Ketamine is an anesthetic drug used for decades in medical settings. In recent years, it has also been investigated and found successful in treating several conditions, including depression (Iqbal and Mattew 2020), anxiety (Ballard et al. 2014), and chronic pain (Yang et al. 2020). It is also reported to reduce opioid tolerance, the opioid requirement (Boenigk et al. 2019). While it is not as widely used as classic treatment options for the mentioned diseases, it holds tremendous therapeutic potential with its unique mechanism of action. Apart from ketamine’s favorable effects, it has various severe toxic effects on memory processes and brain functionality and morphology, including cognitive impairments (Scallet et al. 2004), psychomimetic effects (Pollak et al. 2015), and abuse potential (Bokor et al. 2014), which limits its widespread use. Thus, revealing ketamine’s neurotoxic potential and underlying mechanisms in its therapeutic and toxic effects is essential.
No clear evidence supports memory disturbances with a single and low-dose ketamine application. While high doses and extended applications of ketamine cause neurotoxicity (Newcomer et al. 1999, Zou et al. 2009), low doses increase the development of dendritic spines in the neurons and reduce neurodegeneration (Treccani et al. 2019). This experiment utilized a passive avoidance test to evaluate emotional memory processes (i.e., acquisition, consolidation, and retrieval). In the PA test, ketamine did not impair mentioned memory processes above when applied alone. Interestingly its combination with fluoxetine impaired both memory acquisition and consolidation. Fluoxetine alone also disrupted memory acquisition but not consolidation. Antiserotonergic drugs, PCPA, and methiothepin improved consolidation, which can be related to their hyperalgesic effects (Chia et al. 2016, Taber and Latranyi 1981).
Some studies reported improved memory functions using fluoxetine (El Hage et al. 2004, Lyons et al. 2011), while others reported impairments or no favorable effects (Carlini et al. 2012; Bangs et al. 1994). Various serotonin-enhancing drugs have memory-impairing effects (Gray and Hughes 2015), while some antiserotonergic drugs were reported to reduce memory disruptions (Farr et al. 2000). In the present study, it was observed that drugs that reduce serotonin transmission, methiothepin, and pCPA, augmented emotional memory consolidation. At the same time, they were not beneficial in the acquisition and retrieval process. Fluoxetine alone disrupted the memory acquisition process but not consolidation and retrieval. Its combination with ketamine impaired memory acquisition and consolidation processes.
Increased oxidative stress is known to cause cell injury. Ketamine increases oxidative stress, which is believed to contribute to its neurotoxic effects (de Oliveira et al. 2009). In this study, hippocampal MDA levels increased insignificantly in the ketamine-applied group, and it was concluded that the applied ketamine dose did not affect oxidation levels.
Ketamine administrations induce various morphologic alterations in the brain (Vranken et al. 2006, Ozyurt et al. 2021, Gomes et al. 2011, Yadav et al. 2018). Our histopathologic examinations revealed no significant morphological changes in the vehicle, methiothepin, fluoxetine, and pCPA-applied groups. On the other hand, ketamine-applied groups, including the ketamine-fluoxetine combination, had significant histopathologic changes, including perineural and perivascular edema, satellitozis, and necrosis in a wide range of brain regions. These results indicate that ketamine caused neurodegeneration that could not be prevented by antiserotonergic molecules used in this study.
Ketamine not only disrupts memory functions and impairs memory but also protects it (Yan and Jiang 2014). The determining factors and underlying mechanisms of how ketamine affects cognition are not yet precise. Apart from the serotonergic system, the involvement of non-NMDA glutamatergic receptors and other mechanisms should be unveiled.