Some rats (sign-trackers; STs) are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact Pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to their counterparts, the goal-trackers (GTs), mediated by attenuated cholinergic activity. Poor cholinergic-attentional control contributes to the propensity of STs to approach and utilize Pavlovian drug cues. In STs, increases in neuronal activity fail to translocate choline transporters (CHTs) into synaptosomal plasma membrane, thereby limiting the capacity of cholinergic terminals to sustain cholinergic activity. Here we investigated post-translational modifications responsible for disrupted CHT trafficking in STs, and the hypothesis that attenuated cholinergic activity in STs causes exaggerated (neuro)immune responses. We determined levels of ubiquitinylated CHTs because ubiquitin-mediated processes can account for attenuated externalization of intracellular CHTs, ranging from proteolysis to enhanced internalization or alternative compartmentalization. The proportion of ubiquitinylated CHTs, extracted from cortex and striatum, was robustly higher in STs than in GTs, with no overlap in the data from the two phenotypes. Moreover, modified CHTs located in intracellular domains, but not in synaptosomal plasma membrane, completely accounted for the phenotype-specific ubiquitylation levels. Ongoing experiments suggest elevated spleen levels of pro-inflammatory cytokines in unchallenged STs. Following a systemic lipopolysaccharide (LPS) immune challenge, brain levels of certain cytokines were not elevated based on phenotype. Moreover, following LPS challenge, ubiquitinylation levels of CHTs from the cortex and striatum were drastically increased in GTs, but not STs, suggesting that in unchallenged STs, ubiquitinylated CHTs already are at maximum levels and unresponsive to an additional immune challenge. Together, this evidence supports potentially escalating, bidirectional interactions between disrupted cholinergic signaling and (neuro)immune responses as an integral component of the cognitive-motivational trait indexed by sign-tracking.