Extinction of Cocaine Self-Administration Reveals Functionally and Temporally Distinct Dopaminergic Signals in the Nucleus Accumbens

While Pavlovian and operant conditioning influence drug-seeking behavior, the role of rapid dopamine signaling in modulating these processes is unknown. During self-administration of cocaine, two dopaminergic signals, measured with 100 ms resolution, occurred immediately before and after the lever press (termed pre- and postresponse dopamine transients). Extinction of self-administration revealed that these two signals were functionally distinct. Preresponse transients, which could reflect the motivation to obtain the drug, did not decline during extinction. Remarkably, postresponse dopamine transients attenuated as extinction progressed, suggesting that they encode the learned association between environmental cues and cocaine. A third type of dopamine transient, not time locked to overt stimuli, decreased in frequency during extinction and correlated with calculated cocaine concentrations. These results show that dopamine release transients involved in different aspects of cocaine self-administration are highly plastic—differentially governed by motivation, learned associations linked with environmental stimuli, and the pharmacological actions of cocaine.