The limbic corticostriatal circuitry has long been implicated in drug use disorders (Koob and Volkow, 2016). Recent work on inputs from the mPFC and insula to the NAc is illuminating the role of specific synapses and molecules mediating excessive ethanol drinking. These glutamatergic corticostriatal inputs drive the activity of MSNs, and the NMDAR is key for synaptic function and plasticity at these synapses (Lovinger, 2010). Ethanol drinking alters the NMDAR subtypes by insertion of the NR2C subunit at mPFC and insula synapses onto MSNs in the NAc core, but it leaves these receptors unchanged at glutamatergic inputs from amygdala (Seif et al., 2013). The mPFC and insula synapses appear to drive drinking in the face of aversive consequences, and the NR2C subunit is implicated in the loss of this control (Seif et al., 2013). In addition, projections from the ventral subiculum to the NAc shell are also important for ethanol seeking in the face of aversive consequences, as selective inhibition of this pathway by chemogenetic techniques decreased context-induced relapse (Marchant et al., 2016). These findings show how synapse-specific molecular changes
