Antidepressant actions of histone deacetylase inhibitors.

Full Abstract

Persistent symptoms of depression suggest the involvement of stable molecular adaptations in brain, which may be reflected at the level of chromatin remodeling. We find that chronic social defeat stress in mice causes a transient decrease, followed by a persistent increase, in levels of acetylated histone H3 in the nucleus accumbens, an important limbic brain region. This persistent increase in H3 acetylation is associated with decreased levels of histone deacetylase 2 (HDAC2) in the nucleus accumbens. Similar effects were observed in the nucleus accumbens of depressed humans studied postmortem. These changes in H3 acetylation and HDAC2 expression mediate long-lasting positive neuronal adaptations, since infusion of HDAC inhibitors into the nucleus accumbens, which increases histone acetylation, exerts robust antidepressant-like effects in the social defeat paradigm and other behavioral assays. HDAC inhibitor [N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (MS-275)] infusion also reverses the effects of chronic defeat stress on global patterns of gene expression in the nucleus accumbens, as determined by microarray analysis, with striking similarities to the effects of the standard antidepressant fluoxetine. Stress-regulated genes whose expression is normalized selectively by MS-275 may provide promising targets for the future development of novel antidepressant treatments. Together, these findings provide new insight into the underlying molecular mechanisms of depression and antidepressant action, and support the antidepressant potential of HDAC inhibitors and perhaps other agents that act at the level of chromatin structure.

Author information

Author/s: Covington, Herbert E (HE); Maze, Ian (I); LaPlant, Quincey C (QC); Vialou, Vincent F (VF); Ohnishi, Yoshinori N (YN); Berton, Olivier (O); Fass, Dan M (DM); Renthal, William (W); Rush, Augustus J (AJ); Wu, Emma Y (EY); Ghose, Subroto (S); Krishnan, Vaishnav (V); Russo, Scott J (SJ); Tamminga, Carol (C); Haggarty, Stephen J (SJ); Nestler, Eric J (EJ);

Affiliation: Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2009-Sep; vol 29 (issue 37) : pp 11451-60

Dates: Created 2009/09/17; Completed 2009/10/02; Revised 2009/11/12;

PMID: 19759294, status: MEDLINE (last retrieval date: 11/15/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Analysis of Variance
Animals
Antidepressive Agents - pharmacology
Behavior, Animal - drug effects
Benzamides - pharmacology
Depression - drug therapy; enzymology; pathology
Disease Models, Animal
Dominance-Subordination
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Fluoxetine - pharmacology
Food Preferences - drug effects
Gene Expression Profiling - methods
Gene Expression Regulation, Enzymologic - drug effects; physiology
Histone Deacetylases - antagonists & inhibitors; genetics; metabolism
Histones - genetics; metabolism

Histones - genetics; metabolism
Humans
Hydroxamic Acids
Interpersonal Relations
Male
Mice
Mice, Inbred C57BL
Models, Biological
Nucleus Accumbens - drug effects; enzymology
Oligonucleotide Array Sequence Analysis - methods
Postmortem Changes
Pyridines - pharmacology
RNA, Messenger - metabolism
Repressor Proteins - antagonists & inhibitors; genetics; metabolism
Sucrose - pharmacology
Sweetening Agents - pharmacology

Associated Chemicals: Antidepressive Agents (0) ; Benzamides (0) ; Enzyme Inhibitors (0) ; Histones (0) ; Hydroxamic Acids (0) ; N-(2-aminophenyl)-4-(N-(pyridin-3-ylmethoxycarbonyl)aminomethyl)benzamide (0) ; Pyridines (0) ; RNA, Messenger (0) ; Repressor Proteins (0) ; Sweetening Agents (0) ; vorinostat (149647-78-9) ; Fluoxetine (54910-89-3) ; Sucrose (57-50-1) ; Histone Deacetylases (EC 3.5.1.-) ; histone deacetylase-2 (EC 3.5.1.98)

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