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) D3 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 D3 receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D3 receptor in the rodent and human brain; (2) changes in expression of the DA D3 receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D3 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 D2/D3 receptor antagonists or partial D3 receptor agonists. Growing evidence suggests that selective DA D3 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 D3 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.