Blockade of NMDA GluN2B receptors selectively impairs behavioral flexibility but not initial discrimination learning

Behavioral flexibility is the ability to adjust behavior when environmental contingencies change and is compromised in disease states such as schizophrenia, attention deficit hyperactivity disorder, and following damage to the prefrontal cortex. The present study investigated the contribution of N-methyl-d-aspartate GluN2B receptor subunits in the initial learning and in shifting between or within discrimination strategies (i.e., strategy set-shifting and reversal learning), using tasks conducted in operant chambers. Strategy set-shifting required rats initially to learn a visual-cue discrimination (day 1) and on day 2, shift to using an egocentric spatial response strategy to obtain reward. For reversal learning, rats were trained on a response discrimination on day 1 and then required to select the opposite lever on day 2. Blockade of GluN2B receptors with systemic administration of Ro25-6981 on day 1 did not impair initial acquisition of either a response or visual-cue discrimination nor did these treatments affect performance of strategy or reversal shifts on day 2. However, administration of Ro25-6981 prior to a set-shift or reversal on day 2 significantly impaired performance on both tasks, inducing a selective increase in perseverative errors, indicative of a disruption the ability to suppress a previously acquired prepotent response. These data suggest that systemic blockade of GluN2B receptors Ro25-6981 does not appear to interfere with the initial acquisition of simple visual or response discriminations. However, these receptors do appear to play a central and selective role in the modification of previously acquired strategies or stimulus-reward associations, facilitating behavioral inhibition so that novel patterns of behavior may emerge.