Cue-elicited drug-craving correlates with hyperactivity within prefrontal cortex (PFC), which is theorized to result from dysregulated excitatory neurotransmission. The NMDA glutamate receptor is highly implicated in addiction-related neuroplasticity. As NMDA receptor function is regulated critically by its GluN2 subunits, herein, we assayed the relation between incubated cue-elicited cocaine-seeking following extended access to intravenous cocaine (6 h/d; 0.25 mg/infusion for 10 d) and the expression of GluN2A/B receptor subunits within PFC sub regions during early versus late withdrawal (respectively, 3 vs. 30 days). Cocaine-seeking rats exhibited elevated GluN2B expression within the dorsomedial aspect of the PFC (dmPFC); this effect was apparent at both 3 and 30 days withdrawal and occurred in cocaine-experienced rats, regardless of experiencing an extinction test or not. Thus, elevated dmPFC GluN2B expression appears to reflect a pharmacodynamic response to excessive cocaine intake that is independent of the duration of drug withdrawal or re-exposure to drug-taking context. The functional relevance of elevated dmPFC GluN2B expression for drug-seeking was assessed by the local infusion of the prototypical GluN2B-selective antagonist ifenprodil (1.0 µg/side). Ifenprodil did not alter cue-elicited responding in animals with a history of saline self-administration. In contrast, ifenprodil lowered cue-elicited cocaine-seeking, while potentiating cue-elicited sucrose-seeking. Thus, the effects of an intra-dmPFC ifenprodil infusion upon cue reactivity are reinforcer-specific, arguing in favor of targeting GluN2B-containing NMDA receptors as a pharmacological strategy for reducing behavioral reactivity to drug-associated cues with the potential benefit of heightening the reinforcing properties of cues associated with non-drug primary rewards.