaphorase Staining nNOS mRNA Expression NOx Levels

"

[239]

"

" " " #

[221] [20] [19] [26]

427

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Acute NOS inhibition decreased the nociceptive threshold and reduced the protective effects of lithium on visceral hypersensitivity. Stool frequency was increased in the lithium-treated and water-treated groups by L-NAME administration. These observations suggest a role for NO in this protective effect of lithium [211]. Lithium pretreatment (1 hour) significantly prevented ethanol-induced gastric damage in rats, which was reduced by L-NAME, but not by the selective iNOS inhibitor aminoguanidine [212]. Ethanol seems to induce gastric mucosal injury by disturbing the mucosal microcirculation and decreasing mucosal blood flow. The basal blood flow of the stomach is decreased by NOS inhibitors [213,214], and inhibition of Agonists (e.g. Acetylcholine)

NO formation renders the gastric mucosa more susceptible to injury by ethanol, possibly via changes in the gastric microcirculation [215]. Decreases in resting blood flow by inhibiting NO could decrease oxygen supply to the gastric mucosa and could subsequently increase mucosal vulnerability to intragastric administration of agents that mildly damage the gastric mucosa [216]. According to these results, it seems that the vascular nitrergic system in the gastric mucosa plays a part in the protective effects of lithium on ethanol-induced gastric damage. This result could be confirmed by the observation that the nonselective NOS inhibitor L-NAME prevented this effect of lithium. However, the selective iNOS inhibitor

PLC ein rot P G PIP2

PKC DA

G

IP3 Inositol

IPP IP1

IMPase

S

O

eN

Li+

C

aM

L-citrulline L-arginine O2

NO

Ca2+

Li+ VDCC

Li+ G TP

GC

cG

M

P

CaM

Smooth Muscle

NO

nNOS

L-citrulline

PKG

Re

O2 L-arginine

la

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tio

n

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Figure 2. Possible effects of lithium (Li ) on NO-mediated endothelium-dependent or neurogenic relaxation of vascular smooth muscle. NO, as a major non-adrenergic noncholinergic neurotransmitter, is the principal entity mediating the relaxation of vascular smooth muscle. NO can be also released from vascular endothelial cells via activation of endothelial NOS (eNOS). Messenger molecules such as acetylcholine bind to the G-protein-coupled receptor on an endothelial cell, and share the ability to induce large and transient increase followed by small and sustained increases in Ca2+ through activation of phospholipase C, which liberates IP3 and DAG. IP3 releases calcium sequestered in the endoplasmic reticulum (ER) or increases Ca2+ influx via calcium channels. Then, intracellular Ca2+ binds to calmodulin and activates eNOS, resulting in NO generation. NO acts by stimulating guanylyl cyclase to produce cGMP, which consequently causes smooth muscle to relax. Lithium could possibly affect this pathway at several steps. Firstly, lithium inhibits IMPase, an effect suggested to diminish signaling through phosphatidylinositol (PI)-linked second messengers and, in turn, Ca2+. The elevation of intracellular Ca2+ is a key factor for activation of eNOS; attenuation by lithium of intracellular Ca2+ decreases NOS activity and thereby NO production in endothelia. Secondly, lithium decreases the Ca2+ current from the ER to the intracellular space and reduces ER calcium stores in various tissues [53,224]. This may explain the mechanism by which lithium decreases NO production in endothelial cells and thereby causes endothelium-mediated smooth muscle relaxation. Thirdly, the observation that lithium decreases the production of NO metabolites or L-citrulline in various tissues as well as blood [26] reflects the possible direct effects of lithium on the eNOS. Lastly, NO-mediated cGMP signaling seems unlikely to contribute to the effect of lithium because relaxant responses to NO donors and guanylyl cyclase activators in various vascular tissues are unaffected by lithium [19,20,210,218,219,223]. CaM, calmodulin; cGMP, cyclic guanosine monophosphate; DAG, 1,2-diacylglycerol; eNOS, endothelial nitric oxide synthase; GC, guanylyl cyclase; GTP, guanosine triphosphate; IMPase, inositol monophosphatase; IP3, inositol 1,4,5-triphosphate; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; PIP2, phosphoinositide 4,5-biphosphate; PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; VDCC, voltage-dependent calcium channel.

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Review aminoguanidine had no effect, which indicates that inflammatory processes that induce iNOS activation may not have a role in this effect. Genitourinary and vascular system Approximately 31% of bipolar or schizoaffective patients receiving lithium report sexual dysfunction [217]. NO, as a major NANC neurotransmitter, is the principal mediator of relaxation of the corpus cavernosum (a critical tissue for erection) and thereby penile erection. Acute in-vitro and 30-day chronic lithium administration significantly impaired the neurogenic NANC relaxation of the rat corpus cavernosum [20,218,219]. L-NAME exacerbated this effect, whereas L-arginine administration led to improved function (Figure 2). The endothelium-generated NO synthesized by eNOS also has a pivotal role in maintaining an erection [20,219]. Acute in vitro and chronic ex vivo lithium administration impaired endothelium-mediated relaxation of the rat corpus cavernosum [20,219]. Acute in-vitro lithium injection also decreased endothelium-mediated relaxation in the guinea pig corpus cavernosum [220]. L-NAME potentiated the lithium effect, whereas L-arginine prevented it. NADPH-diaphorase staining of cavernosal tissue was significantly different between chronic lithium-treated and control rats [20], which is in accordance with our recent study on rat mesenteric beds (Table 3) [221]. The serum level of lithium was 0.33 mM in chronic lithium-treated rats, suggesting that this adverse effect may occur below the therapeutic blood levels of lithium [20]. Lithium also alters endothelial relaxation in other vascular tissues, including rat aorta and mesenteric beds [222,223]. Mechanisms that probably underlie the effect of lithium on NO-mediated endothelium-dependent vascular relaxation are depicted schematically in Figure 2. Concluding remarks Increasing evidence has recently focused on the mechanisms underlying the therapeutic effects of lithium. Several signaling targets have been proposed for the action of lithium (e.g. PI cycle and GSK-3b). Some evidence also indicates that glutamatergic/NO transmission may mediate the therapeutic (especially neuroprotective and neurotrophic) effects of lithium. The ramifications of the alteration in NMDA/NO signaling by lithium are potentially manifold because this signaling pathway influences a large and diverse number of processes. Lithium affects this system directly via modulating synaptic glutamate release and reuptake, NMDAR mRNA expression and function, and possibly nNOS activation or indirectly via influencing several other neurotransmitters such as serotonin, adrenaline, dopamine, GABA, neurotrophic factors (BDNF), and the cholinergic system, all of which have bidirectional interaction with NMDA/NO signaling in the CNS. NMDAR/NO signaling may also contribute to several pre-clinical behavioral effects of lithium. For instance, the antidepressant-like effects of lithium in the FST, its effects on cognitive performances such as memory, some animal models of BPD, PPI of the acoustic startle response, and seizure threshold could be mediated by NMDAR/NO signaling. Combination treatment with lithium and other

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