Antidepressant-like effect of CP-101,606: Evidence of mTOR pathway activation

• Published in: Molecular and cellular neuroscience 2023-03, Vol.124, p.103821-103821, Article 103821
• Main Authors: Qin, Yu, Guo, Xinlei, Song, Wenyue, Liang, Zehuai, Wang, Yahui, Feng, Dan, Yang, Yiru, Li, Mingxing, Gao, Mingqi
• Format: Article
• Language: English
• Subjects: Animals; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; CP-101,606; CUMS; Depression; Depression - drug therapy; Depression - metabolism; Disease Models, Animal; Hippocampus - metabolism; Mice; mTOR; NR2B; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - pharmacology; Stress, Psychological - metabolism; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2023.103821

As a non-competitive N-methyl d-aspartate receptor antagonist, ketamine exerts rapid-onset and long-lasting antidepressant effects on depression, but some side effects limit its use. To identify a safer compound that may provide similar antidepressant effects, here we investigated whether CP-101,606, a selective NR2B receptor inhibitor, provides similar antidepressant effects and explored its underlying mechanisms. To mimic depressive-like behavior, mice were subjected to chronic unpredictable mild stress (CUMS) for 21 days. Mice were treated with CP-101,606 at 10, 20, and 40 mg/kg doses for 7, 14, and 21 days, respectively, followed by a sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). Western blot analysis was performed on several targets (mTOR, p-mTOR, p70S6K, p-p70S6K, PSD-95, and GluA1), along with immunohistochemistry (GluA1) and immunofluorescence (p-mTOR) assays, using hippocampal tissue. CP-101,606 at 20 and 40 mg/kg doses for 7 and 14 days and fluoxetine 10 mg/kg and CP-101606 20 mg/kg for 21 days ameliorated depression-like behaviors in the SPT, TST, and FST. The effects of CP-101,606 were associated with a reversal of the CUMS-induced decrease in mTOR (Ser2448) and p70S6K (Thr389) phosphorylation and increasing PSD95 and GluA1 synthesis in the hippocampus. Our results demonstrate that CP-101,606 produces antidepressant effects in CUMS mice, which may be mediated by mTOR signaling cascade upregulation. Our findings suggest the possible utility of CP-101,606 as a treatment for depression. •CP-101,606 reversed depression-like behaviors induced by CUMS.•CUMS-induced behavioral changes were correlated with synaptic proteins expression.•The molecular mechanisms of CP-101,606 may be related to mTOR signaling pathways.•Appropriate dose of CP-101,606 can exert its antidepressant effects.