Several results suggest that activation of VTA DA neurons alone is sufficient to elicit this form of drug-evoked synaptic plasticity when paired with spontaneous activity. Applying cocaine to isolated midbrain slices caused an increase in the AMPAR/NMDAR ratio in DA cells when measured several hours later (Argilli et al., 2008). In vivo, driving burst firing in DA cells using light activation of channelrhodopsin (ChR2) also caused a synaptic adaptations in DA cells when measured 24 hours later (Brown et al., 2010). The synaptic plasticity induced by both of these manipulations was prevented by pharmacological blockade of D1/D5 receptors in the VTA suggesting that an increase in DA within the VTA is a critical trigger (Schilstrom et al., 2006). Consistent with this conclusion is the finding that this plasticity is not elicited in mice expressing a mutated DAT that is insensitive to cocaine (Brown et al., 2010). An additional induction requirement for this drug-evoked synaptic plasticity is activation of NMDARs on the DA neurons. This conclusion is based on the observations that systemic administration of an NMDAR antagonist blocks the plasticity
