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      Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis

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          Abstract

          The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy.

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          Most cited references166

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          Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy.

          Drug self-administration studies have recently employed progressive ratio (PR) schedules to examine psychostimulant and opiate reinforcement. This review addresses the technical, statistical, and theoretical issues related to the use of the PR schedule in self-administration studies in rats. Session parameters adopted for use in our laboratory and the considerations relevant to them are described. The strengths and weaknesses of the PR schedule are also discussed.
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            Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist.

            Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.
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              The reinstatement model of drug relapse: history, methodology and major findings.

              The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.
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                Author and article information

                Journal
                J Med Chem
                J. Med. Chem
                jm
                jmcmar
                Journal of Medicinal Chemistry
                American Chemical Society
                0022-2623
                1520-4804
                31 March 2016
                31 March 2015
                23 July 2015
                : 58
                : 14
                : 5361-5380
                Affiliations
                []Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse—Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States
                []Department of Chemistry & Biochemistry, College of Science and Mathematics; Department of Biomedical & Translational Sciences, School of Biomedical Science & Health Professions, Rowan University , 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States
                [§ ]Department of Physiology and Pharmacology, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157-1083, United States
                Author notes
                [* ]Phone: (443)-740-2887. Fax: (443)-740-2111. E-mail: anewman@ 123456intra.nida.nih.gov .
                Article
                10.1021/jm501512b
                4516313
                25826710
                47b3910b-1c31-45ca-8e96-84d4dd5bd13c
                Copyright © 2015 American Chemical Society

                This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

                History
                : 01 October 2014
                Funding
                National Institutes of Health, United States
                Categories
                Perspective
                Custom metadata
                jm501512b
                jm-2014-01512b

                Pharmaceutical chemistry
                Pharmaceutical chemistry

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