induced by voluntary cocaine self-administration remained potentiated even after drug-seeking behavior was extinguished, and AMPAR function was not further enhanced following cue-induced reinstatement (Chen et al., 2008). Together these data suggest that glutamate function at VTA DA neurons is maximally potentiated following cocaine self-administration; more importantly, this potentiation is unchanged even after cocaine-seeking behavior is extinguished. The intractability of cocaine-induced potentiation at DA neurons is in sharp contrast to plasticity induced by natural-reward learning. For example, extinction of behaviors associated with natural-reward learning also reverses the synaptic potentiation induced during the initial acquisition of these tasks (Pan et al. 2008). This suggests that glutamate synapses onto VTA DA neurons are capable of expressing bi-directional plasticity to support both learning and unlearning. Thus, the persistent potentiation at VTA DA neuron synapses following cocaine self-administration may be instrumental in the maintenance of a drug memory despite years of abstinence that may facilitate the reinstatement of drug-seeking behaviors (Nestler, 2001).
