Modulation of chromatin modification facilitates extinction of cocaine-induced conditioned place preference.
BACKGROUND
Recent evidence suggests that epigenetic mechanisms have an important role in the development of addictive behavior. However, little is known about the role of epigenetic mechanisms in the extinction of drug-induced behavioral changes. In this study, we examined the ability of histone deacetylase (HDAC) inhibitors to facilitate extinction and attenuate reinstatement of cocaine-induced conditioned place preference (CPP).


METHODS
C57BL/6 mice were subject to cocaine-induced CPP using 20 mg/kg dose. To facilitate extinction, mice were administered an HDAC inhibitor following nonreinforced exposure to the conditioned context. To measure persistence, mice were subject to a reinstatement test using 10 mg/kg dose of cocaine.


RESULTS
We demonstrate that HDAC inhibition during extinction consolidation can facilitate extinction of cocaine-induced CPP. Animals treated with an HDAC inhibitor extinguished cocaine-induced CPP both more quickly and to a greater extent than did vehicle-treated animals. We also show that the extinction of cocaine seeking via HDAC inhibition modulates extinction learning such that reinstatement behavior is significantly attenuated. Acetylation of histone H3 in the nucleus accumbens following extinction was increased by HDAC inhibition.


CONCLUSIONS
This study provides the first evidence that modulation of chromatin modification can facilitate extinction and prevent reinstatement of drug-induced behavioral changes. These findings provide a potential novel approach to the development of treatments that facilitate extinction of drug-seeking behavior.
Malvaez
Melissa
M
Department of Neurobiology and Behavior, University of California, Irvine, Center for the Neurobiology of Learning and Memory, Irvine, California 92697-3800, USA.
Sanchis-Segura
Carles
C
Vo
Darren
D
Lattal
K Matthew
KM
Wood
Marcelo A
MA
D000704:Analysis of Variance; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects; D012055:Reinforcement Schedule
D002087:Butyrates; D002843:Chromatin; D018765:Dopamine Uptake Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D003042:Cocaine