AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test

Gould, Todd D.; Einat, Haim; Bhat, Ratan V.; Manji, Husseini K.

doi:10.1017/s1461145704004535

Cited by 288 publications

(223 citation statements)

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“…17 The major finding of this study is that three of the four GSK3B SNPs investigated are strongly associated with 4-week SSRI antidepressant therapeutic response. This association between the GSK3B genetic variants and therapeutic response to SSRIs is supported by data from animal studies showing that GSK3 inhibitors had antidepressant-like activity 10,11 and that fluoxetine inhibited GSK3B activity. 3 Furthermore, a recent study of Italian bipolar depression patients found that the C/C homozygote for the GSK3B rs334558 polymorphism (À50C/T) SNP showed acute effects of total sleep deprivation treatment on perceived mood.…”

Section: Discussionmentioning

confidence: 76%

“…9 Thirdly, two studies in 2004 demonstrated that rats treated with GSK3 inhibitors showed reduced duration of immobility when exposed to the forced swim test, a well-established model for antidepressant efficacy, suggesting the potential of GSK3 inhibitors as antidepressants. 10,11 Finally, a recent post-mortem study demonstrated that there was no change in GSK3B protein levels in the ventral prefrontal cortex of MDD patients but that GSK3B activity increased significantly compared with control subjects. 12 The human GSK3B, located on chromosome 3q13.33, is about 268 kb in length and includes 12 exons.…”

Section: Introductionmentioning

confidence: 99%

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Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder

et al. 2008

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Evidence suggests that glycogen synthase kinase-3b (GSK3B) activity is increased significantly in the brain of patients with major depressive disorders (MDD). Inhibition of GSK3B is thought to be a key feature in the therapeutic mechanism of antidepressants. To investigate whether common genetic variants in the GSK3B gene are associated with MDD and the therapeutic response to antidepressants, four polymorphisms (rs334558 (À50 T4C), rs13321783 (IVS7 þ 9227 A4G), rs2319398 (IVS7 þ 11660 G4T) and rs6808874 (IVS11 þ 4251 T4A)) of the GSK3B gene were genotyped in 230 Chinese MDD patients and 415 controls. Among the MDD patients, 168 accepted selective serotonin reuptake inhibitor (SSRI) (fluoxetine or citalopram) antidepressant treatment and therapeutic evaluation for 4 weeks and 117 for 8 weeks. Significant association with MDD was not shown in the alleles and genotypes of single loci or four-locus haplotypes. However, three of the four polymorphisms investigated were significantly associated with 4-week antidepressant therapeutic effect (P ¼ 0.002-0.011). Of the four-locus haplotype analysis, the GSK3B TAGT carriers showed a poorer response to antidepressants in 4-week (Po0.0001) and 8-week (P ¼ 0.015) evaluation compared with other haplotype groups and would quite likely be the nonremitter to 8-week antidepressant treatment (P ¼ 0.006). Our findings show, for the first time, that GSK3B genetic variants play a role in the SSRI antidepressant therapeutic response and support the hypothesis that drugs regulating GSK3B activity may represent a novel treatment strategy for MDD.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder

et al. 2008

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“…However, additional effects of lithium on glutamate release or reuptake, or postsynaptic effects on glutamate receptors, downstream signaling, or direct effects on the receptor cannot be excluded. Recent data have suggested that lithium exerts some of its behavioral actions through inhibition of GSK-3 (Beaulieu et al, 2004;Gould et al, 2004;Kaidanovich-Beilin et al, 2004;O'Brien et al, 2004). Future studies will examine the link between GSK-3 inhibition and regulation of AMPA receptors.…”

Section: Discussionmentioning

confidence: 98%

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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“…For example, lithium, GSK-3b knockout and other GSK-3 inhibitors show antidepressant effects in rodents. [39][40][41] Lithium and other GSK-3 inhibitors also attenuate the hyperactivity induced by amphetamine in rats 40 or dopamine transporter knockout in mice. 42 Valproic acid-induced promoter IV activation is mimicked by treatment with other HDAC inhibitors, SB and TSA, or by gene knockdown with HDAC1-specific siRNA (Figure 5), suggesting the involvement of HDAC inhibition.…”

Section: Discussionmentioning

confidence: 99%

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

et al. 2007

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Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium-or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium-or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3a or GSK-3b isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.

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AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test

Cited by 288 publications

References 10 publications

Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder

Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder

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

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

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