Decreases in Cued Reward Seeking After Reward-Paired Inhibition of Mesolimbic Dopamine.

Reward-paired optogenetic manipulation of dopamine neurons can increase or decrease behavioral responding to antecedent cues when subjects have the opportunity for new learning, in accordance with a dopamine-mediated error learning signal. Here we examined the impact of reward-paired dopamine neuron inhibition on behavioral responding to reward-predictive cues after subjects had learned. We trained male TH-IRES-Cre mice to lever press for food reward in a progressive ratio procedure, a 2-cue choice procedure, or when continuously reinforced; in all procedures, completion of the response requirement was signaled by an auditory cue presented prior to food delivery. After training, mice underwent successive sessions in which optogenetic inhibition of dopamine neurons was triggered during food receipt. Rather than mimic brief inhibitions associated with negative reward prediction errors, we applied inhibition throughout the ingestion period on each trial. We found in all procedures that optogenetic inhibition of dopamine neurons during reward receipt decreased behavioral responding to the preceding reward-predictive cue over days, a behavioral change observed during time periods without optogenetic neuronal inhibition. Extinction-like behavioral responding was selective for learned associations: it was observed in the 2-cue choice procedure in which each subject was trained on two associations and inhibition was paired with reward for only one of the associations. Thus, inhibition during reward receipt can decrease responding to reward-predictive cues, sharing some features of behavioral extinction. These findings suggest changes in mesolimbic dopaminergic transmission at the time of experienced reward impacts subsequent responding to cues in well-trained subjects as predicted for a learning signal.