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Sandbox of Adilyn Voss, Patricia Tomacruz, Eric Garcia

Epigenetics of Addiction

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Drug addiction has been characterized by an alteration in physical and mental state and especially desire/craving for drugs[1]. Epigenetic changes, those that occur on the genomic level in consequence to an individual's environment, have potential to induce functional changes in health and pathology, including addiction. Studies have shown that drugs of abuse can cause epigenetic alteration in the brain: histone acetylations and histone methylations, DNA methylation at CpG sites, and changes in epigenetic regulation of microRNAs (see Epigenetics of Cocaine Addiction).

Epigenetic Modifications by Substance

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Alcohol[2]

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Both acute and chronic exposure to alcohol have the potential to induce histone acetylation, methylation and phosphorylation.

Acute Alcohol Exposure

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Acute alcohol exposure has been shown to induce changes within the epigenome via remodeling mechanisms and effects signaling cascades known to be involved in both stress and addiction. The amygdalar signaling pathway involving cyclic AMP response element binding protein (CREB) is modulated by neuronal activation and was shown to be induced following acute alcohol exposure[3]. In its active form, phosphorylated CREB (pCREB) and CREB-binding protein (CBP) were both increased within the central nucleus of the amygdala and the medial nucleus of the amygdala following acute alcohol exposure in addition to brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (Arc), and neuropeptide Y[3]. Alcohol's anxiolytic affects were shown to be modulated via a microRNA, miR-494; when consumed acutely, alcohol induced a down regulation of miR-494 in the amygdala, ultimately increasing transcription for a variety of target genes and histone acetylation[4].

Chronic Alcohol Exposure

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Consuming alcohol chronically leads to brain adaptations of which serve to counterbalance the effects of alcohol on neural circuitry, resulting in behavioral tolerance.

Cocaine

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Chronic and acute cocaine administration has been shown to alter the epigenome, resulting in changes in brain circuitry that facilitate the transition of cocaine use to abuse/dependence[5]. The gene expression alterations that are precipitated in consequence to cocaine use and/or abuse have primarily been studied in postmortem brain samples and are primarily categorized as differential transcription regulation and signal transduction. Myelin-related genes in addition to those involved in glial function were found to be altered in the NAc, specifically in the expression of PLP1. The identification of alterations in gene expression of genes relating to dopamine metabolic processes is of important note, due to cocaine's ability to block dopamine reuptake[6].

The transcription factor NFAT5 was shown to be increased in DA neurons in consequence to cocaine exposure. This alteration suggests that cocaine-induced regulation of gene expression may be mediated in some way by NFAT-dependent transcription[7]. The study of this finding also demonstrated the down-regulation of miR-9, miR-153, and miR-124 upon cocaine exposure. A gene-based association study also found these miRNAs to be associated with cocaine dependence.

Variants of Phospholipase C beta 1 protein (PLCB1) have been found in drug dependence. Specifically, an increase in PLCB1 expression was found in the NAc of canine abusers and in DA neurons treated with cocaine[8]. These findings were also expressed in studies with mice self-administering cocaine and during withdrawal[9].

Altered expression within the hippocampus of cocaine abusers was found to be induced by KCTD20, a member of the KCTD protein family[10]. KCTD20 specifically regulates AKT signaling, while the KCTD family is involved in processes including proteasome function, GABA signaling and transcription regulation.

MDMA

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MDMA is associated with inducing epigenetic changes through specific histone alterations which modify opioid gene expression regulation. Nociceptin, also known as orphanin FQ(N/OFQ), is structurally similar to dynorphin A (DYN-A), both acting as endogenous ligands for the nociceptin opioid (NOP) receptor.[11] In vivo studies revealed that MDMA treatment causes specific changes in the  dynorphinergic system of rats. A single MDMA administration elicited an increase in DYN-A and prodynorphin (pDYN) mRNA levels in the striatum and promoted pDYN down-regulation in the ventral tegmental area.[12]Showing that the response to MDMA was dependent on the brain area.

Sprague-Dawley rats, when given acute (8 mg/kg) or repeated (seven days) administration of MDMA, showed through gene expression analysis, down-regulation of the nociceptin system and up-regulation of the dynorphin (DYN) system in the nucleus accumbens (NAc). This was analyzed by chromatin immunoprecipitation (ChIP) assays, which identifies links between DNA and proteins by monitoring histone modification.[13]

Analyzing the histone acetylation patterns at the opioid gene promoter region and focusing on two prominent permissive transcription markers, acH3K9 and me3H3K4, and two repressive markers me3H3K27 and me2H3K9. Researchers have found acute MDMA exposure in rats increased permissive marker me3H3K4 at the N/OFQ and DYN promoters, while repeated treatment of MDMA reduced the other permissive marker acH3K9 at the N/OFQ promoter. Showing MDMA administration can lead to epigenetic modification through activation of the dynergergic system and inactivation of the nociceptin–a stress and anti-stress pathway respectively.[13]

Opioids[14]

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Opioid exposure, whether prolonged or given at higher doses, can have a significant influence on gene expression through several epigenetic modifications. Firstly, opioid use can affect the histones in which DNA is wound around, impacting its ability to be accessed and transcribed. There is a pattern of hyperacetylation of histone marks on the H3 proteins of histones, specifically on H3K27ac, located in the striatum; similarly, there is an increase in acetylation in certain marks of the H4 proteins in the nucleus accumbens[14]. This process of increased acetylation opens up the DNA to being transcribed more - therefore with increased or prolonged use, there will be neuroplasticity towards these behaviors, and predisposing one to addiction. Secondly, DNA methylation, which blocks gene transcription by preventing RNA polymerase II to bind to the DNA, is impacted by opioid use as well. The µ-opioid receptor gene (OPRM1) transcribes the molecular target of opioids. The promoter of this gene has a CpG island, and this region becomes hypermethylated not only with prolonged use of opioids, but at high doses as well[15]. Thirdly, opioid use affects enzymes and transcription factors involved in gene expression, therefore affecting the sequences and cascades that allow transcription to occur smoothly and uninterrupted. For example, the activity of histone deacetylase 5 (HDAC5), an enzyme that chemically alters histone tails, is downregulated, specifically in the NAc[16]. This modification increased transcription at these target genes. Similarly to increased acetylation, plasticity can be influenced by the effects of opioids on transcription factors. For example, the activator protein-1 (AP-1) mediates gene regulation and “promotes plasticity within reward regions,” and is responsible for the behavioral responses to cocaine specifically[17].

THC

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Epigenetic alterations that occur due to chronic exposure of ∆9-THC, tetrahydrocannabinol can include, but are not limited to, histone acetylation and DNA methylation, which have been prominent hallmarks shown in rats[18]. Increases in histone acetylation, especially in the NAc, also known as the mesolimbic rewarding pathway, at H3K14, supports the hypothesis that NAc histone acetylation is correlated to addiction-related behaviors like place conditioning[18] .

Histone acetylation states can alter chromatin structure by loosening or tightening the DNA, which is wrapped around a nucleosome, leaving DNA exposed for or protected from transcription inducing proteins like RNA polymerase[19]. Histone deacetylase (HDAC) allows for transcription to occur by giving slack to the DNA adhered to the nucleosome, allowing for proteins like FosB, which have been hypothesized to be crucial in addiction, to increase in production. The family of proteins called Fos, are comprised of FOS, FOSB, FOSL1, and FOSL2, and expressed transiently following acute exposure to drugs of addiction, but FosB is especially produced in the reward-related pathways of the striatum[20]. After chronic administration of drugs with abuse liability, FosB begins to be expressed with enduring effect and has incited important support for research into the long-lasting effects produced by FosB mediating relapse[2].

Histone Modifications

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Histone modification can alter chromatin structure by loosening or tightening the DNA, which is wrapped around a nucleosome, leaving DNA exposed for or protected from transcription inducing proteins like RNA polymerase[19]. Histone deacetylase (HDAC) allows for transcription to occur by giving slack to the DNA adhered to the nucleosome. This process increases the production of transcription factors, such as those included in the Fos family of proteins, which have been shown to be crucial in the mechanisms underlying addiction. The transcription factors FOS, FOSB, FOSL1, and FOSL2 are expressed transiently following acute exposure to drugs of addiction; however, FOSB is the most prevalent transcription factor found within the reward-related pathways of the striatum[20]. After chronic administration of drugs with abuse liability, FosB begins to be expressed with enduring effect and has incited important support for research into the long-lasting effects produced by FosB mediating relapse[19].

Epigenetic Transmission

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In Utero Exposure

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Many studies have identified epigenetic modifications in offspring who have been exposed to substances of abuse in utero; this is defined as transgenerational inheritance[21].

Alcohol

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Fetal alcohol exposure has been shown to cause deficits in cognitive and behavioral development; many studies have identified the epigenetic mechanisms that may contribute to these consequences induced by alcohol[22]. Altered methylation patterns in mice were observed depending on which parent was exposed to a binge-like drinking schedule. Interestingly, the most abundant hypermethylated and hypomethylated regions were observed in pups born from parents who were both exposed to ethanol[23]. Variants in genes encoding dehydrogenases, aldehyde dehydrogenases, and cytochrome P450 2E1, all of which are enzymes implicated in the metabolism of alcohol, have been observed in both mothers who have consumed alcohol and in the offspring of these mothers[24]. Folate metabolism, the pathway of which supplies methyl groups for DNA methylation, displays a reduction in bioavailability in consequence to excessive alcohol exposure[25]. In addition, DNA methylation is inhibited within the dentate gyrus, a region involved in cognitive development, upon in utero ethanol exposure[26].

Nicotine

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Studies focused on fetal exposure to nicotine have identified alterations in brain development as a consequence of maternal smoking[27]. In addition, genome-wide studies performed on cortical samples in mice found up-regulated transcription of Ash21, a gene that plays a critical role in histone methylation[28]. The authors further explored the role of Ash21 in nicotinic fetal exposure using Ash21 knockdown mice. They found Ash21 knockdowns to lack dendritic complexity typically associated with nicotine exposure.

Bibliography

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Bali, Purva, and Paul J Kenny. “Transcriptional Mechanisms of Drug Addiction.” Dialogues in clinical neuroscience 21.4 (2019): 379–387. Web.

Browne CJ, Godino A, Salery M, Nestler EJ. Epigenetic Mechanisms of Opioid Addiction. Biol Psychiatry. 2020 Jan 1;87(1):22-33. doi: 10.1016/j.biopsych.2019.06.027. Epub 2019 Jul 8. PMID: 31477236; PMCID: PMC6898774.

Feng, J.; Nestler, E.J. Epigenetic mechanisms of drug addiction. Curr. Opin. Neurobiol. 2013, 23, 521–528

Murphy, Susan K et al. “Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm.” Epigenetics 13.12 (2018): 1208–1221. Web.

Nestler, Eric J. “Transcriptional mechanisms of drug addiction.” Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology vol. 10,3 (2012): 136-43. doi:10.9758/cpn.2012.10.3.136. Web.

Nielsen DA, Utrankar A, Reyes JA, Simons DD, Kosten TR. Epigenetics of drug abuse: predisposition or response. Pharmacogenomics. 2012 Jul;13(10):1149-60. doi: 10.2217/pgs.12.94. PMID: 22909205; PMCID: PMC3463407.

Prini, Pamela et al. “Chronic Δ9-THC Exposure Differently Affects Histone Modifications in the Adolescent and Adult Rat Brain.” International journal of molecular sciences 18.10 (2017): 2094–. Web.

Sandoval-Sierra JV, Salgado García FI, Brooks JH, Derefinko KJ, Mozhui K. Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter. Clin Epigenetics. 2020 Jun 3;12(1):76. doi: 10.1186/s13148-020-00868-8. PMID: 32493461; PMCID: PMC7268244.

Sinha, Rajita. “Modeling Stress and Drug Craving in the Laboratory: Implications for Addiction Treatment Development.” Addiction Biology, vol. 14, no. 1, Jan. 2009, pp. 84–98. EBSCOhost, https://doi.org/10.1111/j.1369-1600.2008.00134.x. Web.

Wang Y, Krishnan HR, Ghezzi A, Yin JCP, Atkinson NS (2007) Drug-induced epigenetic changes produce drug tolerance. PLoS Biol 5(10): e265. doi:10.1371/journal. pbio.0050265. Web.

Wong, Chloe C. Y, Jonathan Mill, and Cathy Fernandes. “Drugs and Addiction: An Introduction to Epigenetics.” Addiction (Abingdon, England) 106.3 (2011): 480–489. Web.

References

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https://doi.org/10.1016/B978-0-12-819641-0.00089-X

https://www.sciencedirect.com/science/article/pii/S0959438819300297

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