Examination of Cognitive Deficits Produced by Sub-Chronic Ketamine Exposure in Rats

Chronic NMDA receptor suppression by NMDA antagonists (ketamine), induce structural changes in neocortical and limbic brain regions, resulting in similar cognitive deficits to that observed clinically in schizophrenia. Objectives: This study was designed to evaluate cognitive deficits following ketamine administration in rodents, assessed through an attentional set-shifting paradigm. Thus, allowing evaluation of cognitive flexibility in the form of discrimination acquisition, reversal learning and intra/extra-dimensional shifts (ability to switch between dimensions). Methods: Forty four male Lister Hooded rats, underwent a five day daily sub-chronic treatment regime prior to habituation. The three treatment groups where; VEH, ketamine (10mg/kg, IP) and ketamine (30mg/kg, IP). Rats underwent habituation two days post treatment cessation, consisting of a simple odour and medium discrimination.24 Hours later, rats were assessed on a attentional set shifting task. Results: Sub-chronic ketamine treatment impaired reversal learning in a dose dependent manner. Animals treated with ketamine (30mg/kg), required significantly more trials to criterion for all three reversal trials (REV1-3). Ketamine (10mg/kg) treatment significantly impaired acquisition during REV2. Ketamine (30mg/kg) treated rats made significantly more errors during each reversal (REV1-3). A clear trend emerged between ketamine exposure and latency; rats treated with ketamine (30mg/kg) required longer to complete REV1 to EDS. Ketamine (30mg/kg) treatment resulted in a significant deficit in the acquisition of the odour and medium tasks, during habituation. Conclusion: These results show sub-chronic ketamine treatment impairs reversal learning. Our findings support the impairments observed clinically following CANTAB assessment in schizophrenic patients. Hence, our data suggests sub-chronic ketamine treatment results in similar cognitive deficits. Our results support the hypothesis that ketamine is an important pharmacological compound to model cognitive deficits in rats.