Elsevier

Neuroscience Letters

Volume 483, Issue 2, 11 October 2010, Pages 137-142
Neuroscience Letters

The extinction of morphine-induced conditioned place preference by histone deacetylase inhibition

https://doi.org/10.1016/j.neulet.2010.07.080Get rights and content

Abstract

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 morphine-induced behavioral changes. In this study, we will examine the effect of histone deacetylase (HDAC) inhibitors on extinction of morphine-induced conditioned place preference (CPP). To facilitate extinction, rats will be administered an HDAC inhibitor (HDACi) following nonreinforced exposure to the conditioned context. To measure persistence, rats were subject to a reinstatement test using 3 mg/kg dose of morphine. To exclude the effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session, rats received injection of either NaBut or vehicle for 8 days. We found that HDAC inhibition during nonconfined extinction or confined extinction consolidation can facilitate extinction of morphine-induced CPP. We also showed that the extinction of drug seeking via HDAC inhibition modulates extinction learning such that reinstatement behavior is significantly attenuated. There is no effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session. In conclusion, our results extend earlier reports on the ability of HDACi to modify the behavioral effects of drugs of abuse. Our increasing understanding of these epigenetic mechanisms will provide key answers to basic processes in drug addiction and hopefully provide insight into designing improved treatments for drug addiction.

Introduction

Chronic exposure to drugs of abuse can elicit persistent structural and functional changes in the central nervous system [2]. These phenomena are usually referred as ‘drug-induced neuroplasticity’ and depend on changes in gene expression [12]. According to recent theories, epigenetic mechanisms that may produce these long-lasting effects are stable changes in cellular function leading to stable changes in neuronal plasticity. Changes in the structure of the chromatin could underlie long-lasting changes on neuronal gene expression and ultimately contribute to explain the persistence of addictive behavior [13]. There are numerous chromatin modifications carried out by a number of histone-modifying enzymes to regulate access to DNA, and one of the best studied chromatin modifications is acetylation of histones [6]. Histone acetyltransferases (HATs) add acetyl groups to relax chromatin structure, while histone deacetylases (HDACs) remove acetyl groups, generally resulting in transcriptional silencing [6]. Previous studies have shown 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 [11].

However, the contribution of histone modifications related to epigenetic mechanisms that may be associated with the process of morphine addiction is currently unknown. Therefore, in the present study, we investigated the effects of chromatin remodeling extinction of morphine-induced CPP.

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Animals

Sprague–Dawley male rats weighing 220–240 g were obtained from the Laboratory Animal Center, Peking University Health Science Center. Rats weighed ∼300–320 g when experiments began. They were housed individually in a temperature (23 ± 2 °C) and humidity (50 ± 5%)-controlled room with food and water available ad libitum. They were kept on a reverse 12 h light/dark cycle. All treatments of the rats were performed in accordance with the National Institutes of Health Guide for the Care and Use of

HDAC inhibition facilitates nonconfined extinction and reduces reinstatement of morphine-induced conditioned place preference

To examine the ability of HDAC inhibitors to facilitate extinction of morphine-induced CPP, we administered systemic injections of sodium butyrate (NaBut, 1.2 g/kg, IP) or vehicle (water, 1.0 ml/kg, IP) immediately after eight nonconfined extinction sessions of CPP (Fig. 1A). In experiment 1, a two-way ANOVA conducted on CPP score using group (NaBut or vehicle group) as the between-subject factor and test condition (preconditioning or postconditioning) as the within-subject factor, there was a

Discussion

In this study, we found that HDAC inhibition during nonconfined extinction or confined extinction consolidation can facilitate extinction of morphine-induced CPP. We also showed that the extinction of drug seeking via HDAC inhibition modulates extinction learning such that reinstatement behavior is significantly attenuated. In addition, our finding indicated that there is no effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session. Recent studies have

Acknowledgment

This work was supported in part by the grants of the National Basic Research Program of China Grants (No: 30873440).

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