Antidepressant-like effect of CP-101,606: Evidence of mTOR pathway activation.
Mol Cell Neurosci
; 124: 103821, 2023 03.
Article
en En
| MEDLINE
| ID: mdl-36775184
ABSTRACT
BACKGROUND:
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.METHODS:
To mimic depressive-like behavior, mice were subjected to chronic unpredictable mild stress (CUMS) for 21â¯days. Mice were treated with CP-101,606 at 10, 20, and 40â¯mg/kg doses for 7, 14, and 21â¯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.RESULTS:
CP-101,606 at 20 and 40â¯mg/kg doses for 7 and 14â¯days and fluoxetine 10â¯mg/kg and CP-101606 20â¯mg/kg for 21â¯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.CONCLUSIONS:
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.Palabras clave
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Banco de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas S6 Ribosómicas 70-kDa
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Depresión
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2023
Tipo del documento:
Article