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Molecular Pharmacology

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Research ArticleArticle

α2δ Ligands Act as Positive Modulators of Adult Hippocampal Neurogenesis and Prevent Depression-Like Behavior Induced by Chronic Restraint Stress

Maria Maddalena Valente, Valeria Bortolotto, Bruna Cuccurazzu, Federica Ubezio, Vasco Meneghini, Maria Teresa Francese, Pier Luigi Canonico and Mariagrazia Grilli
Molecular Pharmacology August 2012, 82 (2) 271-280; DOI: https://doi.org/10.1124/mol.112.077636
Maria Maddalena Valente
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Valeria Bortolotto
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Bruna Cuccurazzu
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Federica Ubezio
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Vasco Meneghini
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Maria Teresa Francese
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Pier Luigi Canonico
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Mariagrazia Grilli
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Abstract

Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggested that the process is involved in cognitive and emotional functions and is deregulated in various neuropsychiatric disorders, including major depression. Several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid] and pregabalin (PGB) [(S)-(+)-3-isobutyl-GABA or (S)-3-(aminomethyl)-5-methylhexanoic acid] can produce concentration-dependent increases in the numbers of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, because significantly increased numbers of adult cell-generated neurons were observed in the hippocampal region of mice receiving prolonged treatment with PGB (10 mg/kg i.p. for 21 days), compared with vehicle-treated mice. We demonstrated that PGB administration prevented the appearance of depression-like behaviors induced by chronic restraint stress and, in parallel, promoted hippocampal neurogenesis in adult stressed mice. Finally, we provided data suggesting involvement of the α2δ1 subunit and the nuclear factor-κB signaling pathway in drug-mediated proneurogenic effects. The new pharmacological activities of α2δ ligands may help explain their therapeutic activity as supplemental therapy for major depression and depressive symptoms in post-traumatic stress disorder and generalized anxiety disorders. These data contribute to the identification of novel molecular pathways that may represent potential targets for pharmacological modulation in depression.

Footnotes

  • This work was supported by Fondazione delle Comunità del Novarese and by Fondazione Cariplo (grants to M.G.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.077636.

  • ABBREVIATIONS:

    MDD
    major depressive disorder
    NPC
    neural progenitor cell
    GBP
    gabapentin
    PGB
    pregabalin
    VGCC
    voltage-gated calcium channel
    MAP-2
    microtubule-associated protein-2
    BrdU
    bromodeoxyuridine
    GFAP
    glial fibrillary acidic protein
    NeuN
    neuronal nuclei
    TST
    tail suspension test
    FST
    forced swim test
    DG
    dentate gyrus
    NF-κB
    nuclear factor-κB
    ANOVA
    analysis of variance
    JSH-23
    4-methyl-N1-(3-phenylpropyl)-1,2-benzenediamine
    SC-514
    4-amino-[2,3′-bithiophene]-5-carboxamide.

  • Received January 11, 2012.
  • Accepted May 9, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (2)
Molecular Pharmacology
Vol. 82, Issue 2
1 Aug 2012
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Research ArticleArticle

Antidepressant-Like Activity of α2δ Ligands

Maria Maddalena Valente, Valeria Bortolotto, Bruna Cuccurazzu, Federica Ubezio, Vasco Meneghini, Maria Teresa Francese, Pier Luigi Canonico and Mariagrazia Grilli
Molecular Pharmacology August 1, 2012, 82 (2) 271-280; DOI: https://doi.org/10.1124/mol.112.077636

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Research ArticleArticle

Antidepressant-Like Activity of α2δ Ligands

Maria Maddalena Valente, Valeria Bortolotto, Bruna Cuccurazzu, Federica Ubezio, Vasco Meneghini, Maria Teresa Francese, Pier Luigi Canonico and Mariagrazia Grilli
Molecular Pharmacology August 1, 2012, 82 (2) 271-280; DOI: https://doi.org/10.1124/mol.112.077636
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