One study has attempted to directly link early changes induced by cocaine in the VTA (i.e. increased AMPAR/NMDAR ratios and appearance of inward rectification in AMPAR EPSCs) to later cocaine-evoked plasticity in the NAc (i.e. decreased AMPAR/NMDAR ratios followed by inward rectification after prolonged withdrawal) (Mameli et al., 2009). Consistent with a causal link, abolishing the drug-evoked synaptic plasticity only in the VTA by inducible deletion of the obligatory NMDAR subunit NR1 only in DA cells (see above) prevented drug-evoked synaptic changes in the NAc. Furthermore, manipulating the persistence of the cocaine-evoked plasticity in the VTA controlled synaptic plasticity in the NAc. These results are reminiscent of earlier findings suggesting that the induction of psychostimulant-induced behavioral sensitization requires the VTA but that its expression is independent of the VTA and requires modifications within the NAc (Wolf, 1998). They also support the idea that there is a hierarchical relationship between these forms of drug-evoked synaptic plasticity in the early phases of the spiral.
