Antidepressant actions of histone deacetylase inhibitors.
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.
Covington
Herbert E
HE
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
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
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D005518:Food Preferences / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011180:Postmortem Changes; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013395:Sucrose / Q000494:pharmacology; D013549:Sweetening Agents / Q000494:pharmacology; D000077337:Vorinostat
D000928:Antidepressive Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011725:Pyridines; D012333:RNA, Messenger; D012097:Repressor Proteins; D013549:Sweetening Agents; D005473:Fluoxetine; C118739:entinostat; D013395:Sucrose; D000077337:Vorinostat; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases