Stress and Ketamine, Bimodal Influence on Cognitive Functions

The glutamate N-methyl-D-aspartate receptor (NMDAR) non-selective antagonist, ketamine, has been recently repurposed as a rapidly acting antidepressant, catalyzing the vigorous investigation of glutamate-signaling modulators as novel therapeutic agents for depressive disorders. Beneficial effects of this drug in the quick-acting treatment of depression are recognized. The long-term effects of ketamine have not been known, including the cognitive sphere. It is well acknowledged that prolonged exposure to stress induces depression and cognitive impairment. It seemed reasonable to ask how the long-term ketamine administration would affect stressed animals in the aspect of cognitive functions. In the current study we tested whether it is possible for ketamine, used in prolonged-regimen in rats, to alleviate stress-evoked memory deficits? Stressed (restraint 2 h daily for 21 days) and non-stressed rats (6-weeks-old) were treated with ketamine for 21 days and next subjected to a battery of behavioral tests: for the assessment of working and reference spatial memory (Morris water maze (MWM) and Barnes maze (BM)), stereotypy (stereotypy test - ST), locomotor functions (Open field - OF) and anxiety behavior (Elevated plus maze - EPM). Ketamine administration resulted in a significant stereotype behaviour in rats tested in ST. Stressed rats displayed a significant decline in the spatial working and reference memory. The effect of chronic ketamine administration depended on the type of test and differed between control rats and animals simultaneously exposed to chronic stress. However, in the MWM the impact was quite unequivocal, as we observed an improvement in spatial memory in stressed animals and a deterioration in non-stressed animals after ketamine administration. In the BM, the effect of ketamine changed in successive attempts, from favorable in the initial period to negative at the end of the test in the group of stressed animals and without a significant impact on control animals. We found no significant effects of ketamine on locomotor performance and on the level of anxiety. Taken together, these findings demonstrate that ketamine potently abolishes or prevents some kinds of stress-induced memory impairments and cognitive decline in rats, although in some circumstances, it could even increase damage to memory, especially in unstressed animals. It seems that the prolonged use of ketamine in the prevention of stress-induced memory declines can fulfill its role.