Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats.
Regulation of gene expression is known to contribute to the long-term adaptations taking place in response to drugs of abuse. Recent studies highlighted the regulation of gene transcription in neurons by chromatin remodeling, a process in which posttranslational modifications of histones play a major role. To test the involvement of epigenetic regulation on drug-reinforcing properties, we submitted rats to the cocaine operant self-administration paradigm. Using the fixed ratio 1 schedule, we found that the histone deacetylase (HDAC) inhibitors trichostatin A and phenylbutyrate dose-dependently reduced cocaine self-administration. Under the progressive ratio schedule, both trichostatin A and depudecin significantly reduced the breaking point, indicating that HDAC inhibition attenuated the motivation of rats for cocaine. Conversely, HDAC inhibition did not decrease self-administration for the natural reinforcer sucrose. This observation was correlated with measurements of HDAC activity in the frontal cortex, which was inhibited in response to cocaine, but not to sucrose self-administration. Control experiments showed that the decrease in the motivation for the drug was not attributable to a general motivational dysfunction because trichostatin A had no adverse effect on locomotion during the habituation session or on cocaine-induced hyperlocomotion. It was not attributable to anhedonia because the inhibitor had no effect on the sucrose preference test. In contrast, trichostatin A completely blocked the cocaine-induced behavioral sensitization. Together, the data show that epigenetic regulation of gene transcription in adult brain is able to influence a motivated behavior and suggest that HDAC inhibition may counteract the neural sensitization leading to drug dependence.
Romieu
Pascal
P
Inserm, U575, Centre de Neurochimie, 67084 Strasbourg, France, Institut Fédératif de Recherche 37 Neurosciences, 67085 Strasbourg, France. romieu@neurochem.u-strasbg.fr
Host
Lionel
L
Gobaille
Serge
S
Sandner
Guy
G
Aunis
Dominique
D
Zwiller
Jean
J
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003216:Conditioning, Operant; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D010654:Phenylbutyrates / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D013395:Sucrose / Q000494:pharmacology
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010654:Phenylbutyrates; C012589:trichostatin A; D013395:Sucrose; D006655:Histone Deacetylases; D003042:Cocaine
Biochem J. 2003 Mar 15;370(Pt 3):737-49
12429021
Neurosci Biobehav Rev. 1999 May;23(5):717-41
10392662
Ann N Y Acad Sci. 1998 May 30;844:7-20
9668660
Neuron. 2005 Oct 20;48(2):303-14
16242410
Brain Res Brain Res Rev. 1991 Sep-Dec;16(3):223-44
1665095
Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5764-8
1631058
Mol Pharmacol. 2006 Aug;70(2):487-92
16670375
FEBS Lett. 1993 Feb 15;317(3):175-80
8425601
Science. 2003 Oct 31;302(5646):885-9
14593183
J Neurosci. 1992 Jul;12(7):2609-22
1613551
Mol Pharmacol. 2006 Aug;70(2):440-3
16728645
Pharmacol Biochem Behav. 1993 Jul;45(3):539-48
8332614
Nat Rev Neurosci. 2006 Oct;7(10):784-96
16988654
Nat Neurosci. 2006 Apr;9(4):519-25
16501568
Pharmacol Biochem Behav. 1997 Jul;57(3):441-7
9218268
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3356-61
9520369
Eur J Pharmacol. 2005 Dec 5;526(1-3):199-206
16256105
J Neurosci. 2007 Dec 19;27(51):14179-89
18094257
Neurosci Lett. 2008 Feb 13;432(1):54-7
18164815
Science. 2001 Aug 10;293(5532):1074-80
11498575
Cell. 2000 Oct 13;103(2):263-71
11057899
Nat Rev Neurosci. 2004 Jun;5(6):483-94
15152198
Neuron. 2007 Nov 8;56(3):517-29
17988634
Neuromolecular Med. 2002;1(2):137-51
12025859
Nat Rev Neurosci. 2001 Feb;2(2):119-28
11252991
Addict Biol. 2006 Mar;11(1):2-38
16759333
J Neurosci Methods. 1996 May;66(1):1-11
8794935
Psychopharmacology (Berl). 2000 Aug;151(2-3):99-120
10972458
J Biol Chem. 1990 Oct 5;265(28):17174-9
2211619
Cell. 2002 Nov 1;111(3):285-91
12419240
Physiol Behav. 2002 Jul;76(3):379-87
12117574
J Neurosci. 2005 Nov 9;25(45):10379-89
16280577
J Pharmacol Exp Ther. 1993 Oct;267(1):496-505
8229780
Brain Res Brain Res Rev. 1993 Sep-Dec;18(3):247-91
8401595