GluA2‐lacking AMPA receptors in the nucleus accumbens core and shell contribute to the incubation of oxycodone craving in male rats

Abstract One of the most challenging issues in the treatment of substance use disorder, including misuse of opioids such as oxycodone, is persistent vulnerability to relapse, often triggered by cues or contexts previously associated with drug use. In rats, cue‐induced craving progressively intensifies (‘incubates’) during withdrawal from extended‐access self‐administration of several classes of misused drugs, including the psychostimulants cocaine and methamphetamine. For these psychostimulants, incubation is associated with strengthening of excitatory synapses in the nucleus accumbens (NAc) through incorporation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors that lack the GluA2 subunit and are therefore Ca 2+ ‐permeable (CP‐AMPARs). Once CP‐AMPAR upregulation occurs, their stimulation is required for expression of incubation. It is not known if a similar mechanism contributes to incubation of oxycodone craving. Using male rats, we established that incubation occurs by withdrawal day (WD) 15 and persists through WD30. Then, using cell‐surface biotinylation, we found that surface levels of the AMPAR subunit GluA1 but not GluA2 are elevated in NAc core and shell of oxycodone rats on WD15, although this wanes by WD30. Next, using intra‐NAc injection of the selective CP‐AMPAR antagonist Naspm before a seeking test, we demonstrate that CP‐AMPAR blockade in either subregion decreases oxycodone seeking on WD15 or WD30 (after incubation), but not WD1, and has no effect in saline self‐administering animals. The Naspm results suggest CP‐AMPARs persist in synapses through WD30 even if total cell surface levels wane. These results suggest that a common neurobiological mechanism contributes to expression of incubation of craving for oxycodone and psychostimulants.