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Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders

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Therapeutic Applications of Dopamine D3 Receptor Function

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 60))

Abstract

Over three decades of evidence indicate that dopamine (DA) D3 receptors (D3R) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective D3R antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, D3R are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the D3R system. Third, the synthesis and characterization of highly potent and selective D3R antagonists/partial agonists have further strengthened the role of the D3R in SUD. Based on extensive preclinical and preliminary clinical evidence, the D3R shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective D3R antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective D3R antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.

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Acknowledgements

The authors acknowledge all our colleagues and collaborators who have worked with us over the years to investigate the D3R and its role in SUD. A.H.N. and Z.-X.X. acknowledge support from the National Institute on Drug Abuse-Intramural Research Program (ZIADA000424).

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Authors and Affiliations

  1. Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, MD, USA

    Amy Hauck Newman & Zheng-Xiong Xi

  2. Indivior Inc., Richmond, VA, USA

    Christian Heidbreder

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  1. Amy Hauck Newman
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  2. Zheng-Xiong Xi
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  3. Christian Heidbreder
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Correspondence to Amy Hauck Newman .

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Editors and Affiliations

  1. Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Isabelle Boileau

  2. Dept of Molecular&Translational Medicine, University of Brescia, Brescia, Italy

    Ginetta Collo

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Newman, A.H., Xi, ZX., Heidbreder, C. (2022). Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders. In: Boileau, I., Collo, G. (eds) Therapeutic Applications of Dopamine D3 Receptor Function. Current Topics in Behavioral Neurosciences, vol 60. Springer, Cham. https://doi.org/10.1007/7854_2022_347

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