DNA Methylation Dynamics and Cocaine in the Brain: Progress and Prospects

Vaillancourt, Kathryn; Ernst, Carl; Mash, Deborah C.; Turecki, Gustavo

doi:10.3390/genes8050138

Cited by 39 publications

(23 citation statements)

References 100 publications

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“…GADD45B contains two LXXLL motifs, domains that are commonly found in other transcriptional coactivators and appear to be required for GADD45B to act as a transcriptional regulator [57]. Several prior reports have revealed locus-specific changes in DNA methylation following cocaine experience [20], as well as a global decrease in NAc methylcytosine following cocaine selfadministration and reinstatement [14]. Here, we examined DNA methylation profiles using RRBS following Gadd45b knockdown in striatal neurons.…”

Section: Ieg Action and Transcriptional Dynamics Of Gadd45bmentioning

confidence: 99%

Regulation of dopamine-dependent transcription and cocaine action by Gadd45b

Zipperly

Sultan

Graham

et al. 2020

Neuropsychopharmacol.

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Exposure to drugs of abuse produces robust transcriptional and epigenetic reorganization within brain reward circuits that outlives the direct effects of the drug and may contribute to addiction. DNA methylation is a covalent epigenetic modification that is altered following stimulant exposure and is critical for behavioral and physiological adaptations to drugs of abuse. Although activity-related loss of DNA methylation requires the Gadd45 (Growth arrest and DNA-damage-inducible) gene family, very little is known about how this family regulates activity within the nucleus accumbens or behavioral responses to drugs of abuse. Here, we combined genome-wide transcriptional profiling, pharmacological manipulations, electrophysiological measurements, and CRISPR tools with traditional knockout and behavioral approaches in rodent model systems to dissect the role of Gadd45b in dopamine-dependent epigenetic regulation and cocaine reward. We show that acute cocaine administration induces rapid upregulation of Gadd45b mRNA in the rat nucleus accumbens, and that knockout or site-specific CRISPR/Cas9 gene knockdown of Gadd45b blocks cocaine conditioned place preference. In vitro, dopamine treatment in primary striatal neurons increases Gadd45b mRNA expression through a dopamine receptor type 1 (DRD1)-dependent mechanism. Moreover, shRNA-induced Gadd45b knockdown decreases expression of genes involved in psychostimulant addiction, blocks induction of immediate early genes by DRD1 stimulation, and prevents DRD1-mediated changes in DNA methylation. Finally, we demonstrate that Gadd45b knockdown decreases striatal neuron action potential burst duration in vitro, without altering other electrophysiological characteristics. These results suggest that striatal Gadd45b functions as a dopamine-induced gene that is necessary for cocaine reward memory and DRD1-mediated transcriptional activity.

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Section: Ieg Action and Transcriptional Dynamics Of Gadd45bmentioning

confidence: 99%

Regulation of dopamine-dependent transcription and cocaine action by Gadd45b

Zipperly

Sultan

Graham

et al. 2020

Neuropsychopharmacol.

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“…Methylation of multiple CpGs in an island, via enzymes such as DNA methyltransferases (DNMTs), can result in the stable silencing of gene transcription. In contrast, cytosine methylation within the gene body can promote gene expression [102]. Interactions with other proteins is necessary to produce DNA conformational changes.…”

Section: Dna Methylationmentioning

confidence: 99%

Environmental, genetic and epigenetic contributions to cocaine addiction

Pierce

Fant

Swinford-Jackson

et al. 2018

Neuropsychopharmacol

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Decades of research on cocaine has produced volumes of data that have answered many important questions about the nature of this highly addictive drug. Sadly, none of this information has translated into the development of effective therapies for the treatment of cocaine addiction. This review endeavors to assess the current state of cocaine research in an attempt to identify novel pathways for therapeutic development. For example, risk of cocaine addiction is highly heritable but genome-wide analyses comparing cocaine-dependent individuals to controls have not resulted in promising targets for drug development. Is this because the genetics of addiction is too complex or because the existing research methodologies are inadequate? Likewise, animal studies have revealed dozens of enduring changes in gene expression following prolonged exposure to cocaine, none of which have translated into therapeutics either because the resulting compounds were ineffective or produced intolerable side-effects. Recently, attention has focused on epigenetic modifications resulting from repeated cocaine intake, some of which appear to be heritable through changes in the germline. While epigenetic changes represent new vistas for therapeutic development, selective manipulation of epigenetic marks is currently challenging even in animals such that translational potential is a distant prospect. This review will reveal that despite the enormous progress made in understanding the molecular and physiological bases of cocaine addiction, there is much that remains a mystery. Continued advances in genetics and molecular biology hold potential for revealing multiple pathways toward the development of treatments for the continuing scourge of cocaine addiction.

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“…Alteration in signalling pathways, genetic variations and environmental factors including epigenetic modifications may play a critical role in the development of opioid addiction and individual-specific response to maintenance pharmacotherapies 77–79. Chronic exposure to higher doses of opioids is significantly associated with hypermethylation in the promoter region of OPRM1 gene that may impede gene expression and consequently result in reduced µ opioid expression in human reward regions 33,78,80.…”

Section: Medication Strategies For Opioid Addictionmentioning

confidence: 99%

<p><em>OPRM1</em> A118G Polymorphisms and Its Role in Opioid Addiction: Implication on Severity and Treatment Approaches</p>

Taqi¹,

Faisal²,

Zaman³

2019

PGPM

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The epidemic of opioid addiction is shaping up as the most serious clinical issues of current times. Opioids have the greatest propensity to develop addiction after first exposure. Molecular, genetic variations, epigenetic alterations, and environmental factors are also implicated in the development of opioid addiction. Genetic and epigenetic variations in candidate genes have been identified for their associations with opioid addiction. OPRM1 nonsynonymous single nucleotide polymorphism rs1799971 (A118G) is the most prominent candidate due to its significant association with onset and treatment of opioid addiction. Marked inter-individual variability in response to available maintenance pharmacotherapies is the common feature observed in individuals with opioid addiction. Several therapies are only effective among subgroups of opioid individuals which indicate that ethnic, environmental factors and genetic polymorphism including rs1799971 may be responsible for the response to treatment. Pharmacogenetics has the potential to enhance our understanding around the underlying genetic, epigenetic and molecular mechanisms responsible for the heterogeneous response of maintenance pharmacotherapies in opioid addiction. A more detailed understanding of molecular, epigenetic and genetic variants especially the implication of OPRM1 A118G polymorphism in an individual may serve as the way forward to address the opioid epidemic. Personalized medicine, which involves developing targeted pharmacotherapies in accordance with individual genetic and epigenetic makeup, are required to develop safe and effective treatments for opioid addiction.

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DNA Methylation Dynamics and Cocaine in the Brain: Progress and Prospects

Cited by 39 publications

References 100 publications

Regulation of dopamine-dependent transcription and cocaine action by Gadd45b

Regulation of dopamine-dependent transcription and cocaine action by Gadd45b

Environmental, genetic and epigenetic contributions to cocaine addiction

<p><em>OPRM1</em> A118G Polymorphisms and Its Role in Opioid Addiction: Implication on Severity and Treatment Approaches</p>

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