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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-03, Vol.110 (12), p.4804-4809
• Main Authors: Nasca, Carla, Xenos, Dionysios, Barone, Ylenia, Caruso, Alessandra, Scaccianoce, Sergio, Matrisciano, Francesco, Battaglia, Giuseppe, Mathé, Aleksander A., Pittaluga, Anna, Lionetto, Luana, Simmaco, Maurizio, Nicoletti, Ferdinando
• Format: Article
• Language: English
• Subjects: Acetylation; Acetylation - drug effects; Acetylcarnitine - pharmacology; Amino Acids; Animals; Antidepressants; Antidepressive Agents - pharmacology; Biological Sciences; Clomipramine - pharmacology; Depressive disorders; Epigenesis, Genetic - drug effects; Epigenetics; Excitatory Amino Acid Antagonists - pharmacology; Farmakologi och toxikologi; Gene expression; Genetic variation; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones; Histones - genetics; Histones - metabolism; Humans; Klinisk medicin; Major depressive disorder; Male; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Knockout; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurologi; NF-kappa B - genetics; NF-kappa B - metabolism; Nootropic Agents - pharmacology; Prefrontal cortex; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Rats; Receptors; Receptors, Metabotropic Glutamate - biosynthesis; Receptors, Metabotropic Glutamate - genetics; Rodents; Serotonin Uptake Inhibitors - pharmacology; Stress, Psychological - drug therapy; Stress, Psychological - metabolism; Stress, Psychological - pathology; T cell receptors; Time Factors; Xanthenes
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1216100110

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 welltolerated 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-KB-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-κB 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.