Medium spiny neurons of the nucleus accumbens serve as the interface between corticolimbic regions that elicit and modulate motivated behaviors, including those related to drugs of abuse, and motor regions responsible for their execution. Medium spiny neurons are excited primarily by AMPA-type glutamate receptors, making AMPA receptor transmission in the accumbens a key regulatory point for addictive behaviors. In animal models of cocaine addiction, changes in the strength of AMPA receptor transmission onto accumbens medium spiny neurons have been shown to underlie cocaine-induced behavioral adaptations related to cocaine seeking. Here we review changes in AMPA receptor levels and subunit composition that occur after discontinuing different types of cocaine exposure, as well as changes elicited by cocaine reexposure following abstinence or extinction. Signaling pathways that regulate these cocaine-induced adaptations will also be considered, as they represent potential targets for addiction pharmacotherapies.