Modulation of Chromatin Modification Facilitates Extinction of Cocaine-Induced Conditioned Place Preference

Malvaez, Melissa; Sanchis-Segura, Carles; Vo, Darren; Lattal, K. Matthew; Wood, Marcelo A.

doi:10.1016/j.biopsych.2009.07.032

« Previous Next »Biological Psychiatry
Volume 67, Issue 1 , Pages 36-43, 1 January 2010

Modulation of Chromatin Modification Facilitates Extinction of Cocaine-Induced Conditioned Place Preference

Melissa Malvaez
- Department of Neurobiology and Behavior, University of California, Irvine, Center for the Neurobiology of Learning and Memory, Irvine, California
Carles Sanchis-Segura
- Department of Neurobiology and Behavior, University of California, Irvine, Center for the Neurobiology of Learning and Memory, Irvine, California
- Area de Psicobiologia, Universitat Jaume I, Castellon, Spain
Darren Vo
- Department of Neurobiology and Behavior, University of California, Irvine, Center for the Neurobiology of Learning and Memory, Irvine, California
K. Matthew Lattal
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon
Marcelo A. Wood
- Department of Neurobiology and Behavior, University of California, Irvine, Center for the Neurobiology of Learning and Memory, Irvine, California
- Address correspondence to Marcelo A. Wood, Ph.D., University of California, Irvine, Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, 106 Bonney Research Laboratory, Irvine, CA 92697-3800

Received 10 April 2009; received in revised form 3 July 2009; accepted 26 July 2009. published online 22 September 2009.

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.

Key Words: Chromatin, cocaine, conditioned place preference, extinction, histone deacetylase, reinstatement