Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticlePerspectives in Pharmacology

Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates

Kyle C. Schmitt, Richard B. Rothman and Maarten E. A. Reith
Journal of Pharmacology and Experimental Therapeutics July 2013, 346 (1) 2-10; DOI: https://doi.org/10.1124/jpet.111.191056
Kyle C. Schmitt
Department of Neurosurgery (K.C.S.) and Departments of Pharmacology and Psychiatry (M.E.A.R.), New York University School of Medicine, New York, New York; and Medicinal Chemistry Section of the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (R.B.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard B. Rothman
Department of Neurosurgery (K.C.S.) and Departments of Pharmacology and Psychiatry (M.E.A.R.), New York University School of Medicine, New York, New York; and Medicinal Chemistry Section of the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (R.B.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maarten E. A. Reith
Department of Neurosurgery (K.C.S.) and Departments of Pharmacology and Psychiatry (M.E.A.R.), New York University School of Medicine, New York, New York; and Medicinal Chemistry Section of the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (R.B.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

The dopamine transporter (DAT) is a sodium-coupled symporter protein responsible for modulating the concentration of extraneuronal dopamine in the brain. The DAT is a principle target of various psychostimulant, nootropic, and antidepressant drugs, as well as certain drugs used recreationally, including the notoriously addictive stimulant cocaine. DAT ligands have traditionally been divided into two categories: cocaine-like inhibitors and amphetamine-like substrates. Whereas inhibitors block monoamine uptake by the DAT but are not translocated across the membrane, substrates are actively translocated and trigger DAT-mediated release of dopamine by reversal of the translocation cycle. Because both inhibitors and substrates increase extraneuronal dopamine levels, it is often assumed that all DAT ligands possess an addictive liability equivalent to that of cocaine. However, certain recently developed ligands, such as atypical benztropine-like DAT inhibitors with reduced or even a complete lack of cocaine-like rewarding effects, suggest that addictiveness is not a constant property of DAT-affecting compounds. These atypical ligands do not conform to the classic preconception that all DAT inhibitors (or substrates) are functionally and mechanistically alike. Instead, they suggest the possibility that the DAT exhibits some of the ligand-specific pleiotropic functional qualities inherent to G-protein–coupled receptors. That is, ligands with different chemical structures induce specific conformational changes in the transporter protein that can be differentially transduced by the cell, ultimately eliciting unique behavioral and psychological effects. The present overview discusses compounds with conformation-specific activity, useful not only as tools for studying the mechanics of dopamine transport, but also as leads for medication development in addictive disorders.

Footnotes

    • Received February 12, 2013.
    • Accepted April 2, 2013.
  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01 DA019676]; the National Institutes of Health National Institute of Mental Health [Grant R01 MH083840]; and the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse].

  • dx.doi.org/10.1124/jpet.111.191056.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 346 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 1
1 Jul 2013
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticlePerspectives in Pharmacology

Pleiotropic Characteristics of DAT Ligands

Kyle C. Schmitt, Richard B. Rothman and Maarten E. A. Reith
Journal of Pharmacology and Experimental Therapeutics July 1, 2013, 346 (1) 2-10; DOI: https://doi.org/10.1124/jpet.111.191056

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticlePerspectives in Pharmacology

Pleiotropic Characteristics of DAT Ligands

Kyle C. Schmitt, Richard B. Rothman and Maarten E. A. Reith
Journal of Pharmacology and Experimental Therapeutics July 1, 2013, 346 (1) 2-10; DOI: https://doi.org/10.1124/jpet.111.191056
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • The Conformational Cycle of the NSS Protein Family
    • Partial Substrates and Allosteric Modulators: Differential Effects on Uptake Versus Efflux
    • Atypical Uptake Inhibitors: Conformation-Specific Binding Mechanisms
    • Conclusions: Molecular Mechanisms of Action for Atypical DAT Ligands
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Acute and Delayed Clinical Manifestations of OP Toxicity
  • Miltefosine as Mediator of the Immune Response
  • Histamine Receptor Knockout Mice
Show more Perspectives in Pharmacology

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2022 by the American Society for Pharmacology and Experimental Therapeutics