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Behavioral flexibility or ‘set-shifting’ refers to the ability to modify ongoing behavior in response to changing goals or environmental contingencies. Impaired behavioral flexibility is associated with disorders such as schizophrenia and addiction. Hypofunction of N-methyl-D-aspartate (NMDA) receptors has been implicated in these impairments. Metabotropic glutamate 5 (mGlu5) receptors closely interact with NMDA receptors and may provide a feasible pharmacological target for indirect manipulation of NMDA receptor function in disease states. The aim of this study was to examine the impact of NMDA and mGlu5 receptors on set-shifting ability. We developed a computer-controlled, operant-based set-shifting task that requires rats to learn sequential discrimination rules based on two distinct perceptual dimensions. Using this task, we found that administration of the NMDA receptor antagonist MK801, both systemically and intracortically, significantly impaired task performance, whereas stimulation or inhibition of mGlu5 receptors did not impair task performance. However, when administered after MK801, potentiation of mGlu5 receptor function reduced the performance impairments observed with MK801 alone. These results suggest an interaction between NMDA and mGlu5 receptors in cognitive flexibility and may provide a novel therapeutic approach for treating disorders associated with aberrant NMDA function.