Nucleus accumbens core 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 due to the cues having motivational value, or incentive salience. The nucleus accumbens core (NAc) has been implicated in mediating the sign-tracking response. Additionally, acetylcholine (ACh) transmission throughout the striatum has been attributed to both incentive motivation and behavioral flexibility. Here, we demonstrate a role for NAc ACh receptors in the flexibility of sign-tracking. Sign-tracking animals were exposed to an omission contingency, in which vigorous sign-tracking was punished by reward omission. Animals rapidly adjusted their behavior, but they maintained sign-tracking in a less vigorous manner that did not cancel reward. Within this context of sign-tracking being persistent yet flexible in structure, blockade of NAc nicotinic receptors (nAChRs) led to a persistence in the initial sign-tracking response during omission followed by a period of change in the makeup of sign-tracking, whereas blockade of muscarinic receptors (mAChRs) oppositely enhanced the omission-related development of the new sign-tracking behaviors. Later, once omission learning had occurred, nAChR blockade uniquely led to reduced sign-tracking and elevated reward-directed behaviors instead. These results indicate that NAc ACh receptors have opposing roles in maintaining learned patterns of sign-tracking, with nAChRs having a special involvement in regulating the structure of the sign-tracking response.