Nucleus accumbens acetylcholine receptors modulate the balance of flexible and inflexible cue-directed motivation

Sign-tracking is a conditioned response where animals interact with reward-predictive cues and can be used as a means to approximate a cue’s motivational value. The nucleus accumbens core (NAc) has been highly implicated in mediating the sign-tracking response. Additionally, acetylcholine (ACh) transmission throughout the striatum broadly has been attributed to both incentive motivation and behavioral flexibility. Here, we show that sign-tracking responses are indeed flexible in the face of a contingency change in the form of an omission schedule, and that this flexibility is mediated by NAc ACh. Using behavioral and pharmacological methods, we show that blockade of NAc nicotinic receptors (nAChRs) augmented sign-tracking persistence, while blockade of muscarinic receptors (mAChRs) enhanced response flexibility following introduction of the omission schedule. Further, we detail how mAChR or nAChR antagonism impacted the microstructure of sign-tracking responses. These results indicate that NAc ACh receptors have opposing roles in the regulation of sign-tracking response flexibility without altering the motivational value of the cue.