Genetic ablation of the isoform γ of PI3K decreases antidepressant efficacy of ketamine in male mice.
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
IBRO neuroscience reports December 1, 2024 DOI: 10.1016/j.ibneur.2024.06.002 via PubMed
Summary
AI-generated from the abstractMice lacking the PI3Kγ gene did not respond to standard doses of ketamine or to classic antidepressants such as imipramine and fluoxetine, as measured by the forced swimming test. This unresponsiveness required a chronic deficiency of the PI3Kγ-mediated pathway, not just acute inhibition. The findings suggest PI3Kγ plays a role in antidepressant activity and may be involved in treatment resistance observed in some patients with major depressive disorder.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | PI3Kγ knock-out mice |
| Interventions | Ketamine imipramine fluoxetine |
| Dose | classical doses |
| Topics | Depression Ketamine |
| Keywords | Coping behavior Pi3kγ Antidepressants antidepressant medication Depression medication |
| Key finding | PI3Kγ knock-out mice were unresponsive to both rapid and sustained antidepressant-like effects of ketamine and to imipramine and fluoxetine, indicating PI3Kγ is necessary for the effects of these drugs. |
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.