Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by persistent drug seeking and impaired behavioral control. Dopaminergic signaling has long been recognized as a central regulator of reinforcement learning, motivation, and habit formation. Addictive substances profoundly alter dopamine transmission through multiple mechanisms. These drug-induced changes contribute to the initiation, escalation, and persistence of addictive behaviors. In addition to dopamine, the cholinergic system has emerged as an important modulator of striatal circuit function. Acetylcholine and its receptors interact extensively with dopaminergic pathways, shaping striatal signaling dynamics and influencing learning and action selection, with particularly strong relevance for nicotine dependence. In this review, we discuss how striatal dopamine and acetylcholine contribute to learning, habit formation, and addiction-related behaviors, as well as how these systems interact at the circuit level. By integrating these findings, we propose a framework for understanding how dopamine–acetylcholine interactions may influence behavioral regulation relevant to substance use disorders.

Background/Objectives: Dopamine is well known for its role in reward learning, where phasic activity encodes prediction errors and supports the formation of cue–outcome associations. More recently, dopamine has been implicated in encoding salience, novelty, and aversive events, suggesting a broader function in shaping learning and memory across motivational contexts. However, how accumbal dopamine contributes to the recovery of extinguished fear, a process central to relapse in anxiety and trauma-related disorders, remains unclear. Methods: Here, we examined NAc core dopamine dynamics during shock-induced reinstatement of an extinguished fear memory. Using dLight fiber photometry, we found that a sustained decrease in baseline dopamine marked extinction recall. In contrast, an unexpected reminder footshock prevented this reduction, maintaining dopamine levels near baseline as freezing behavior re-emerged. Results: The reminder shock also evoked a transient dopamine peak, and optogenetic manipulations demonstrated that dopamine signaling during this period bidirectionally modulated reinstatement, with enhancement of dopamine release increasing reinstatement and inhibition of dopamine terminals markedly attenuating it. Together, these results demonstrate that unexpected aversive events reset NAc core dopamine levels and gate the return of extinguished fear. Conclusions: By revealing that accumbal dopamine contributes to fear recovery, this work broadens current models of dopamine function and identifies a neural mechanism through which surprising events may promote relapse of aversive memories in anxiety- and stress-related disorders.