Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview

Tardito, Daniela; Pérez, Jorge; Tiraboschi, Ettore; Musazzi, Laura; Racagni, Giorgio; Popoli, Maurizio

doi:10.1124/pr.58.1.7

Cited by 280 publications

(185 citation statements)

References 122 publications

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“…There is also abundant evidence that brain-derived neurotrophic factor (BDNF) contributes to the actions of antidepressant drugs (Malberg and Blendy, 2005;Tardito et al, 2006). The significance of σ receptors in these effects was recently demonstrated, particularly with regard to the role of BDNF signaling in glutamate release (Yagasaki et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice

Wang

Mack

Coop

et al. 2007

European Neuropsychopharmacology

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Many antidepressant drugs interact with σ receptors and accumulating evidence suggests that these proteins mediate antidepressant-like effects in animals and humans. σ Receptors are localized in brain regions affected in depression, further strengthening the hypothesis that they represent logical drug development targets. In this study, two novel σ receptor agonists (UMB23, UMB82) were evaluated for antidepressant-like activity in mice. First, radioligand binding studies confirmed that the novel compounds had preferential affinity for σ receptors. Second, the forced swim test, a well established animal model for screening potential antidepressant drugs, showed that both compounds dose-dependently reduced immobility time. The σ receptor antagonist BD1047 attenuated the antidepressant-like effects of UMB23 and UMB82. Third, locomotor activity suggested that the effects of UMB23 and UMB82 in the forced swim test were not due to non-specific motor activating effects. Together, the data provide further evidence that σ receptor agonists represent a possible new class of antidepressant medication.

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Section: Discussionmentioning

confidence: 99%

Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice

Wang

Mack

Coop

et al. 2007

European Neuropsychopharmacology

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“…118,119 Indeed, several antidepressants are believed to act on independent pathways that ultimately converge on the cAMP system, 120,121 and synaptic plasticity is modulated by many drugs used to treat mood disorders. 122,123 Moreover, the PDE4 inhibitor rolipram produces behavioural effects similar to those resulting from antipsychotic treatment of rats and mice, 124,125 and this antipsychotic action is mediated by PDE4 isoforms.…”

Section: Pde4b As a Risk Factor For Psychiatric Illness: Interaction mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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“…BDNF mRNA levels are reduced in the brains of suicide victims (with the possible diagnosis of depression) (Chen et al, 2001) and are also decreased by stress, an important precipitating factor in mood disorders. Moreover, chronic antidepressant treatment can increase BDNF expression, thus counteracting the effects of stress (Nibuya et al, 1995;Tsankova et al, 2006;Tardito et al, 2006), whereas mice with impaired synthesis of the neurotrophin fail to respond to antidepressant drugs (Saarelainen et al, 2003;Monteggia et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…However, a close examination of the literature indicates that, apart from the strong modulation of BDNF by electroconvulsive therapy, limited changes (in terms of magnitude and anatomical profile) have been described with other antidepressants (Tardito et al, 2006). Moreover, restricted information is present on the modulation of neurotrophin protein levels, which rarely parallel the changes observed at mRNA levels (Tardito et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Chronic Duloxetine Treatment Induces Specific Changes in the Expression of BDNF Transcripts and in the Subcellular Localization of the Neurotrophin Protein

Calabrese

Molteni

Maj

et al. 2007

Neuropsychopharmacol

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110

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There is growing evidence that brain-derived neurotrophic factor (BDNF) can be relevant to mood disorders and that modulation of its biosynthesis following prolonged antidepressant treatment may contribute to neuroplastic changes required for clinical response. In the present study, we investigated the effects of the novel antidepressant duloxetine on BDNF in the rat brain. Duloxetine is a serotoninnorepinephrine reuptake inhibitor that differs from other antidepressants by virtue of its balanced potency on both neurotransmitter systems. We found that chronic, but not acute, treatment with duloxetine produces a robust increase of exon V BDNF mRNA levels in frontal cortex when the animals were killed 1 or 24 h after the last administration. The expression of the neurotrophin was also increased in other cortical subregions, but not in the hippocampus. We also found that the increased expression of BDNF in frontal cortex was mainly sustained by enhanced mRNA levels for exons I and III, whereas the expression of exon IV was reduced. Protein analysis in different subcellular fractions showed that chronic treatment with duloxetine, but not with the prototypical SSRI fluoxetine, reduced mature BDNF in the cytosol, but markedly increased its levels in the crude synaptosomal fraction. Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin. These changes might improve synaptic plasticity and cognitive function that are defective in depressed subjects.

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Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview

Cited by 280 publications

References 122 publications

Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice

Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice

The DISC locus in psychiatric illness

Chronic Duloxetine Treatment Induces Specific Changes in the Expression of BDNF Transcripts and in the Subcellular Localization of the Neurotrophin Protein

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