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

Abstract

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 20mg/kg dose. To facilitate extinction, mice were administered an HDAC inhibitor following non-reinforced exposure to the conditioned context. To measure persistence, mice were subject to a reinstatement test using 10mg/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 context-drug associated memories 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.

The Efficacy of Exercise to Attenuate Cocaine Relapse is Associated with Changes in Bdnf and Altered by Sex and Estrous Cycle Phase.

“…Our findings showing the NaBu treatment reduced both cocaine-seeking and Bdnf exon IV expression are consistent with other reports showing beneficial effects of HDAC inhibition in reducing cocaine-seeking and extinction of conditioned place preference for cocaine (Malvaez et al 2010;2013). Although NaBu is a non-specific HDAC inhibitor, and in this study its effects were examined following systemic administration, evidence suggests that inhibition of HDAC activity affects the expression of only approximately 2% of genes (Van Lint et al 1996;Davie et al 2003).…”

“…In support of this possibility we also demonstrated that treatment of sodium butyrate, a HDAC inhibitor that, like exercise, modulates gene transcription, including Bdnf exon IV expression, provided beginning during early abstinence mimicked both the behavioral and molecular effects of wheel running. This finding is consistent with other reports showing beneficial effects of HDAC inhibition in reducing cocaine-seeking and extinction of conditioned place preference for cocaine (Malvaez et al 2010;2013) and further suggests epigenetic modification of chromatin containing the Bdnf gene during early abstinence as a possible mechanism.…”

“…Chromatin remodeling, including histone modifications and DNA methylation, and its influence on gene regulation, specifically regulation of the Bdnf gene, has become an increasing focus in drug addiction research Maze and Nestler, 2011;McQuown and Wood, 2011). (Yasuda et al 2009), decreases motivation for cocaine, cocaine-seeking, and cocaine-induced locomotor sensitization (Malvaez et al 2010;2013;Romieu et al 2011;Kennedy et al 2013). Further evidence supporting the hypothesis that altering histone acetylation may provide beneficial behavioral and molecular effects on cocaine-seeking will be presented in Chapter II of this dissertation.…”

Hippocampal Focal Knockout of CBP Affects Specific Histone Modifications, Long-Term Potentiation, and Long-Term Memory

“…Tissue preparation and immunohistochemical analysis was performed as described previously (Vecsey et al, 2007;Malvaez et al, 2010). Briefly, coronal sections of paraformaldehyde-fixed, cryoprotected brains were cut with a cryostat at a thickness of 20 mm at the level of the hippocampus and collected in PBS.…”

Addiction et régulations épigénétiques

“…Chez les rongeurs, cette approche suggère que le développement des comportements liés à l'addiction était sans doute relié à des modifications épigénétiques, même si les résultats ne sont pas toujours concordants. C'est ainsi que des inhibiteurs non sélectifs des HDAC : (1) réduisent la consommation de cocaïne pendant la phase d'acquisition de l'autoadministration, ainsi que la motivation des rats à s'autoadministrer la drogue [42] ; (2) réduisent la consommation d'éthanol par des souris et la motivation des rats à s'administrer de l'éthanol [43] ; (3) facilitent l'extinction de la préférence de place induite par la cocaïne [44] ; (4) réduisent la préférence de place induite par la nicotine, mais pas l'aversion de place provoquée par des doses plus élevées [45] ; (5) inhibent la sensibilisation comportementale provoquée par l'éthanol [46] ; et (6) réduisent le comportement de recherche de cocaïne après une période de sevrage de trois semaines (rechute) [47]. D'autre part, un traitement similaire avec souvent les mêmes Les HDAC sistent pendant une bonne partie de la vie, sous-tendraient la trace d'évènements traumatisants se produisant durant les tout premiers jours de vie.…”