Given that the VTA has been implicated in both behavioral sensitization and CPP, several studies have attempted to link these drug-induced behavioral changes with drug-evoked plasticity of excitatory transmission in the VTA. Initial findings indeed seemed to confirm the link; pharmacological inhibition of NMDARs in the VTA blocks both the drug-evoked synaptic plasticity and behavioral sensitization (Dunn et al., 2005; Kalivas and Alesdatter, 1993; Vezina and Queen, 2000) as well as CPP (Harris and Aston-Jones, 2003; Harris et al., 2004). Furthermore, the expression via viral vectors of the AMPAR subunit GluA1 in the VTA led to behavioral sensitization in animals that had never been exposed to cocaine (Carlezon and Nestler, 2002). Surprisingly, however, behavioral sensitization to cocaine could still be elicited in GluA1−/− mice even though the drug evoked increase in the AMPAR/NMDAR ratio was abolished (Dong et al., 2004). The GluA1−/− mice did exhibit impaired CPP, which suggested that the drug-evoked plasticity of excitatory synaptic transmission in VTA DA neurons, although not required for behavioral sensitization per se, may contribute to the attribution of incentive value to drug-associated cues.
