Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines

Morón, José A.; Brockington, Alicia; Wise, Roy A.; Rocha, Beatriz A.; Hope, Bruce T.

doi:10.1523/jneurosci.22-02-00389.2002

Cited by 681Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchParkinson's Disease Mechanisms and Treatments

Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines

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Morón, José A., Brockington, Alicia, Wise, Roy A., Rocha, Beatriz A., Hope, Bruce T.·2002·The Journal of Neuroscience

DOI 10.1523/jneurosci.22-02-00389.2002PMC PMC6758674

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Abstract

Selective blockers of the norepinephrine transporter (NET) inhibit dopamine uptake in the prefrontal cortex. This suggests that dopamine in this region is normally cleared by the somewhat promiscuous NET. We have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of 3H-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice. At transporter-specific concentrations, nisoxetine and GBR12909 failed to block dopamine uptake into frontal cortex synaptosomes from NET knock-out mice. The efficacy of cocaine at the highest dose (1 mm) was normal in DAT knock-out mice but reduced by 70% in NET knock-out mice. Nisoxetine inhibited dopamine uptake by 20% in caudate and nucleus accumbens synaptosomes from wild-type and DAT knock-out mice but had no effect in those from NET knock-out mice. Cocaine failed to block dopamine uptake into caudate or nucleus accumbens synaptosomes from DAT knock-out mice. Cocaine and GBR12909 each inhibited dopamine uptake into caudate synaptosomes from NET knock-out mice, but cocaine effectiveness was reduced in the case of nucleus accumbens synaptosomes. Thus, whereas dopamine uptake in caudate and nucleus accumbens depends primarily on the DAT, dopamine uptake in frontal cortex depends primarily on the NET. These data underscore the fact that which transporter clears dopamine from a given region depends on both the affinities and the local densities of the transporters.

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In prefrontal cortex, norepinephrine transporters contribute to dopamine reuptake and mediate dopamine increases.
“Although prefrontal regions expresses low DAT levels (Sesack et al., 1998), MP also blocks norepinephrine transporters (Hannestad et al., 2010), which in prefrontal cortex contribute to DA reuptake and mediate DA increases (Carboni et al., 1990; Morón et al., 2002).”
From Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder (2012) · cites this paper as Morón et al., 2002

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Authors: Morón, J. A., Brockington, A., Wise, R. A., Rocha, B. A., & Hope, B. T.
Affiliations: National Institutes of Health (US)
ORCID: Morón, José A.
Wise, Roy A.
Rocha, Beatriz A.
Hope, Bruce T.
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2002-01-15
Volume: 22
Issue: 2
Pages: 389-395
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.22-02-00389.2002
PMC: PMC6758674
OpenAlex: W1493305388
Cited by: 681
References: 50
Citations by year: 2026: 15 · 2025: 15 · 2024: 36 · 2023: 16 · 2022: 22 · 2021: 18 · 2020: 26 · 2019: 20 · 2018: 29 · 2017: 20 · 2016: 30 · 2015: 30 · 2014: 35 · 2013: 36 · 2012: 26
FWCI: 12.01
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
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 uptake, norepinephrine transporter, dopamine transporter, cocaine, nisoxetine, GBR 12909, monoamine transporters, frontal cortex, caudate nucleus, nucleus accumbens, synaptosomes, dopamine clearance
MeSH terms: Animals, Brain, Brain Chemistry, Caudate Nucleus, Cocaine, Dopamine, Dose-Response Relationship, Drug, Fluoxetine, Frontal Lobe, Membrane Glycoproteins, Nerve Tissue Proteins, Norepinephrine, Nucleus Accumbens, Piperazines, Synaptosomes, Mice, Knockout, Dopamine Uptake Inhibitors, Membrane Transport Proteins, Symporters, Dopamine Plasma Membrane Transport Proteins, Norepinephrine Plasma Membrane Transport Proteins, Mice

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Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines

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