Interactions of lithium and drugs that affect signal transduction on behaviour in rats.

The therapeutic mechanism of the action of lithium in the treatment of bipolar affective disorder is not known, in spite of a burgeoning number of biochemical studies linking lithium to signal transduction processes. This article reviews a decade of studies examining the behavioural manifestations of manipulating inositol, cyclic adenosine monophosphate (cAMP) and G proteins in rats. Inositol, forskolin, dibutyryl cAMP and pertussis toxin all interacted with lithium when rearing behavior was measured. Lithium potentiated the increase in locomotion induced by injections of cholera toxin into the nucleus accumbens, consistent with the hypothesis that it inactivates inhibitory G proteins. More specific interactions were found between lithium and inositol following cholinergic and serotonergic stimulation. Inositol, but not forskolin, attenuated lithium-pilocarpine seizures and the enhancement of the serotonin syndrome; however, inositol had no effect on lithium-induced attenuation of wet dog shakes following an injection of 5-hydroxytryptophan. Behavioural evidence supports biochemical findings suggesting that lithium's interactions with the phoshphatidyl inositol and cyclic AMP signal transduction systems may be relevant to its therapeutic effects in bipolar disorder. Further research on more specific behaviours may elucidate the relevant pharmacological mechanisms underlying the therapeutic effect of lithium.     

The effects of central nervous system-active valproic acid constitutional isomers, cyclopropyl analogs, and amide derivatives on neuronal growth cone behavior

Valproic acid (VPA) is an effective antiepileptic drug with an additional activity for the treatment of bipolar disorder. It has been assumed that both activities arise from a common target. At the molecular level, VPA targets a number of distinct proteins that are involved in signal transduction. VPA inhibition of inositol synthase reduces the cellular concentration of myo-inositol, an effect common to the mood stabilizers lithium and carbamazepine. VPA inhibition of histone deacetylases activates Wnt signaling via elevated beta-catenin expression and causes teratogenicity. Given the VPA chemical structure, it may be possible to design VPA derivatives and analogs that modulate specific protein targets but leave the others unaffected. Indeed, it has been shown that some nonteratogenic VPA derivatives retain antiepileptic and inositol signaling effects. In this study, we describe a further set of VPA analogs and derivatives that separate anticonvulsant activity from effects on neuronal growth cone morphology. Lithium, carbamazepine, and VPA induce inositol-dependent spread of neuronal growth cones, providing a cell-based assay that correlates with mood-stabilizing activity. We find that two constitutional isomers of VPA, propylisopropylacetic acid and diisopropylacetic acid, but not their corresponding amides, and N-methyl-2,2,3,3-tetramethyl-cyclopropanecarboaxamide are more effective than VPA in increasing growth cone spreading. We show that these effects are associated with inositol depletion, and not changes in beta-catenin-mediated Wnt signaling. These results suggest a route to a new generation of central nervous system-active VPA analogs that specifically target bipolar disorder.     

Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain.

One of the mechanisms underlying lithium's efficacy as a mood stabilizer in bipolar disorder has been proposed to be via its effects on the phosphoinositol cycle (PI cycle), where it is an inhibitor of the enzyme converting inositol monophosphates to myoinositol. In contrast, sodium valproate, another commonly used mood stabilizer, appears to have no direct effects on this enzyme and was thus believed to have a different mechanism of action. In the present study, high-resolution nuclear magnetic resonance (NMR) spectroscopy was used to study the chronic effects of both lithium and sodium valproate on the concentrations of myoinositol and inositol monophosphates in rat brain. As predicted, lithium-treated rats exhibited a significant increase in the concentration of inositol monophosphates and a significant decrease in myoinositol concentration compared to saline-treated controls. However, unexpectedly, sodium valproate administration produced exactly the same results as lithium administration. These novel findings suggest that both lithium and sodium valproate may share a common mechanism of action in the treatment of bipolar disorder via actions on the PI cycle.     

The NMDA receptor/nitric oxide pathway: a target for the therapeutic and toxic effects of lithium

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.     

Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs?

The mechanism of action of antibipolar drugs like lithium, carbamazepine, and valproate that are used in the treatment of manic-depressive illness, is unknown. Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs.     

Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs.

Despite many decades of clinical use, the therapeutic target of lithium remains uncertain. It is recognized that therapeutic concentrations of lithium, through competition with the similarly sized magnesium cation, inhibit the activity of select enzymes. Among these is glycogen synthase kinase-3 (GSK-3). Recent preclinical evidence, including biochemical, pharmacological, genetic, and rodent behavioral models, supports the hypothesis that inhibition of GSK-3 may represent a target for lithium's mood-stabilizing properties. Specifically, it has been demonstrated that lithium administration regulates multiple GSK-3 targets in vivo and that multiple additional classes of mood-stabilizing and antidepressant drugs regulate GSK-3 signaling. Pharmacological or genetic inhibition of GSK-3 results in mood stabilizer-like behavior in rodent models, and genetic association studies implicate GSK-3 as a possible modulator of particular aspects of bipolar disorder including response to lithium. Furthermore, numerous recent studies have provided a more complete understanding of GSK-3's role in diverse neurological processes strengthening the hypothesis that GSK-3 may represent a therapeutically relevant target of lithium. For example, GSK-3 is a primary regulator of neuronal survival, and cellular responses to glucocorticoids and estrogen may involve GSK-3-regulated pathways. While the preclinical evidence discussed in this review is encouraging, ultimate validation of GSK-3 as a therapeutically relevant target will require clinical trials of selective novel inhibitors. In this regard, as is discussed, there is a major effort underway to develop novel, specific, GSK-3 inhibitors.     

Lithium and serotonin function: implications for the serotonin hypothesis of depression

Lithium enjoys wide clinical use in the treatment of affective disorders, but the mechanism of its action in these conditions is still controversial. Recent studies have shown that lithium can interact with other antidepressant drugs to enhance their efficacy, perhaps by specific effects on serotonin (5-HT) function. A large body of independent evidence suggests that 5-HT function is abnormal in depression. This review documents preclinical evidence of lithium's effects on 5-HT function at the levels of precursor uptake, synthesis, storage, catabolism, release, receptors, and receptor-effector interactions. The weight of this evidence suggests that lithium's primary actions on 5-HT may be presynaptic, with many secondary postsynaptic effects. Studies in humans, using very different methodological approaches, generally suggest that lithium has a net enhancing effect on 5-HT function. These actions of lithium may serve to correct as-yet unspeccified abnormalities of 5-HT function involved in the pathogenesis of depression.     

Homologous and heterologous regulation of receptor-stimulated phosphoinositide hydrolysis

Signal transduction at a diverse range of pharmacologically distinct receptors is effected by the enhanced turnover of inositol phospholipids, with the attendant formation of inositol 1,4,5-trisphosphate and diacylglycerol. Although considerable progress has been made in recent years towards the identification and characterization of the individual components of this pathway, much less is known of mechanisms that may underlie its regulation. In this review, evidence is presented for the potential regulation of inositol lipid turnover at the level of receptor, phosphoinositide-specific phospholipase C and substrate availability in response to either homologous or heterologous stimuli. Available data indicate that the extent of receptor-stimulated inositol lipid hydrolysis is regulated by multiple mechanisms that operate at different levels of the signal transduction pathway.     

Effect of chronic lithium treatment on the turnover of α2-adrenoceptors after chemical inactivation in rats

One of the most effective psychotherapeutic agents in the treatment of bipolar disease is lithium. Chronic lithium treatment affects some signal transduction mechanisms such as cAMP, cGMP, inositol 1,4,5 P(3), Gi protein, protein kinase C and can also modify gene expression in rat brain. In a previous study, we observed a greater inhibitory effect of lithium on cAMP production after blockade of alpha(2)-adrenoceptors in rat cerebral cortex. Here we examine the influence of chronic lithium treatment on turnover of alpha(2)-adrenoceptors after their inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) in rat cerebral cortex. After treatment with lithium for 10 days (120 mg/kg/day, i.p.), there was a significant increase in the appearance and disappearance rate constants of these adrenoceptors and a significant reduction of their half-life. These results suggest that chronic lithium administration alters the alpha(2)-adrenoceptor turnover in rat brain.     

Search for a common mechanism of mood stabilizers

Manic-depression, or bipolar affective disorder, is a prevalent mental disorder with a global impact. Mood stabilizers have acute and long-term effects and at a minimum are prophylactic for manic or depressive poles without detriment to the other. Lithium has significant effects on mania and depression, but may be augmented or substituted by some antiepileptic drugs. The biochemical basis for mood stabilizer therapies or the molecular origins of bipolar disorder is unknown. One approach to this problem is to seek a common target of all mood stabilizers. Lithium directly inhibits two evolutionarily conserved signal transduction pathways. It both suppresses inositol signaling through depletion of intracellular inositol and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase. A number of GSK-3 substrates are involved in neuronal function and organization, and therefore present plausible targets for therapy. Valproic acid (VPA) is an antiepileptic drug with mood-stabilizing properties. It may indirectly reduce GSK-3 activity, and can up-regulate gene expression through inhibition of histone deacetylase. These effects, however, are not conserved between different cell types. VPA also inhibits inositol signaling through an inositol-depletion mechanism. There is no evidence for GSK-3 inhibition by carbamazepine, a second antiepileptic mood stabilizer. In contrast, this drug alters neuronal morphology through an inositol-depletion mechanism as seen with lithium and VPA. Studies on the enzyme prolyl oligopeptidase and the sodium myo-inositol transporter support an inositol-depletion mechanism for mood stabilizer action. Despite these intriguing observations, it remains unclear how changes in inositol signaling underlie the origins of bipolar disorder.     

A new anti-platelet drug, E5510, has multiple suppressive sites during receptor-mediated signal transduction in human platelets.

The mode of action of E5510, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, which has very potent anti-platelet activities, was investigated by examining its effects on the biochemical responses in the process of human platelet activation. In a whole-cell system, E5510 inhibited the increased turnover of inositol phospholipids arising from phospholipase C activation, arachidonic acid release from phospholipids by phospholipase A2, mobilization of intracellular free Ca2+, protein kinase C activation, and thromboxane A2 production. In a cell-free system, E5510 inhibited cyclooxygenase activity and cyclic AMP-dependent phosphodiesterase activity in a dose-dependent manner. An elevation of cyclic AMP in platelets was also observed at a relatively high concentration of E5510. It was suggested that receptor-mediated turnover of inositol phospholipids, intracellular Ca2+ increase, arachidonic acid release from phospholipids and protein kinase C activation might be indirectly inhibited by the increased cyclic AMP level in platelets. Thromboxane A2 production in the whole-cell system was very strongly inhibited by E5510, and the IC50 for this effect was 100 times lower than that of direct inhibition of cyclooxygenase in the cell-free system. It was concluded that although the primary mode of action of E5510 is the inhibition of the cyclooxygenase pathway of positive signal transduction in platelets, E5510 has another mode of action by increasing platelet cyclic AMP, which can act as a negative messenger in platelet signal transduction, and these multiple sites of action synergistically antagonize platelet cellular activation.     

Inositol-Related Gene Knockouts Mimic Lithium's Effect on Mitochondrial Function

The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium''s/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium''s effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium''s effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.     

锂盐神经保护作用机制的研究进展

锂盐作为治疗躁狂抑郁症的主要药物，在近年来的研究中发现它在体内外均具有很好的神经保护作用，可用于治疗阿尔茨海默病、亨廷顿舞蹈病和脑缺血等脑血管疾病。其神经保护作用机制涉及多个方面，包括糖原合酶激酶，3、NMDA离子通道、bcl-2蛋白家族、脑源性神经营养因子信号传导通路、丝裂原激活的蛋白激酶信号传导通路、c-fos及c-jun，目前尚未完全阐明。综述锂盐的神经保护作用及其机制的研究进展。     

Lithium pharmacokinetics.

Lithium, in various forms, has been used in the treatment and prophylaxis of bipolar affective disorder since the mid-1960s. In the past 30-plus years, much has been learned regarding lithium's effects on the renal function, improved ways and forms of administering and monitoring serum lithium levels, the effect of mood state on lithium kinetics, and the influence of age and disease factors. Furthermore, the interaction of lithium with other psychotropics as well as with non-psychotropics, in particular, the diuretics and nonsteroidal anti-inflammatory agents, has frequently become a source of concern. This review highlights current knowledge on these topics with a view toward future developments.     

The inositol monophosphatase inhibitor L-690,330 affects pilocarpine-behavior and the forced swim test

Rationale

Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization.

Objectives

The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L-690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST).

Methods

The inhibitor was administered intracerebroventricularly in liposomes.

Results

L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST.

Conclusions

It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor’s effect with intracerebroventricular inositol would be an important further step in proof.     

Historical perspectives and current highlights on lithium treatment in manic-depressive illness

This article reviews the use of lithium from Roman times, when physicians first recommended alkaline springs in the treatment of mania, to the present. Serious interest in lithium began in 1949, with a report of improvement of mania in 10 of 10 patients. Since then, lithium has become increasingly popular both for treating acute mania and as a prophylactic agent. Its use in depression is also described. Finally, lithium's clinical spectrum is discussed, noting that its use extends far beyond the treatment of mania.     

Lithium therapy and signal transduction

Lithium is the simplest therapeutic agent available for the treatment of depression and has been used for over 100 years, yet no definitive mechanism for its effect has been established. Among the proposed mechanisms, two lithium-sensitive signal transduction pathways are active in the brain; these are mediated by glycogen synthase kinase 3beta (GSK-3beta) and inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] signalling. This article describes recent experiments in cell and developmental biology that advance our understanding of how lithium works and it presents new directions for the study of both depression and Alzheimer's disease (AD).     

Muscarinic receptors in human airway smooth muscle are coupled to phosphoinositide metabolism

In the present study we investigated whether muscarinic receptors in human airway smooth muscle are coupled to phosphoinositide metabolism as a possible transduction mechanism of contraction. Using isolated bronchial smooth muscle preparations, we found that the muscarinic agonist methacholine caused a time- and concentration-dependent accumulation of inositol phosphates in the presence of lithium, an effect which could be inhibited by atropine. Apart from its physiological significance, this finding may have great relevance for the biochemical investigation of cholinergic hyperresponsiveness in the airways of asthmatic patients.     

Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila.

Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3beta gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3beta gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3beta as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3beta heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.     

Is the prophylactic antidepressant efficacy of lithium in bipolar I disorder dependent on study design and lithium level?

In the 1970s, several randomized controlled trials demonstrated significant antimanic and antidepressant properties of lithium in the prophylactic treatment of bipolar disorder. However, a recent meta-analysis of randomized, placebo-controlled trials of lithium in bipolar disorder found that its protective effect against depressive relapse/recurrence was equivocal. By examining potentially relevant parameters of recent randomized controlled trials with regard to lithium's prophylactic antidepressant efficacy, we try to identify factors which might help to explain these discrepant results across the different trials. Lithium's efficacy against manic relapse/recurrence appears rather robust at plasma levels between 0.8 and 1.2 mmol/L, whereas lithium's efficacy against depressive relapse/recurrence may be more modest and dependent on whether a response during the preceding acute episode was achieved by lithium treatment. Furthermore, it might be advisable to continue lithium without interruption at the same dose/plasma level, which yielded the initial response. A lithium level between 0.5 and 0.8 mmol/L may be equally efficacious against overall relapse and associated with equal or even superior efficacy regarding depressive relapse/recurrence. To provide evidence-based guidelines on this issue, large prospective, randomized, double-blind, placebo-controlled trials are needed comparing the efficacy of lithium at different plasma levels against manic and depressive relapse/recurrence. In these trials, factors previously associated with predicting response to lithium should also be assessed.