Abstract
Despite decades of research, investigations into effective neural and pharmacological therapies for many drugs of abuse, such as cocaine, have produced no FDA-approved approaches. This difficulty derives from the complexity of substance use disorders, which encompass a variety of behavioral, psychological, and neural circuit-based changes that occur as a result of repeated experience with the drug. Dopamine signaling has been demonstrated to play a key role in several aspects of drug abuse-from mediating its reinforcing properties and drug-seeking to triggering relapse-while also mediating a number of important aspects of normal (nondrug related) motivated behaviors and actions. Real-time recording methods such as in vivo voltammetry, electrophysiology, and calcium imaging demonstrate that the signaling properties of dopamine for motivationally relevant stimuli are highly dynamic and spatiotemporally circumscribed within afferent target regions. In this review, we identify the origins and functional consequences of heterogeneous dopamine release in the limbic system, and how these properties are persistently altered in the drug-experienced brain. We propose that these spatiotemporally parallel dopaminergic signals are simultaneously available to the animal, but that these circuits are impaired following prolonged drug experience by disrupting the location and content of dopamine signals in afferent target regions. These findings are discussed in the context of relapse and pathways to discovering new treatments for addiction disorders.