Dopamine D3 receptor ligands for drug addiction treatment: update on recent findings

The dopamine D-3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D-3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013. Novel neurobiological findings indicate that drugs of abuse can lead to significant structural plasticity in rodent brain and that this is dependent on the availability of functional dopamine D-3 autoreceptor, whose activation increased phosphorylation in the ERK pathway and in the Akt/mTORC1 pathway indicating the parallel engagement of a series of intracellular signaling pathways all involved in cell growth and survival. Preclinical findings using animal models of drug-seeking behaviors confirm that D-3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D-3 is now feasible in human subjects. Notably, the development of (+)-4-propyl-9-hydroxynaphthoxazine ligand used in positron emission tomography (PET) studies in humans allows to measure D-3 and D-2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D-3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D-3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D-3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D-3 ligands to treat drug addiction.