Infralimbic NR2A-containing NMDA receptors are necessary for the reconsolidation of cocaine self-administration memory.

Addiction is characterized by high susceptibility to relapse, which can be triggered by drug-associated cues. Cue presentation results in retrieval of the original drug-cue memory that becomes labile and must be reconsolidated back into long-term storage. Repeated unpaired cue presentation, however, induces extinction. Thus, cue-reactivity can be reduced by either blocking reconsolidation or facilitating extinction. Previous research revealed that systemic blockade of NMDA receptors (NMDArs) can disrupt reconsolidation of drug-cue associations in a modified self-administration paradigm (Milton et al., 2008) or extinction in a standard self-administration paradigm (Hafenbreidel et al., 2014). To further characterize these processes, we examined the effects of post-extinction injections of an NMDAr antagonist on drug seeking following self-administration. Rats acquired cocaine self-administration (0.25 mg/inf, i.v., 90 min/day) followed by extinction. Extinction consisted of four 45-min extinction sessions in which rats were administered the NMDAr antagonist CPP (10 mg/kg, i.p.) immediately after each session. Extinction retention was then tested during a subsequent 90-min session. CPP treatment decreased lever pressing during subsequent extinction sessions, suggesting either disrupted reconsolidation or facilitated extinction consolidation. We next targeted the infralimbic medial prefrontal cortex (IL-mPFC), a structure implicated in extinction (Quirk & Mueller, 2008). Using the same procedure, CPP infusions (36 µg/ 0.3 µL) before or after four brief extinction sessions resulted in a similar reduction in lever pressing across subsequent days. To determine the NMDAr subtype involved, we infused either the NR2A-selective antagonist NVP (1 mg/ 0.3 mL) or the NR2B-selective antagonist Ro25 (2 mg/ 0.3 mL) after four 45-min extinction sessions. Similar to the effects of nonspecific NMDAr blockade, blocking NR2A- but not NR2B-containing NMDArs reduced lever pressing across subsequent days. Finally, to dissociate if blocking NR2A-containing NMDArs disrupts reconsolidation or facilitates extinction consolidation, NVP was infused into the IL-mPFC after four 10-min reactivation trials or in the absence of behavioral testing. Memory retention was then tested during a subsequent 90-min session, revealing that blocking NR2A-containing NMDArs after memory reactivation results in reduced lever pressing. Overall, these results indicate that blocking NR2A-containing NMDArs in the IL-mPFC disrupts reconsolidation following reactivation of the original drug-cue memory rather than facilitates extinction consolidation. Support by DA027870 and the University of Wisconsin-Milwaukee Research Growth Initiativ