Geordi Cortez-Neavel, MS

Introduction: While significant research indicates multiple external factors (e.g. trauma, environmental stressors) may upregulate genes influencing addiction, the pathways surrounding cocaine addiction are not completely understood. Genetic influences appear to consistently explain the majority of risk for cocaine addiction.^1,2 The Nucleus Accumbens (NAc), in particular, serves as the primary target for epigenetic promotion of cocaine-seeking behavior (CSB) and addiction.^3,4New research appears to elucidate the effects of cocaine use on upregulation of specific genes related to persistence of addiction, abuse, and CSB.^5-9  This review will seek synthesize the core component pathways regulating the epigenetic promotion of genes involved in cocaine addiction and CSB, in order to identify areas for possible drug therapies. However, human studies are difficult to perform given cocaine’s DEA status as a schedule 2 drug and the necessity of brain biopsy, hence this review will focus on rodent models. Methods: Five rodent studies were reviewed for findings on pathways relating to epigenetic modifications triggered by sustained cocaine self-administration (CSA). Each study ran numerous trials against controls. At the end of each trial period, rodents were euthanized before extraction of their NAc for analysis via Quantitative real-time RT-PCR. Three studies assessed Calcium Responsive Transactivator (CREST), Histones H3 and H4, as well as, genes Cdk5, Arc, Cart, NFκB, or Period 1.^5,6,8  The fourth study used tagging of histone H3.3 to clarify novel areas of the molecular cascade throughout CSA.⁷ The final study investigated the effects of potential therapeutics at histone H3 on reducing cocaine addiction relapse and recurrent CSB, after CSA.⁹ Results: Data indicates that CREST is directly involved in sustaining CSB, with a downstream increase in acetylation of H3 upon CSA.^5,6 H3 was also proven to serve as the primary site for transcription of genes Cdk5, Arc, Cart, NFκB, and Period 1, which were previously found to promote CSB and addiction.^7,8 Utilization of drug-therapies (such as HDAC3 inhibitors) that specifically target H3, reduce relapse of recurrent CSB and addiction, with stronger effects shown upon administration prior to first extinction event.⁹ Conclusion: The extant literature indicates that CREST upregulation, H3 histone acetylation, and transcription of relevant genes serve as significant milestones involved in the epigenetic regulation of CSB and addiction.^5-8 The remaining gaps in the molecular cascade, particularly relating to CREST, indicate areas for further potential research. However, the findings from studies utilizing HDAC3 inhibitors as a therapeutic show promising results in managing addictive behaviors and support further investigation of previously mentioned mechanisms as they relate to drug-therapy.⁹

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