ArticleProceedings of the National Academy of Sciences of the United States of America2013
L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers, 2 of them syntheses that pooled it.
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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.
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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.
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Who cites it
130 citing papers in PubMed, 2 syntheses or guidelines pooled it, 262 citations in OpenAlex.
- An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder.Molecular psychiatry · 2021Pooled it
- Psychological Stress and Mitochondria: A Systematic Review.Psychosomatic medicinePooled it
- Acetyl-l-carnitine deficiency in patients with major depressive disorder.Proceedings of the National Academy of Sciences of the United States of America · 2018Trial
- Carnitine and/or Acetylcarnitine Deficiency as a Cause of Higher Levels of Ammonia.BioMed research international · 2016Trial
- Divergent Roles of mGlu2 and mGlu3 Receptors in Amyloid-β Production and Cognitive Dysfunctions in Alzheimer's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Astroglial kappa opioid receptor-mediated reduction of glutamate exchanger xCT in the prelimbic cortex underlies chronic stress-induced depressive-like behaviors.Molecular psychiatry · 2026Article
- Acetyl-carnitine improves hyperactivity and learning deficits inLife science alliance · 2026Article
- Metabolomics Highlights Reduced Glutamate and Acetylcarnitine in the Amniotic Fluid of Cytomegalovirus-Infected Pregnant Women.Journal of proteome research · 2026Article
- Curing the brain: in search for new astrocyte-specific therapies.Experimental & molecular medicine · 2026Review
- Article
- Astrocyte Ezrin defines resilience to stress-induced depressive behaviours in mice.National science review · 2026Article
- Current Evidence of Acetyl-L-Carnitine Use in Mood Disorders-: A Systematic Review and Meta-Analysis.Neuropsychiatric disease and treatment · 2026Review
- Molecular Characteristics of Spontaneous Remission in Major Depressive Disorder: Changes in Serum Acetylcarnitine and Glycerophosphcholine Levels.Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology · 2025Article
- Targeting metabotropic glutamate receptors for symptomatic and disease-modifying treatment in Parkinson's disease.NPJ Parkinson's disease · 2025Review
- Advances in discerning the mechanisms underlying depression and resiliency: relation to the neurobiology of stress and the effects of antidepressants.Molecular psychiatry · 2025Review
- Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer's disease in two independent study cohorts.Molecular psychiatry · 2025Article
- Review
- Multifaceted therapeutic potentials of catalpol, an iridoid glycoside: an updated comprehensive review.Inflammopharmacology · 2025Review
- Comprehensive review of the expanding roles of the carnitine pool in metabolic physiology: beyond fatty acid oxidation.Journal of translational medicine · 2025Review
- Acylcarnitines metabolism in depression: association with diagnostic status, depression severity and symptom profile in the NESDA cohort.Translational psychiatry · 2025Article
70 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.
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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.