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Prog Brain Res. 2014;211:255-75. doi: 10.1016/B978-0-444-63425-2.00011-8.

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

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  • 1Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Family and Community Medicine, Pharmacology and Toxicology, Psychiatry, Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Electronic address: bernard.lefoll@camh.ca.
  • 2Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
  • 3Imanova, Centre for Imaging Sciences, London, UK; Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College, London, UK.
  • 4Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada.
  • 5F. Hoffmann-La Roche, Basel, Switzerland.
  • 6Pierre Fabre Research Institute, Castres, France.

Abstract

The dopamine D3 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 D3 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 D3 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 D3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D3 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 D3 and D2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D3 ligands to treat drug addiction.

© 2014 Elsevier B.V. All rights reserved.

KEYWORDS:

D(2); D(3); PET imaging; animal model; dopamine; human clinical trial; motivation; occupancy; reinstatement

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