The use of reward-predictive cues to guide behavior critically involves the nucleus accumbens. However, little is known regarding the role of ionotropic glutamate receptors in the core subregion of the nucleus accumbens (AcbC) in instrumental learning guided by reward-predictive cues. Here we examined the effects of an intra-AcbC blockade of NMDA and AMPA/KA receptors on the acquisition of an instrumental response in a reaction time (RT) task in rats. In this task, discriminative cues signaled in advance the upcoming reward magnitude (5 or 1 food pellet) associated with a lever release. During early acquisition (days 1-6) rats received daily bilateral injections of either the NMDA receptor antagonist AP5 (5.0 microg per side, n = 14), the AMPA/KA receptor antagonist CNQX (2.5 microg per side, n = 14) or vehicle (0.5 microL per side, n = 19). No treatment was given during late acquisition (days 7-12). The main result was that rats which received intra-AcbC injections of AP5 or CNQX during early acquisition exhibited a general RT increase of responses to high and low reward. However, treatment with AP5 and CNQX did not interfere with discriminative guidance of RTs by cue-associated reward magnitudes, i.e. during acquisition RTs of responses to expected high reward became significantly faster than RTs of responses to expected low reward. Our findings suggest that NMDA and AMPA/KA receptors in the AcbC play a critical role in invigorating responding during instrumental learning, but seem less important in guiding responding according to reward-predictive cues.