Cocaine preference and neuroadaptations are maintained by astrocytic NMDA receptors in the nucleus accumbens

Cocaine-associated memories induce cravings and interfere with the ability of users to cease cocaine use. Reducing the strength of cue-drug memories by facilitating extinction may have therapeutic value for the treatment of cocaine addiction. Here, we demonstrate the expression of GluN1/2A/2C NMDA receptor currents in astrocytes in the nucleus accumbens core. Selective ablation of GluN1 subunit from astrocytes in the nucleus accumbens enhanced extinction of cocaine preference memory but did not affect cocaine conditioning or reinstatement. Repeated cocaine exposure up-regulated GluN2C subunit expression and increased astrocytic NMDA receptor currents. Furthermore, intra-accumbal inhibition of GluN2C/2D-containing receptors and GluN2C subunit deletion facilitated extinction of cocaine memory. Cocaine-induced neuroadaptations including dendritic spine maturation and AMPA receptor recruitment were absent in GluN2C knockout mice. Impaired retention of cocaine preference memory in GluN2C knockout mice was restored by exogenous administration of recombinant glypican 4. Together, these results identify a previously unknown astrocytic GluN2C-containing NMDA receptor mechanism underlying maintenance of cocaine preference memory.