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Sigma‐1 receptor agonist and fluvoxamine rescue depressive behaviors in CaMKIV null mice
Author(s) -
Fukunaga Kohji,
Sakagami Hiroyuki,
Moriguchi Shigeki
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.931.3
Subject(s) - fluvoxamine , dentate gyrus , neurogenesis , stimulation , sigma 1 receptor , endocrinology , medicine , agonist , hippocampal formation , receptor , biology , chemistry , microbiology and biotechnology , fluoxetine , serotonin
Sigma‐1 receptor (Sig‐1R) is a molecular chaperon regulating calcium transport from the neuronal endoplasmic reticulum to mitochondria (Shioda and Fukunaga, JBC 2012;287:23318). Recently Song et al (Int J Neuropsychopharmacol 2012;16:803) reported that CaMKIV null mice exhibit depressive behaviors and impaired neurogenesis as assessed by bromodeoxyuridine (BrdU) incorporation into newborn cells of the hippocampal dentate gyrus (DG). Moreover, the typical SSRI fluoxetine fails to induced DG neurogenesis and lacks of its anti‐depressive effects in CaMKIV null mice. Here, we addressed whether Sig‐1R agonist (SA4503) and SSRI (fluvoxamine) with affinity for Sig‐1R rescue the depressive behaviors in CaMKIV null mice. Treatment with SA4503 or fluvoxamine for 14 days completely rescued the depressive behaviors in CaMKIV null mice. By contrast, treatment with paroxetine, which lacks affinity for Sig‐1R, did not alter these behaviors. Reduced numbers of BrdU‐positive cells and decreased BDNF mRNA expression seen in the DG of CaMKIV null mice were significantly restored by chronic Sig‐1R stimulation with SA4503 or fluvoxamine. We previously reported that Sig‐1R stimulation with SA4503 and fluvoxamine promotes ATP production through increased mitochondrial calcium transport (Tagashira et al., BBA2013;1830:3082). As expected, the reduced ATP production in the DG of CaMKIV null mice was improved by chronic Sig‐1R stimulation. Taken together, Sig‐1R stimulation rescues the SSRI‐resistant depressive behaviors observed in CaMKIV null mice, suggesting attractive therapeutics for SSRI‐resistant depressive patients.