Effects Of Cocaine-induced Histone Acetylation In The Nucleus Accumbens On Gene Expression And Cocaine Addiction

Drug addiction is currently viewed as a chronic brain disease characterized primarily by compulsive drug-taking and drug seeking, withdrawal symptom when access to the drug is prevented. Long-term adaptation such as synaptic transmission and neuronal architectural plasticity in addiction-related brain regions, attributes to the abnormal addictive behaviors. Many researches indicated that the abnormal expression of genes induced by drug abuse in specific brain regions is through to result in neural and synaptic plasticity.Epigenetic modifications regulate gene transcription by altering chromatin structure, which is an important manner. It is regarded that the hyperacetylation of histone H3 and H4 acetylation is mainly associated with gene transcriptional activation. While the hypoacetylation of histone H3 and H4 is related to inactivation of genes.Drug motivation is important not only for the acquisition and the mantainance, but also for the compulsive drug-seeking behavior and relapse. Recent researches indicate that epigenetic modifications play a critical role in drug-induced neuronal and behavioral plasticity. However, the effect of epigenetic modifications on drug motivation is yet unclear.We adopted the intravenous drug self-administration as it’s a powerful tool for imitating the human addiction. Our research focuses on the role of histone acetylation modification in drug motivation and the changes of histone acetylation and gene expression under cue-induced reinstatement. The detailed results are as follows:1. Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIa in the nucleus accumbens is critical for motivation for drug reinforcement.(1). HDAC inhibitor infusions in the NAc shell increase motivation for cocaine self-administration. We found that acetylation of histone H3 and H4 in the NAc shell were increased after chronic cocaine self-administration. Daily HDAC inhibitor infusions in the NAc shell increased the motivation for cocaine and and augmented the histone acetylation.(2). HDAC4 overexpression in the NAc shell decreases motivation for cocaine self-administration. We detected the role of HDAC4 overexpression in the motivation for cocaine and found that HDAC4 overexpression in the NAc shell attenuates the motivation for cocaine by neutralizing the elevation of histone acetylation induced by chronic cocaine self-administration, which indicated that hisotne acetylation induced by chronic cocaine play a role in the mantainance of motivation for cocaine.(3).The motivation for cocaine self-administration is positively correlated with the acetylation of histone H3 in the NAc shell. The motivation for cocaine is not related to histone H4 acetylation.(4). Chronic cocaine induced histone acetylation in the NAc shell controls genes’transcriptional activation. We found that the genes’transcriptional activity is mainly modulated by H3 acetylation in the NAc shell. Motivation for cocaine was correlated with genes’transcriptional activation modulated by H3 acetylation. Results indicated that the genes’transcriptional activity regulated by acetylation of histone H3 may play a critical role in the motivation for cocaine self-administration.(5). Lentivirus mediated knockdown of CaMKIIa in the NAc shell decreases the motivation for cocaine self-administration. The expression of CaMKIIa regulated by H3 acetylation in the NAc shell, is positively correlated with motivation for cocaine self-administration. The knockdown of CaMKⅡαin the NAc shell decreases the motivation for cocaine. Results indicated that the CaMKIIa regulated by acetylation of histone H3 under chronic cocaine self-administration play a critical role in the motivation for cocaine self-administration.The research above mentioned has been published in the Neuropsychopharmacology journal.2. Changes of histone acetylation and gene expression in the NAc after cue-induced cocaine reinstatement.(1) Histone acetylation is increased in the NAc core after cue-induced cocaine reinstatement. We adopted the reinstatement model of cocaine self-administration and examined the histone acetylation regulated by cue-induced cocaine reinstatement. Our results indicated that the levels of acetylation of histone H3 and H4 in the NAc core were elevated after cue-induced cocaine reinstatement.(2) Changes of gene expression in the NAc after cue-induced cocaine reinstatement. The changed genes were mainly in the NAc core and modulated by the acetylation of hisonte H3 after cue-induced cocaine reinstatement.Taken together, Our research point out the effect of histone acetylation on the stages of reinforcement and extinction of cocaine self-administration. In the present study, we explored the novel role of acetylation of histone H3 and CaMKⅡαtranscriptional activity in motivation for cocaine self-administration; Secondly, histone acetylation in the NAc core is increased after cue-induced cocaine reinstatement.. Our results indicate that the important effect of histone acetylation on drug motivation and cue extinction.