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Mechanisms of dopamine transporter regulation in normal and disease states

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Vaughan, Roxanne A., Foster, James D.·2013·Trends in Pharmacological Sciences
DOI 10.1016/j.tips.2013.07.005PMC PMC3831354
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Abstract

The dopamine (DA) transporter (DAT) controls the spatial and temporal dynamics of DA neurotransmission by driving reuptake of extracellular transmitter into presynaptic neurons. Many diseases such as depression, bipolar disorder, Parkinson's disease (PD), and attention deficit hyperactivity disorder (ADHD) are associated with abnormal DA levels, implicating DAT as a factor in their etiology. Medications used to treat these disorders and many addictive drugs target DAT and enhance dopaminergic signaling by suppressing transmitter reuptake. We now understand that the transport and binding properties of DAT are regulated by complex and overlapping mechanisms that provide neurons with the ability to modulate DA clearance in response to physiological demands. These processes are controlled by endogenous signaling pathways and affected by exogenous transporter ligands, demonstrating their importance for normal neurotransmission, drug abuse, and disease treatments. Increasing evidence supports the disruption of these mechanisms in DA disorders, implicating dysregulation of transport in disease etiologies and suggesting these processes as potential points for therapeutic manipulation of DA availability.

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  • Inhibition of DAT1, targeted by both drugs, leads to no reuptake of DA to the cytosol.

    “The inhibition of DAT1, targeted by both drugs, leads to no reuptake of the DA to the cytosol [166]; LDX also reduces monoamine degradation by MAO inhibition [167, 168].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [166]

    The Abstract (page not provided) says drugs targeting DAT suppress dopamine reuptake, supporting the general mechanism. But the Psychostimulant Drugs section (page not provided) reports reduced transport under some conditions and increased transport during the first minutes of amphetamine exposure; it does not support the absolute claim of no reuptake. The two drugs are not named in the cited sentence, so their individual mechanisms cannot be checked here. (LLM, conf=0.86)

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Authors
Vaughan, R. A., & Foster, J. D.
Affiliations
University of North Dakota (US)
Corresponding author
Vaughan, Roxanne A.
ORCID
Venue
Trends in Pharmacological Sciences
Publisher
Elsevier BV
Published
2013-09
Volume
34
Issue
9
Pages
489-496
ISSN
0165-6147 (ISSN-L)
DOI
10.1016/j.tips.2013.07.005
PMC
PMC3831354
OpenAlex
W2052500414
Cited by
419
References
3
Citations by year
2026: 27 · 2025: 29 · 2024: 23 · 2023: 42 · 2022: 38 · 2021: 39 · 2020: 41 · 2019: 47 · 2018: 30 · 2017: 36 · 2016: 22 · 2015: 30 · 2014: 13 · 2013: 1
FWCI
2.24
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Pharmacological Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Drug Abuse (R01DA015175, R15DA031991, R01DA027845, DA27845, R01DA013147, DA 13147, DA31991)
  • National Institute of General Medical Sciences (P20GM103442)
  • National Center for Research Resources (P20RR016741, P20RR017699)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
dopamine transporter, dopamine reuptake, dopamine signaling, transporter regulation, depression, bipolar disorder, Parkinson's disease, attention deficit hyperactivity disorder, drugs of abuse, dopamine availability
MeSH terms
Amino Acid Sequence, Animals, Attention Deficit Disorder with Hyperactivity, Mental Disorders, Bipolar Disorder, Humans, Molecular Sequence Data, Parkinson Disease, Protein Processing, Post-Translational, Dopamine Plasma Membrane Transport Proteins

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