title: L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors.
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.
authors: Department of Physiology and Pharmacology, University of Rome Sapienza, 00185 Rome, Italy. carlanasca@hotmail.com
authors: Carla
authors: C
authors: Nasca
authors: Dionysios
authors: D
authors: Xenos
authors: Ylenia
authors: Y
authors: Barone
authors: Alessandra
authors: A
authors: Caruso
authors: Sergio
authors: S
authors: Scaccianoce
authors: Francesco
authors: F
authors: Matrisciano
authors: Giuseppe
authors: G
authors: Battaglia
authors: Aleksander A
authors: AA
authors: Mathé
authors: Anna
authors: A
authors: Pittaluga
authors: Luana
authors: L
authors: Lionetto
authors: Maurizio
authors: M
authors: Simmaco
authors: Ferdinando
authors: F
authors: Nicoletti
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000108:Acetylcarnitine / Q000494:pharmacology*; D000596:Amino Acids; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002997:Clomipramine / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D018697:Nootropic Agents / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis* / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014966:Xanthenes
chemical_list: D000108:Acetylcarnitine; D000596:Amino Acids; D000928:Antidepressive Agents; D002997:Clomipramine; D018691:Excitatory Amino Acid Antagonists; D006655:Histone Deacetylases; D006657:Histones; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D018094:Receptors, Metabotropic Glutamate; D017367:Selective Serotonin Reuptake Inhibitors; D014966:Xanthenes; C114624:LY 341495; C108822:metabotropic glutamate receptor 2
references: Eur Neuropsychopharmacol. 2006 May;16(4):281-7
references: 16316746
references: Science. 1959 Feb 6;129(3345):334-5
references: 13624727
references: Front Biosci (Landmark Ed). 2009 Jun 01;14:5031-51
references: 19482603
references: Biol Psychiatry. 2008 Sep 15;64(6):527-32
references: 18571629
references: Biol Psychiatry. 2002 May 15;51(10):775-87
references: 12007451
references: Eur Neuropsychopharmacol. 2007 Mar;17(4):298-308
references: 16904299
references: Neuroscience. 1997 Mar;77(1):65-73
references: 9044375
references: Science. 1996 Nov 22;274(5291):1383-5
references: 8910280
references: Arch Gen Psychiatry. 2006 May;63(5):530-8
references: 16651510
references: Physiol Behav. 1993 Dec;54(6):1215-20
references: 8295967
references: Am J Psychiatry. 2010 Nov;167(11):1305-20
references: 20843874
references: Psychopharmacology (Berl). 2006 Jul;186(4):587-93
references: 16612616
references: Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4170-5
references: 15753323
references: Prog Neuropsychopharmacol Biol Psychiatry. 2009 Aug 1;33(5):875-9
references: 19386277
references: Biol Psychiatry. 2009 Nov 1;66(9):812-3
references: 19833253
references: Mol Psychiatry. 2007 Sep;12(9):799-814
references: 17420765
references: Drugs Exp Clin Res. 1990;16(2):101-6
references: 2205455
references: CNS Drugs. 2011 Jun 1;25(6):459-71
references: 21649447
references: Int J Neuropsychopharmacol. 2008 Dec;11(8):1135-47
references: 18570703
references: J Pharmacol Exp Ther. 2011 Jan;336(1):165-77
references: 20947638
references: Mol Psychiatry. 2010 Mar;15(3):237-49
references: 19704408
references: Neuropharmacology. 2013 Mar;66:40-52
references: 22640631
references: Neuropharmacology. 2011 Jun;60(7-8):1017-41
references: 21036182
references: Brain Res Rev. 2009 Apr;60(1):226-42
references: 19162070
references: Biol Psychiatry. 2003 Jul 1;54(1):70-5
references: 12842310
references: Nature. 2008 Oct 16;455(7215):894-902
references: 18923511
references: Mol Pain. 2006 Jun 09;2:20
references: 16764720
references: J Neurosci. 2009 Sep 16;29(37):11451-60
references: 19759294
references: Neurochem Res. 2000 Oct;25(9-10):1265-74
references: 11059801
references: Trends Pharmacol Sci. 2010 Apr;31(4):153-60
references: 20064669
references: Ann Hematol. 2010 Feb;89(2):185-90
references: 19633847
references: Science. 2001 Aug 31;293(5535):1653-7
references: 11533489
references: Mol Pharmacol. 2009 May;75(5):1014-20
references: 19255242
references: CNS Drugs. 2007;21 Suppl 1:25-30; discussion 45-6
references: 17696590
references: Neurology. 1987 May;37(5):804-8
references: 3574681
references: Clin Cancer Res. 2009 Jun 15;15(12):3958-69
references: 19509172
references: Nat Neurosci. 2004 Aug;7(8):847-54
references: 15220929
references: Nat Rev Neurosci. 2011 Nov 30;13(1):22-37
references: 22127301
references: Bioorg Med Chem. 2006 Jun 15;14(12):4193-207
references: 16487713
references: Neuropharmacology. 1999 Oct;38(10):1431-76
references: 10530808
references: Int J Neuropsychopharmacol. 2010 Jun;13(5):563-72
references: 19796445
references: Neuropharmacology. 2008 Sep;55(4):525-31
references: 18590921
references: J Neurochem. 1995 Jul;65(1):268-74
references: 7790870
references: Nat Neurosci. 2006 Apr;9(4):519-25
references: 16501568
references: Mol Psychiatry. 2007 Aug;12(8):704-6
references: 17653204
references: Nat Rev Drug Discov. 2010 Aug;9(8):628-42
references: 20577266
references: Brain Res Bull. 2012 Mar 10;87(4-5):406-12
references: 22310150
references: Nat Neurosci. 2012 Sep;15(9):1245-54
references: 22864611