This review considers the potential use of the
dopamine D(3) receptor (DRD3) as a novel therapeutic target for the treatment of
tobacco dependence. Among the 5
dopamine receptors identified, the DRD3 is located in the nucleus accumbens, ventral tegmental area and amygdala: 3 brain structures that are implicated in the motivational control of
drug-seeking behaviour and
drug-conditioning processes. Although it has been proposed that modulating
dopamine transmission would be effective in the treatment of
drug dependence, no validation has been provided in humans so far. Several highly selective DRD3
ligands have recently been evaluated in preclinical models of
drug dependence. These
ligands act as DRD3 antagonists in vivo and are able to decrease the motivation to take various drugs of abuse and reduce the influence of associated
drug-conditioned behaviour. Of note is that these effects have been found with
nicotine-seeking behaviour and
nicotine relapse in rodents, suggesting a potential use of these
ligands for the treatment of tobacco smokers. In contrast to
nicotine replacement therapy,
varenicline and
bupropion (which are currently used for the treatment of smokers), DRD3 antagonists do not seem to produce
nicotine-like effects in experimental animals and, therefore, may not substitute for
nicotine or alleviate
nicotine withdrawal symptoms in human smokers. This behavioural profile, which was also reported recently with
cannabinoid CB(1) receptor antagonists, may result from effects on specific brain pathways that express DRD3 receptors and are involved in relapse and conditioning processes. These preclinical studies suggest that the clinical evaluation of DRD3
ligands should be performed with clinical trials designed specifically to evaluate the relapse phenomena.