The involvement of the serotonergic system in ketamine and fluoxetine combination-induced cognitive impairments in mice

Abstract

Abstract Glutamatergic N-methyl-D-aspartate (NMDA) receptors have vital roles in memory formation. Changes in the activity of these receptors can influence memory processes. Ketamine is a non-competitive NMDA receptor antagonist drug with promising mood-altering and pain-reducing effects in low doses. The present study investigated the effects of low-dose ketamine administrations on memory acquisition, consolidation, and retrieval processes. Sixty-four male BALB/c mice used in this experiment were treated with a selective serotonin reuptake inhibitor, fluoxetine, and a serotonin depletion agent, p-chlorophenylalanine (pCPA). A serotonin antagonist, methiothepin, and ketamine were administered 60 mins before or after the behavioral tests. A passive avoidance test measured emotional memory acquisition, consolidation, and retrieval processes. Hippocampi malondialdehyde (MDA) levels were analyzed, and histopathological examinations were performed. Ketamine alone did not significantly affect memory encoding processes, while the ketamine-fluoxetine combination disrupted memory consolidation. Antiserotonergic drugs, pCPA, and methiothepin augmented memory only in the consolidation trial. The memory acquisition process was also affected by fluoxetine. Ketamine application insignificantly increased MDA levels. In all ketamine-applied groups, histopathologic alterations were evident. Ketamine, even in low doses, combined with fluoxetine, can potentially disrupt memory-encoding processes and cause neurotoxicity through increased serotonergic activity.