ArticleNature medicine2010
Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis.
Article in Nature medicine, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT03831971 (The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers), which is not on this map. Cited by 53 papers, 1 of them a synthesis that pooled it.
What it found
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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.
The Influence of ANS-6637 on Midazolam Pharmacokinetics in Healthy Volunteers (SEARCH PK)
Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 97 citations in OpenAlex.
- Pooled it
- Preliminary effects of oral ANS-6637, an ALDH2 inhibitor, on cue-induced craving, safety and alcohol consumption among adults with alcohol use disorder: a proof-of-concept, randomized, human laboratory trial.Alcohol and alcoholism (Oxford, Oxfordshire) · 2025Trial
- Pharmacogenetic randomized trial for cocaine abuse: disulfiram and dopamine β-hydroxylase.Biological psychiatry · 2013Trial
- The impact of disulfiram treatment on the reinforcing effects of cocaine: a randomized clinical trial.PloS one · 2012Trial
- A Novel ALDH2 Inhibitor for the Treatment of Alcohol Use Disorder: Preclinical Findings.Cells · 2026Article
- Identification and functional verification of key genes involved in alkaloid biosynthesis inFrontiers in plant science · 2026Article
- Pharmacological agents targeting drug-tolerant persister cells in cancer.Pharmacological research · 2024Review
- ALDEFLUOR activity, ALDH isoforms, and their clinical significance in cancers.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation.Molecules (Basel, Switzerland) · 2023Article
- Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase.Molecules (Basel, Switzerland) · 2022Article
- The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management.International journal of molecular sciences · 2022Review
- Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells.Development (Cambridge, England) · 2022Article
- Computational Investigation of Structural Basis for Enhanced Binding of Isoflavone Analogues with Mitochondrial Aldehyde Dehydrogenase.ACS omega · 2022Article
- Striatal miR-183-5p inhibits methamphetamine-induced locomotion by regulating glucocorticoid receptor signaling.Frontiers in pharmacology · 2022Article
- TheGenome research · 2021Article
- Daidzein modulates cocaine-reinforcing effects and cue-induced cocaine reinstatement in CD-1 male mice.Psychopharmacology · 2021Article
- Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.Nature metabolism · 2021Article
- Alcohol and Cocaine Combined Substance Use on Adult Hypothalamic Neural Stem Cells and Neurogenesis.Brain plasticity (Amsterdam, Netherlands) · 2020Review
- The Effect of GS-548351 on the Pharmacokinetics of Midazolam Following Multiple Doses of ANS-6637 in Healthy Adults.Journal of clinical pharmacology · 2020Article
- Transcriptional Profiling of Whisker Follicles and of the Striatum in Methamphetamine Self-Administered Rats.International journal of molecular sciences · 2020Article
Corrections and comments
- Commented on by
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- Erratum issued
Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.
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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.