Investigation of acute effects of ketamine administration on cognitive functions

Aim: Current antidepressant therapies to treat Major Depressive Disorder are being insufficient for a significant part of the patients and with a delayed onset of action. This lack of success and suspended effect are causing a vital problem especially in treatment-resistant and suicidal MDD patients. Finding new and fast-acting strategies in depression treatment is, therefore, essential. In numerous preclinical and clinical studies, it is reported that a single low-dose ketamine administration produces robust and prolonged antidepressant-like effects. Current literature implies that various mechanisms may contribute antidepressant effects of ketamine including an increment in serotonergic transmission and increased activity of non-NMDA ionotropic AMPA receptors. In the present study, we aimed to investigate the involvement of serotonergic system and AMPA receptors in antidepressant-like effects of low-dose ketamine and its effects on emotional memory processes. Material and Method: In this outcome, we either blocked the serotonin receptors with methiothepin or depleted serotonin with p-chlorophenyl alanine, and AMPA receptors were blocked with GYKI-52466. Fluoxetine was used as the antidepressant control, and effects of its combination with ketamine were evaluated. We used a forced swimming test to measure depression, an open field test to measure locomotion and an elevated plus maze test to measure anxiety. A passive avoidance test was used to assess effects on emotional learning and memory processes (i.e., acquisition, consolidation, and retrieval). Brain prefrontal cortex and hippocampi tissues were isolated to measure malondialdehyde (MDA) levels as an Ek-5 xviii indicator of lipid peroxidation. Caspase-3 expressions in PFK slices and histopathological assessment of a wide range of brain areas were practiced. Results: Our data demonstrated that single-dose ketamine produces robust antidepressant-like effects and even one week after drug injection it was still effective, yet insignificantly. Furthermore, ketamine failed to produce antidepressant-like effects if serotonin was depleted or its receptors were blocked. Ketamine with an AMPA receptor antagonist also made a similar failure in reducing depression symptoms. Ketamine did not cause a defect in emotional memory when used alone, yet it reduced memory acquisition and consolidation when combined with fluoxetine. Moreover, antiserotonergic drugs as pCPA and methiothepin were improved memory consolidation process. No significant difference was observed in malondialdehyde levels in brain PFK and hippocampi tissues with the drugs applied during the test procedure. Similarly, PFK caspase-3 expression level analyze has shown no significant difference between test groups. Yet, histopathological assessment has shown a variety of neurodegenerative symptoms including; perineural edema in pyramidal neurons, loss of cerebellar Purkinje cells, necrosis in hippocampal neurons and thrombosis in the subpial vascular area. Furthermore, proliferation in oligodendria cells was observed. Conclusion: Repetitive administrations of subanesthetic-dose ketamine did cause neurodegenerative symptoms. Still, the dosage we used was unable to affect emotional memory processes in behavioral tests. A single low-dose ketamine administration produced rapid antidepressant-like effects, and it is understood that the activity of serotonergic system and AMPA receptors are necessary for ketamine to exhibit this effect. Prescribing ketamine a role in depression treatment may be possible with extensive research; to enlighten its mechanism of action, to reduce its side-effects and to prevent its abusive use. In the light of the latest research, an increment in indications of ketamine doesn't seem a distant possibility.