Selective Antagonism at Dopamine D3 Receptors as a Target for Drug Addiction Pharmacotherapy: A Review of Preclinical Evidence

The focal distribution of the dopamine (DA) D-3 receptor in brain regions implicated in emotional and cognitive functions has made this target a main focus of drug discovery efforts. This paper will review the most recent lines of research in support of the use of selective DA D-3 receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D-3 receptor in the rodent and human brain; (2) changes in expression of the DA D-3 receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D-3 receptor antagonists in preclinical paradigms assessing the behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine, and heroin. This manuscript, however, will not review the effects of nonselective DA D-2/D-3 receptor antagonists or partial D-3 receptor agonists. Growing evidence suggests that selective DA D-3 receptor antagonists do not affect the primary reinforcing effects of drugs of abuse, but rather seem to regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. In addition, selective antagonism at DA D-3 receptors appears to disrupt significantly the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior. These preclinical findings will be discussed in the context of translational research relevant to the design of early clinical trials and hypothesis testing in humans.