ArticleProceedings of the National Academy of Sciences of the United States of America2015
Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
65 citing papers in PubMed, 1 synthesis or guideline pooled it, 91 citations in OpenAlex.
- A systematic review of the potential effects of medications and drugs of abuse on dopamine transporter imaging using [European journal of nuclear medicine and molecular imaging · 2023Pooled it
- Trace amine-associated receptor gene polymorphism increases drug craving in individuals with methamphetamine dependence.PloS one · 2019Trial
- Antipsychotic-like effects of the selective Rho-kinase 2 inhibitor KD025 in genetic and pharmacological mouse models of schizophrenia.Molecular psychiatry · 2026Article
- Article
- Synaptojanin1 regulates synaptic dopamine release and axonal integrity via retromer-dependent endosomal sorting.Research square · 2026Article
- Distinct Effects of Nonselective Rho-Kinase Inhibitor Fasudil and Selective Rho-Kinase 2 Inhibitor KD025 on Serotonin and Dopamine Release in the Nucleus Accumbens of Mice.Neuropsychopharmacology reports · 2026Article
- Dynamic Regulation of Cholesterol Metabolism Genes in Dopaminergic Neurons following Methamphetamine Treatment as Revealed by Single-Nucleus RNA Sequencing.bioRxiv : the preprint server for biology · 2025Article
- Absence of TAAR1 function increases methamphetamine-induced excitability of dorsal raphe serotonin neurons and drives binge-level methamphetamine intake.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Regulation of Dopamine Transporter Surface Expression.Advances in neurobiology · 2025Review
- Monoamine transporter ubiquitination and inward-open conformation synergistically maximize transporter endocytosis.Science advances · 2024Article
- Article
- Parkinson's disease gene, Synaptojanin1, dysregulates the surface maintenance of the dopamine transporter.NPJ Parkinson's disease · 2024Article
- Substance Addiction Rehabilitation Drugs.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Article
- Amphetamine Induces Sex-Dependent Loss of the Striatal Dopamine Transporter in Sensitized Mice.eNeuro · 2024Article
- Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice.NPJ Parkinson's disease · 2023Article
- Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target.International journal of molecular sciences · 2023Review
- The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization.The Journal of pharmacology and experimental therapeutics · 2023Article
- Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons.Nature neuroscience · 2023Article
- Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke.Science signaling · 2023Article
5 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
Acute amphetamine (AMPH) exposure elevates extracellular dopamine through a variety of mechanisms that include inhibition of dopamine reuptake, depletion of vesicular stores, and facilitation of dopamine efflux across the plasma membrane. Recent work has shown that the DAT substrate AMPH, unlike cocaine and other nontransported blockers, can also stimulate endocytosis of the plasma membrane dopamine transporter (DAT). Here, we show that when AMPH enters the cytoplasm it rapidly stimulates DAT internalization through a dynamin-dependent, clathrin-independent process. This effect, which can be observed in transfected cells, cultured dopamine neurons, and midbrain slices, is mediated by activation of the small GTPase RhoA. Inhibition of RhoA activity with C3 exotoxin or a dominant-negative RhoA blocks AMPH-induced DAT internalization. These actions depend on AMPH entry into the cell and are blocked by the DAT inhibitor cocaine. AMPH also stimulates cAMP accumulation and PKA-dependent inactivation of RhoA, thus providing a mechanism whereby PKA- and RhoA-dependent signaling pathways can interact to regulate the timing and robustness of AMPH's effects on DAT internalization. Consistent with this model, the activation of D1/D5 receptors that couple to PKA in dopamine neurons antagonizes RhoA activation, DAT internalization, and hyperlocomotion observed in mice after AMPH treatment. These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.