The behavioral actions of lithium in rodent models: Leads to develop novel therapeutics

O’Donnell, Kelley C.; Gould, Todd D.

doi:10.1016/j.neubiorev.2007.04.002

Cited by 121 publications

(103 citation statements)

References 256 publications

(286 reference statements)

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“…We confirmed previous studies demonstrating that pretreatment with lithium intraperitoneally (100 mg/kg) 1 h before amphetamine injection in WT mice attenuates amphetamine-induced hyperactivity relative to WT mice pretreated with saline before injection with amphetamine (30 min after amphetamine, F (4,25) ϭ 11.904, Fisher's p ϭ 0.0035) (Fig. 6C) (Takigawa et al, 1994;Frey et al, 2006;O'Donnell and Gould, 2007). The response to amphetamine of VGF ϩ/Ϫ mice pretreated with LiCl was indistinguishable from that of WT mice pretreated with saline, suggesting that LiCl has no effect in VGF ϩ/Ϫ mice (30 min after amphetamine, F (4,25) ϭ 11.904, Fisher's p ϭ 0.9056).…”

Section: Vgf Mimics the Effects Of Licl And Is Required In A Mouse Sysupporting

confidence: 90%

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

Thakker‐Varia¹,

Jean²,

Parikh³

et al. 2010

Journal of Neuroscience

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Recent studies demonstrate that the neuropeptide VGF (nonacronymic) is regulated in the hippocampus by antidepressant therapies and animal models of depression and that acute VGF treatment has antidepressant-like activity in animal paradigms. However, the role of VGF in human psychiatric disorders is unknown. We now demonstrate using in situ hybridization that VGF is downregulated in bipolar disorder in the CA region of the hippocampus and Brodmann's area 9 of the prefrontal cortex. The mechanism of VGF in relation to LiCl was explored. Both LiCl intraperitoneally and VGF intracerebroventricularly reduced latency to drink in novelty-induced hypophagia, and LiCl was not effective in VGF ϩ/Ϫ mice, suggesting that VGF may contribute to the effects of LiCl in this behavioral procedure that responds to chronic antidepressant treatment. VGF by intrahippocampal injection also had novel activity in an amphetamine-induced hyperlocomotion assay, thus mimicking the actions of LiCl injected intraperitoneally in a system that phenocopies manic-like behavior. Moreover, VGF ϩ/Ϫ mice exhibited increased locomotion after amphetamine treatment and did not respond to LiCl, suggesting that VGF is required for the effects of LiCl in curbing the response to amphetamine. Finally, VGF delivered intracerebroventricularly in vivo activated the same signaling pathways as LiCl and is necessary for the induction of mitogen-activated protein kinase and Akt by LiCl, thus lending insight into the molecular mechanisms underlying the actions of VGF. The dysregulation of VGF in bipolar disorder as well as the behavioral effects of the neuropeptide similar to LiCl suggests that VGF may underlie the pathophysiology of bipolar disorder.

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Section: Vgf Mimics the Effects Of Licl And Is Required In A Mouse Sysupporting

confidence: 90%

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

Thakker‐Varia¹,

Jean²,

Parikh³

et al. 2010

Journal of Neuroscience

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“…In the present manuscript we do not address the role of AMPA receptors in mediating the effects of lithium in models of manic-like behavior. Available rodent models for the antimanic effects of lithium include attenuation of amphetamine-induced hyperlocomotion and attenuation of aggression (O'Donnell and Gould, 2007), which should be evaluated for the relevance of AMPA receptors.…”

Section: Discussionmentioning

confidence: 99%

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

et al. 2008

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In addition to its clinical antimanic effects, lithium also has efficacy in the treatment of depression. However, the mechanism by which lithium exerts its antidepressant effects is unclear. Our objective was to further characterize the effects of peripheral and central administration of lithium in mouse models of antidepressant efficacy as well as to investigate the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in these behaviors. We utilized the mouse forced swim test (FST) and tail suspension test (TST), intracerebroventricular (ICV) lithium administration, AMPA receptor inhibitors, and BS3 crosslinking followed by western blot. Both short-and long-term administration of lithium resulted in robust antidepressant-like effects in the mouse FST and TST. Using ICV administration of lithium, we show that these effects are due to actions of lithium on the brain, rather than to peripheral effects of the drug. Both ICV and rodent chow (0.4% LiCl) administration paradigms resulted in brain lithium concentrations within the human therapeutic range. The effects of lithium to decrease immobility in the FST and TST were blocked by administration of AMPA receptor inhibitors. Additionally, administration of lithium increased the cell surface expression of GluR1 and GluR2 in the mouse hippocampus. Collectively, these data show that lithium exerts centrally mediated antidepressant-like effects in the mouse FST and TST that require AMPA receptor activation. Lithium may exert its antidepressant effects in humans through AMPA receptors, thus further supporting a role of targeting AMPA receptors as a therapeutic approach for the treatment of depression. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Depression is a severe neuropsychiatric disorder that manifests both as a component of bipolar disorder and unipolar depressive disorder. Bipolar disorder affects at least 1% of the world's population when a strict definition (DSM IV bipolar I disorder) is applied. Major depression is more common than bipolar disorder in the overall population (~ 15% lifetime risk as defined by DSM IV) (Kessler et al., 2005;Sullivan et al., 2000). The recognition of the significant morbidity and mortality (suicide rate of 15%) associated with these severe mood disorders (Evans et al., 2005;Jamison, 2000;Kupfer, 2005), as well as the growing appreciation that a significant percentage of patients either do not respond fully to existing treatments or are intolerant of undesirable side effects, has made the challenge of discovering improved therapeutic agents increasing...

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“…The present study showed that TAT-KLCpCDK, a peptide that specifically inhibits the phosphorylation of KLC2, possessed both antidepressantlike and antimanic-like properties in animal models of moodassociated behaviors, thus mimicking lithium's effect on these behaviors. Numerous studies have shown that in addition to its clinical antimanic effects, in animal models lithium has robust antidepressant-like effects in the forced swim and tail suspension tests (30). These antidepressant-like effects can be blocked by the AMPAR inhibitor GYKI52446 (31).…”

Section: Gsk-3 Regulation Of Ampar Trafficking As a Mechanism For Affmentioning

confidence: 99%

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

Wei

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

114

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Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK-3β, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3β capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders.α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor | internalization | kinesin light chain 2

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The behavioral actions of lithium in rodent models: Leads to develop novel therapeutics

Cited by 121 publications

References 256 publications

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

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