Cognitive and psychotic effects of ketamine “short- vs. long-term” therapy in a rat model of depression: Hippocampal TrkB/Akt/GSK-3β/mTOR/autophagy trajectories

Accumulating evidence indicates the role of ketamine as a rapid-onset antidepressant, with a rising controversy regarding its cognitive and psychotic effects, especially with long-term use. However, no previous experimental study has directly compared short-term and long-term ketamine effects using a time schedule that simulates infusion protocols in major depressive disorder patients. This study investigated the short- versus long-term antidepressant, cognitive, and psychotic effects of ketamine (10 mg/kg), with an emphasis on hippocampal mechanistic cascades in a chronic unpredictable stress (CUS) rat model of depression. Both short- and long-term ketamine administration improved CUS-induced depressive-like behaviors and HPA axis activity markers. Short-term ketamine did not elicit significant cognitive changes, whereas in the long-term study, ketamine impaired rats' performance in the novel object recognition test, suggesting a potential exacerbation of the CUS-induced cognitive deficits. However, in the Morris water maze's probe trial, CUS-exposed animals exhibited a trend of cognitive improvement, which was dampened by chronic administration of ketamine. Furthermore, ketamine significantly increased stereotypic behaviors, an important phenotype of psychotic behavior. Interestingly, ketamine enhanced hippocampal expression of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-3β (p-GSK-3β), phosphorylated mechanistic target of rapamycin (p-mTOR), deactivated Unc-51-like autophagy activating kinase 1 (ULK1), and synapsin I, while decreasing phosphorylated eukaryotic elongation factor 2 (p-eEF2), autophagy markers (Beclin-1 and LC3), caspase-3, p-tau, and oxidative/nitrosative stress markers, reflecting the amendment of the CUS-induced disturbed synaptogenesis, autophagy, and tauopathy. This is the first study to highlight the potential cognitive impairments and psychotic behaviors associated with long-term ketamine administration despite its favorable effect on depressive-like symptoms and the implication of the BDNF/TrkB/Akt/GSK-3β/mTOR/autophagy mechanistic cascade in ketamine-induced enhancement of neuronal survival and synaptogenesis.