In sharp contrast to the effect of non-contingent cocaine injections, voluntary cocaine self-administration induced LTP at VTA DA neurons that persisted for up to 3 months of abstinence (Chen et al., 2008). This did not reflect the pharmacological effects of cocaine, as repeated administration of non-contingent i.v. cocaine in a similar pattern and concentration resulted in only a short-lasting potentiation of AMPAR function. These results suggest that the voluntary intake of cocaine plays a critical role in the long-lasting potentiation of AMPAR function on VTA DA neurons that extends beyond the primary mechanism of drug action itself. We speculate that the requirement for voluntary intake may reflect the contribution of an active learning mechanism, so that persistent AMPAR potentiation only develops when the animal undergoes learning in relation to the voluntary intake of cocaine. Furthermore, LTP at VTA DA neurons 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
