Looking at Lithium: Molecular Moods and Complex Behaviour

Department of Anatomy and Physiology, Université Laval/CRULRG, Québec, Canada G1J 2G3.
Molecular Interventions (Impact Factor: 12.14). 11/2008; 8(5):230-41. DOI: 10.1124/mi.8.5.8
Source: PubMed


Lithium and other mood-stabilizing drugs are used for the management of bipolar mood disorders and, to a lesser extent, for augmentation of other psychoactive drugs. Lithium also has neuroprotective properties that may be useful for treatment of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Over the years, lithium has been shown to inhibit inositol monophosphatases and glycogen synthase kinase 3, but the relevance of such enzyme inhibition to the therapeutic effects of lithium has remained difficult to assess. Here, we provide an overview of recent advances in the identification of molecular mechanisms involved in the regulation of behavior by lithium. We also highlight recent findings suggesting that lithium could exert some of its behavioral effects by acting on a dopamine receptor regulated signaling complex composed of Akt, protein phosphatase 2A, and the multifunctional protein scaffold beta-arrestin 2.

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    • "It is worth mentioning that the formation of the Akt : βArr2 : PP2A signalling complex in response to D2 receptor activation represents a mechanism through which dopamine can trigger the inactivation of PI3K/Akt signalling in a regulated fashion. Importantly, the Akt : βArr2 : PP2A signalling complex dissociates in response to lithium, thus providing a probable explanation for the early behavioural observations of the antagonistic effect of lithium on dopaminergic behaviours as well as a reasonable mechanism for the activation of Akt by lithium (Beaulieu and Caron, 2008a; O'Brien et al., 2011; Pan et al., 2011). The details of the mechanism(s) by which lithium triggers this dissociation are not yet fully understood. "
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    ABSTRACT: The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.
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    • "As another example, the mechanism of action of lithium is perhaps most enigmatic among psychiatric medications. Evidence from murine neuronal culture and brain studies suggests that lithium modulates diverse kinase signaling pathways involving GSK3β, AKT,13 MEK, ERK,14, 15 CaM kinase IV16 and protein kinase C.17 On the other hand, lithium is also known to regulate other processes such as cell cycle progression, calcium homeostasis, apoptosis and oxidative stress.18, 19, 20 With so many putative targets of psychiatric drugs, identification of those most physiologically relevant to the human brain is critical to the informed design of new, more specific and safer drugs. "
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    ABSTRACT: Human-induced pluripotent stem cells (hiPSCs) derived from somatic cells of patients have opened possibilities for in vitro modeling of the physiology of neural (and other) cells in psychiatric disease states. Issues in early stages of technology development include (1) establishing a library of cells from adequately phenotyped patients, (2) streamlining laborious, costly hiPSC derivation and characterization, (3) assessing whether mutations or other alterations introduced by reprogramming confound interpretation, (4) developing efficient differentiation strategies to relevant cell types, (5) identifying discernible cellular phenotypes meaningful for cyclic, stress induced or relapsing-remitting diseases, (6) converting phenotypes to screening assays suitable for genome-wide mechanistic studies or large collection compound testing and (7) controlling for variability in relation to disease specificity amidst low sample numbers. Coordination of material for reprogramming from patients well-characterized clinically, genetically and with neuroimaging are beginning, and initial studies have begun to identify cellular phenotypes. Finally, several psychiatric drugs have been found to alter reprogramming efficiency in vitro, suggesting further complexity in applying hiPSCs to psychiatric diseases or that some drugs influence neural differentiation moreso than generally recognized. Despite these challenges, studies utilizing hiPSCs may eventually serve to fill essential niches in the translational pipeline for the discovery of new therapeutics.
    11/2013; 45(11):e59. DOI:10.1038/emm.2013.124
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    • "Similarly, β-arrestin 1 expression is decreased in the hypothalamus and hippocampus in anxious/depressed mice exposed to glucocorticoid elevation, and is restored by chronic fluoxetine treatment (David et al., 2009). Moreover, β-arrestin 1 and 2 signaling is involved in mediating the response to fluoxetine and lithium (Beaulieu et al., 2008; David et al., 2009). Clinical data from Avissar et al. (2004) suggest that β-arrestin 1 mRNA and protein levels are highest in peripheral blood leukocytes of MDD patients. "
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    ABSTRACT: A limited number of biomarkers in the central and peripheral systems which are known may be useful for diagnosing major depressive disorders and predicting the effectiveness of antidepressant (AD) treatments. Since 60% of depressed patients do not respond adequately to medication or are resistant to ADs, it is imperative to delineate more accurate biomarkers. Recent clinical studies suggest that β-arrestin 1 levels in human mononuclear leukocytes may be an efficient biomarker. If potential biomarkers such as β-arrestin 1 could be assessed from a source such as peripheral blood cells, then they could be easily monitored and used to predict therapeutic responses. However, no previous studies have measured β-arrestin 1 levels in peripheral blood mononuclear cells (PBMCs) in anxious/depressive rodents. This study aimed to develop a method to detect β-arrestin protein levels through immunoblot analyses of mouse PBMCs isolated from whole blood. In order to validate the approach, β-arrestin levels were then compared in na\"{\i}ve, anxious/depressed mice, and anxious/depressed mice treated with a selective serotonin reuptake inhibitor (fluoxetine, 18~mg/kg/day in the drinking water). The results demonstrated that mouse whole blood collected by submandibular bleeding permitted isolation of enough PBMCs to assess circulating proteins such as β-arrestin 1. β-Arrestin 1 levels were successfully measured in healthy human subject and na\"{\i}ve mouse PBMCs. Interestingly, PBMCs from anxious/depressed mice showed significantly reduced β-arrestin 1 levels. These decreased β-arrestin 1 expression levels were restored to normal levels with chronic fluoxetine treatment. The results suggest that isolation of PBMCs from mice by submandibular bleeding is a useful technique to screen putative biomarkers of the pathophysiology of mood disorders and the response to ADs. In addition, these results confirm that β-arrestin 1 is a potential biomarker for depression.
    Frontiers in Pharmacology 09/2013; 4:124. DOI:10.3389/fphar.2013.00124 · 3.80 Impact Factor
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