Rationale in support of the use of selective dopamine D₃ receptor antagonists for the pharmacotherapeutic management of substance use disorders

Abstract

Growing evidence indicates that dopamine (DA) D₃ receptors are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders. First, DA D₃ receptors are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse has been shown to produce neuroadaptations in the DA D₃ system. Third, the synthesis and characterization of highly potent and selective DA D₃ receptor antagonists has permitted to further define the role of the DA D₃ receptor in drug addiction. Provided that the available preclinical and preliminary clinical evidence can be translated into clinical proof of concept in human, selective DA D₃ receptor antagonists show promise for the treatment of substance use disorders as reflected by their potential to (1) regulate the motivation to self-administered drugs under schedules of reinforcement that require an increase in work demand and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in the reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, re-exposure to environmental cues that had been previously associated with drug-taking behavior, or stress.