L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors">

L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved December 27, 2012 (received for review September 15, 2012)
February 4, 2013
110 (12) 4804-4809
Commentary
Next generation antidepressants
Scott J. Russo, Dennis S. Charney

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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Acknowledgments

We thank Benedetta Bigio for bioinformatics support. The work was partially supported by Swedish Medical Research Council Grant 10414 and the Karolinska Institute (A.A.M.).

Supporting Information

Supporting Information (PDF)
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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 110 | No. 12
March 19, 2013
PubMed: 23382250

Classifications

Submission history

Published online: February 4, 2013
Published in issue: March 19, 2013

Keywords

  1. BDNF
  2. histone acetylation
  3. MDD
  4. glutamatergic neurotransmission
  5. chromatin

Acknowledgments

We thank Benedetta Bigio for bioinformatics support. The work was partially supported by Swedish Medical Research Council Grant 10414 and the Karolinska Institute (A.A.M.).

Notes

*This Direct Submission article had a prearranged editor.
See Commentary on page 4441.

Authors

Affiliations

Department of Physiology and Pharmacology, University of Rome “Sapienza,” 00185 Rome, Italy;
Dionysios Xenos
Department of Physiology and Pharmacology, University of Rome “Sapienza,” 00185 Rome, Italy;
Ylenia Barone
Psychiatric Clinic, Department of Systems Medicine, University of Rome “Tor Vergata,” 00133 Rome, Italy;
Alessandra Caruso
Department of Physiology and Pharmacology, University of Rome “Sapienza,” 00185 Rome, Italy;
Sergio Scaccianoce
Department of Physiology and Pharmacology, University of Rome “Sapienza,” 00185 Rome, Italy;
Francesco Matrisciano
Department of Physiology and Pharmacology, University of Rome “Sapienza,” 00185 Rome, Italy;
Giuseppe Battaglia
Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, 86077 Pozzilli, Italy;
Aleksander A. Mathé
Clinical Neuroscience, Psychiatry, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden;
Anna Pittaluga
Center of Excellence for Biomedical Research, University of Genoa, 16132 Genoa, Italy; and
Luana Lionetto
Department of Neuroscience and Mental Health, St. Andrea Hospital, 00189 Rome, Italy
Maurizio Simmaco
Department of Neuroscience and Mental Health, St. Andrea Hospital, 00189 Rome, Italy
Ferdinando Nicoletti
Department of Physiology and Pharmacology, University of Rome “Sapienza,” 00185 Rome, Italy;
Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, 86077 Pozzilli, Italy;

Notes

1
To whom correspondence should be addressed. E-mail: [email protected].
Author contributions: C.N., A.A.M., and F.N. designed research; C.N., A.A.M., and F.N. designed experiments; F.N. supervised research; C.N., D.X., Y.B., S.S., and F.M. performed in vivo experiments; C.N., A.C., A.P., L.L., and M.S. performed in vitro experiments; C.N., G.B., and F.N. analyzed data; and C.N., A.A.M., and F.N. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors
    Proceedings of the National Academy of Sciences
    • Vol. 110
    • No. 12
    • pp. 4431-4853

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