Treatment with non-competitive
N-methyl-D-aspartate (
NMDA) antagonists such as
phencyclidine or
ketamine have been shown to induce
schizophrenia-like psychotic and
cognitive symptoms in humans and animals. However, there have been a number of contradictory findings regarding the effects of repeated treatment with these drugs on working memory in experimental animals. We hypothesized that processes dependent on
dopamine transmission in the medial prefrontal cortex (PFC) may be more sensitive to disruption following these treatment. We assessed the effects of repeated treatment with
ketamine on working memory performance using a delayed spatial win-shift procedure conducted on a radial-arm maze, dependent on a neural circuit linking hippocampal and
dopamine inputs to the medial PFC. Rats were trained on the task prior to drug exposure, after which they were subjected to one of two dosing regimes of
ketamine (30 mg/kg twice a day for either 5 or 10 days). After
a 10 day withdrawal period, they were re-tested on the task for 15 days.
Ketamine treatment for 10 days, but not 5 days, increased the number of errors and days to re-achieve the criterion on the delayed task. However, in a separate group of rats, subchronic
ketamine treatment (10 days) did not affect performance of the non-delayed random foraging task, dependent on the hippocampus, but not the PFC. These results indicate that working memory performance assessed with these procedures is sensitive to disruption following repeated exposure to
ketamine. Impairments in working memory induced by these treatments are not attributable to dysfunction of motivational, motor, short-term or spatial memory processes. The use of these procedures may prove useful in modeling impairments in this executive function observed in
schizophrenia.