Genetic Ablation of the Isoform γ of PI3K Decreases Antidepressant Efficacy of Ketamine in Male Mice

Authors

Gabriela N Vaz
Flávia C Turcato
Isabel A V Lima
Franciele F Scarante
Melissa R Araújo
Tamires A V Brigante
Livia C M Rodrigues
Francisco S Guimarães
Jaime E C Hallak
Jose A Crippa
Antonio L Teixeira
Antonio C P de Oliveira
Alline Cristina Campos

Publication Date

12-1-2024

Journal

IBRO Neuroscience Reports

Abstract

About one-third of major depressive disorder (MDD) patients demonstrate unresponsiveness to classic antidepressants, and even the clinical efficacy of fast-acting drugs such as ketamine varies significantly among patients with treatment-resistant depression. Nevertheless, the lack of suitable animal models that mimic a possible ketamine-resistant phenotype challenges the understanding of resistance to drug treatment. In this study, we showed that PI3Kγ knock-out (KO) mice do not respond to classical doses of ketamine and classical antidepressants. PI3Kγ KO mice were unresponsive to both the rapid and sustained antidepressant-like effects of a single dose of ketamine in the forced swimming test. Additionally, they were unresponsive to the antidepressant-like effects induced by the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluoxetine. However, acute pharmacological inhibition of PI3Kγ did not block the antidepressant-like effect of ketamine, showing that a chronic deficiency of the PI3Kγ-mediated pathway is necessary for the effects of classic doses of ketamine and antidepressants. Therefore, we propose that PI3Kγ participates in the antidepressant activity and is likely implicated in the neurobiology and phenotype observed in patients with MDD who demonstrate treatment resistance.

Keywords

PI3Kγ, Major depressive disorder, Ketamine, Antidepressants, Coping behavior

Comments

Associated Data

PMID: 39026898