PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13.
Bottom Line: Our results shown that GLYX-13 dose-dependently reversed the depressive-like behaviors in forced swim test.Finally, antidepressant-like effects of GLYX-13 required AMPA receptor and mTOR activation, as evidenced by the ability of NBQX and rapamycin to block the effects of GLYX-13, respectively.Our results suggest that phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF in hippocampus may be involved in the antidepressant-like effects of GLYX-13.
Affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.Show MeSH
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Mentions: Five sets of experiments were conducted. The first set was performed to assess the fast-acting antidepressant-like effects of acute GLYX-13 administration (Figure 1a). The second set of experiments was to investigate whether 21-day CUMS alters VGF and PI3K/AKT/mTOR signaling in the hippocampus of mice and to determine whether acute treatment of GLYX-13 (0.5, 5, and 10mg/kg, i.p.) reverses the depressive-like behaviors induced by CUMS in mice (Figure 2a). The third set was to demonstrate whether knock down of VGF in hippocampus by Vgf-shRNA-lentivirus blocks the antidepressant-like action of GLYX-13 (10mg/kg, i.p.) (Figure 4a). Lentiviral vectors containing NS-shRNA or Vgf-shRNA-lentivirus (5×107 TU/μL, 1 μL/side) were infused at a rate of 0.2 μL/min with an infusion pump, and the cannulas were left in place for 60 additional seconds to avoid back flow. The fourth set of experiments was to investigate whether i.h. infusion of LY294002 (10 nmol/side), a specific PI3K inhibitor, 30 minutes prior to the administration of GLYX-13 (10mg/kg, i.p.) significantly blocks the antidepressant-like behaviors in the open field test (OFT) (Figure 6a). The fifth set of experiments was to investigate whether i.h. infusions of NBQX (2 μg/side), a AMPA receptor inhibitor (NBQX), or mTOR inhibitor (rapamycin) 30 minutes prior to the administration of GLYX-13 (10mg/kg, i.p.) blocks the antidepressant-like behaviors of GLYX-13 (Figure 8a, e).
Affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.