Another study presented strong evidence that synaptic adaptations within the NAc are important for cue-induced reinstatement of drug self-administration. Withdrawal after prolonged cocaine-self administration is associated with a so-called incubation of craving (Grimm et al., 2001). Specifically, as time passes during the withdrawal period, the presentation of a cue previously associated with the availability of drug leads to increasing efforts (i.e. number of lever presses) to obtain the drug. Over approximately this same time period, the initial depression of excitatory transmission in the NAc reverses into a potentiation and the appearance of calcium permeable AMPARs (see above). The behavioral importance of this change in the stoichiometry of AMPAs was directly tested by infusing into the NAc a compound that blocks GluA2-lacking AMPARs (Conrad et al., 2008). This manipulation prevented the enhanced cue-elicited drug seeking that normally occurs 6–7 weeks after withdrawal from cocaine self-administration. Importantly, infusing this compound into the NAc had no effect on cue-elicited drug seeking the first day of withdrawal nor on sucrose self-administration. Because GluA2-lacking AMPARs have a higher conductance than GluA2-containing AMPARs and this withdrawal
