Cognitive and behavioral effects of ketamine in chronic mild stress-exposed rats: Long-term versus short-term study
Safaa K. Aref, Mohamed Z. Habib, Dalia M. Eid, Magda I. Mohamad, A. Abdel-Tawab, Sawsan Aboul-Fotouh
The Quarterly journal of medicine August 1, 2026 DOI: 10.1093/qjmed/hcag168.110 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study in an animal model Peer reviewed |
|---|---|
| Population | Chronic mild stress-exposed male Wistar rats |
| Intervention | Ketamine |
| Dose | 10 mg/kg |
| Duration | Chronic treatment with short-term and long-term study phases (exact durations not stated) |
| Measures | Morris water maze (MWM) |
| Topics | Esketamine Ketamine |
| Key findings | Chronic ketamine (10 mg/kg) reduced depressive-like behavior and pro-inflammatory mediators and increased hippocampal Trk B/Akt/mTOR signaling in CMS-exposed rats at short and long term. However, it also increased stereotypic behavior suggesting psychosis at both time points and, in the long-term phase, reduced time in the target quadrant in the Morris water maze, indicating cognitive dysfunction. |
Abstract
Accumulating evidence indicates the role of ketamine as a fast-onset antidepressant, with a rising controversy over its cognitive effect. This study aimed at investigating the short- and long-term cognitive and behavioral effects of chronic administration of ketamine, with an emphasis on hippocampal expression of the Trk B/Akt/mTOR signaling pathway in chronic mild stress (CMS)-exposed rats. The effects of chronic ketamine treatment (10 mg/kg) were investigated on behavioral and cognitive deficits and the expression of the Trk B/Akt/mTOR pathway in the hippocampus of CMS-exposed male Wistar rats. CMS induced depressive-like behavior and cognitive dysfunction associated with increased pro-inflammatory mediators and reduced hippocampal expression of the Trk B/Akt/mTOR signaling pathway. Chronic ketamine treatment ameliorated CMS-induced depressive-like symptoms in both short term and long-term studies without affection of cognitive function except inducing significant reduction in time spent in target quadrant in MWM reflecting cognitive dysfunction with long term study only, reduced pro-inflammatory mediators. Additionally, Ketamine induced significantly increased stereotypic behavior denoting psychosis and enhanced the hippocampal expression of the Trk B/Akt/mTOR signaling pathway in both short and long term. This work highlights the potential cognitive deterioration and psychosis with long-term ketamine administration despite of its favorable effect on depressive-like symptoms and Trk B/Akt/mTOR signaling and enhancement of neuronal survival and synaptogenesis.