Epigenetic Mechanisms on Drug Addiction

1 Epigenetic Mechanisms on Drug Addiction Abstract Drug addiction results from the compulsion to seek and abuse drugs even in the presence of negative side effects. Current understanding of drug and substance abuse in addiction and relapse after successful abstinence has been linked to epigenetic modifications, which impacts gene expression. These modifications are involved in the translation of environmental factors into changes in genetic expression. These changes in gene expression impact the brain's reward circuitry, which contributes to the development and tenacity of addiction by inducing pathological drug seeking and use behavior. This discussion explores the epigenetic mechanisms that contributes to addiction, including DNA methylation, the role of non-coding RNA and various histone modifications such as histone acetylation, methylation and phosphorylation. The processes by which these epigenetic mechanisms result in drug addiction will expound based on their specific impact on the translation process. From this, it is evidenced that epigenetic mechanisms are the major drivers in addiction development, providing a critical understanding of addiction that can be utilized in designing effective therapeutic approaches to drug addiction.

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2 Introduction Drug addiction is a behavioral psychiatric condition that compels vulnerable individuals to seek and abuse despite their negative side effects. Drug addicts find it hard to stop using drugs even after successful treatment. After clinical treatment, most of them relapse, suggesting a lifelong behavioral change induced by drug abuse. Whereas there is no clear understanding as to what delineates recreational drug use and drug addiction, it is clear that epigenetic mechanisms are involved in causing changes in gene expression, with drug addicts exhibiting the addiction genotype.

Epigenetic mechanisms are understood as changes in gene expression that can be inherited through the meiotic or mitotic cell division process. Often, this does not cause any change in the DNA sequence. Epigenetic mechanisms contribute immensely to drug and substance abuse, with substantial evidence available to prove their involvement in drug addiction (Beayno et al., 2019).

Understanding these mechanisms and how they contribute to drug addiction is important in designing effective ways to prevent and treat drug addiction.

Environmental factors are believed to be greatest influencer in the expression of epigenetic gene expression in individuals. In drug addiction, the interaction of genetic, environmental factors and biosocial factors is thought to prolong abuse and eventually lead to addiction. The way different genotypes are able to interact with the environment and cause epigenetic change is still unclear. Nonetheless, understanding the epigenetic mechanism helps put back chronic addiction that persists even after treatment.

Over the years, several advancements have been made to understand the involvement of epigenetics in drug addiction. This includes the mechanisms through which epigenetics leads to altered transcription and consequently gene expression. The same way, an understanding of the

3 transition between recreational drug use to chronic addictive state is important in preventing addiction and designing effective therapeutic approaches to address addiction. It is known that an attempt to abstain from prolonged drug use is largely futile because of relapses and withdrawal symptoms (Werner et al., 2020). An understanding of epigenetic modifications at this state provides an explanation to relapses in abstinence.

This discussion will explore the epigenetic mechanisms involved in drug addiction, providing details on epigenetic changes related to histone modifications and DNA methylation. It goes further to explore how these modifications contribute to drug addiction by exerting changes in the transcription process. Questions relating to the epigenetic modifications in drug addiction, mechanisms of addiction and reasons for the persistence of the addictive state will be tackled.

Understanding these processes is essential in demystifying drug addiction as well as designing effective approaches to treating and managing drug addiction.

Discussion Understanding the mechanisms of addictive disorder will help create ways to reduce, stop and reverse incidences of addiction, and prevent relapses after abstinence. This makes it important to explore the epigenetic changes and mechanisms in the brain that contribute to addiction. Ideally, several epigenetic mechanisms are involved in creating significant phenotypic changes that impact the brain's functionality and is evident through the development of addictive behaviors.

Mechanisms of Addiction Addiction is a form of dependence that occurs when the use of a drug for recreational purposes is surpassed and becomes a need. An individual's desire to compulsively abuse drugs can be explained through neurobiological changes that come with continual use causing

4 addiction by activating the abnormal reward circuitry. The continual use of illicit and licit substances affects the brain’s reward circuits in varied ways. In the case of drug and substance use, it possibly induces changes in the genetic expression of various brain reward circuitry, including the prefrontal cortex (PFC), ventral tegmental area (VTA) and nucleus accumbens (NAc) (Walker & Nestler, 2018). Consequently, these changes in gene expression contribute to dependence and addiction.

Addiction does not occur after a single exposure to a drug or substance. Rather, chronic and continual exposure is required for significant change in gene expression. Considerable changes in the brain evidence the transition between exposures to addiction or relapses after abstinence. This includes abnormal transcription of some factors such as FosB in the development of addiction and altered expression of specific genes such as the brain-derived neurotrophic factor (BDNF) and activator of G-protein signaling 3 (AGS3) in relapses (Stewart et al., 2020). Therefore, it is apparent that the brain’s reward region regulates the epigenetic mechanisms thus playing a role in addiction.

Epigenetic Mechanisms Epigenetic mechanism involves the process that results in the expression of a heritable phenotype that is not coded by the DNA but through cellular processes (Beayno et al., 2019).

Several studies have associated this change in phenotypic gene expression with changes in the chromatin structure (Hamilton & Nestler, 2019). The chromatin structure consists mainly of the DNA material wrapped around histone proteins. The histone protein is basically an octamer containing eight protein complexes, which are two copies of H2A, H2B, H3 and H4 core histone proteins, found at the center of the nucleosome core particle. Both the DNA and the histone proteins take part in regulating the transcriptional process hence gene expression. Post-

5 translational modifications of the DNA and the histones are what regulate the structure of the chromatin and thus, the access to its DNA sequence (Browne et al., 2020). The modifications, which include histone acetylation, methylation and phosphorylation and methylation of DNA therefore impacts the transcriptional activity of the underlying gene. This occurs at the accessible histone tails, controlling the DNA-histone interaction thereby influencing the genetic outcomes of transcription (Bastle & Neisewander, 2016).

Histone Acetylation Most studies have explored the role of histone acetylation in drug-induced epigenetic changes.

Histone acetylation is essential in facilitating gene transcription by reducing electrostatic tension between the DNA molecule and the histone, thus opening up the chromatin and making it accessible for transcription (Nestler & Lüscher, 2019). This takes place in histones H3 and H4.

Increased acetylation has been associated with promoting gene activation whereas decreased acetylation reduces gene expression. Acetylation also regulates the cyclic-AMP responsive– element-binding (CREB) protein which modulates gene transcription by binding on specific DNA sequences.

In drug abuse, acute exposure causes increased histone acetylation in histone H4 gene promoters. Continual exposure to drugs enhances acetylation at histones H3 and H4 which consequently makes the chromatin more accessible and increases gene expression. Basically, histone acetylation contributes to drug addiction by remodeling the chromatin (Walker & Nestler, 2018). For heroine drug users, hyper acetylation changes in histone H3 was found to correlate with the period of heroin use. In cocaine users, acute use has been associated with hyperacetylation of histone H4 whereas chronic use increases acetylation at histone H3.

6 Increased acetylation in cocaine users was also found to have an effect on the rewarding circuitry of the brain, hence the behavioral tendency to seek cocaine and consequential addiction.

Histone Methylation Histone methylation exists in three different states; dimethylation, monomethylation and trimethylation, with each state being capable of producing distinct effect on the transcription process. Each histone methylation has unique effect on gene activation and expression.

Essentially, methylation activated or represses gene transcription causing either an increased or decreased gene expression (Hamilton & Nestler, 2019). This is dependent on the amino acid or lysine residue involved in methylation. For example, gene repression has been linked to the H3K27 lysine residue whereas H3K4 lysine residue has been found to activate genes.

The role of histone methylation in drug addiction has not been well studied as acetylation.

Current understanding of histone methylation in drug abuse is hugely based on animal studies, which have evidenced that DNA methylation causes changes in gene expression in vivo. Drugs, alongside other stimuli, have been associated with this change in gene expression by regulating histone methylation (Nestler, 2014).

Histone Phosphorylation Histone phosphorylation influences gene expression by relaxing the chromatin, thereby reducing their affinity to the DNA. Histone phosphorylation is achieved by neutralizing positive charges on histone proteins causing the reduction in DNA-histone affinity. This increases the DNA permissiveness to transcription thus activating the transcriptional process (Browne et al., 2020).

Phosphorylation can occur at different sites of the histone protein. At the H3, it antagonizes the repressive modification of amino acids through the methylation process.

7 Similar to methylation, histone phosphorylation in drug addiction has not been well explored.

However, it is largely associated with activating the gene. Histone phosphorylation potentiates gene activation at histone H3K9 alongside acetylation (Kim et al., 2017). As demonstrated through the exposure to cocaine, regulation of histone phosphorylation by protein kinases alters brain response (Nestler, 2014). This contributes to the behavioral changes seen in substance abuse which links phosphorylation to the regulation of brain function.

DNA Methylation DNA methylation refers to the addition of a methyl group onto the C5 position of the cytosineguanine dinucleotides (5mC). This process is important in cell differentiation and the inactivation of the x-chromosome. It produces a repressive effect on the transcriptional process when it occurs on promoter genes (Brown & Feng, 2017). DNA methylation blocks RNA polymerase II preventing its gene transcription. In other instances, DNA methylation activates the transcription process. This occurs in methylation of the cytosine 5-hydroxymethylation of cytosine (5hmC). DNA methylation greatly influences gene expression by initiating gene silencing (Anderson et al., 2019).

In drug abusers, DNA methylation is increased depending on the period of drug abuse. Heroin users have been found to have elongated DNA methylation as well as higher levels of methylation. Long term exposure to opioid painkillers and heroine have been found to cause increased methylation at the mu OR gene and the methyl CpG binding protein 2 (MeCP2 protein) (Brown & Feng, 2017). Changes exerted on the MeCP2 protein result in behavioral changes in drug abuse and control the expression of the BDNF gene in cocaine abusers.

However, there is no determined linkage to the reward system and behavioral change associated

8 with the levels of gene expression, warranting further studies on the contribution of DNA methylation in drug addiction (Nestler & Lüscher, 2019).

The Role of Non-Coding RNA Both long non-coding RNAs and short, non-coding Micro-RNAs regulate gene expression after the transcription process alongside epigenetic mechanisms. Histone modifications and DNA methylation impact gene expression of the non-coding RNA through epigenetic regulators such as DNA methyltransferases and histone deacetylases (Duempelmann et al., 2020). The same way, micro RNAs control the expression of these regulators, creating an epigenetics–miRNA controlled circuit (Kenny, 2014). Any disturbance caused on this circuitry interferes with normal physiologic functioning. Drug dependence and addiction are associated with up and down regulation of the micro RNA, impacting the reward system (Yao et al., 2019). Drug-induced alterations on the micro-RNA have been shown to affect addiction models such as the glutamate receptor subunits, dopamine transporter and FosB. The Role of Epigenetic Mechanisms in Drug Addiction Drug addiction results when an individual compulsively seeks and uses drugs, causing pathological consequences. Drug addiction is chronic and relapses, making it hard for an individual to break away from the habit. Genetic modifications play a great role in the development of addictive behaviors, explaining the relapses even after successful abstinence (Werner et al., 2020). Histone modifications and other epigenetic mechanisms influence gene expression, thus contributing to behavioral changes depicted in addiction. Basically, new behaviors are adapted in response to environmental influences, characterized by repetitive and persistent behavior (Heinz et al., 2019).

The Process of Addiction

9 The development of addiction is characterized by the transition from recreational use to dependency and incontrollable urge to abuse drugs. During recreational use, memories are created based on cues such as drug use, social influences, and temporal cues that widen with every use (Norouzitallab et al., 2019). Eventually, a person develops powerful drug cravings every time they interact with these cues. The cue-drug association is dependent on such memory and eventually compels one to addiction. Epigenetic mechanisms mediate the memory process, thus playing a role in the development of addiction.

The memory process involves encoding, consolidating and retrieving cues. At first, cues are encoded based on the user's environment and consolidated into a memory which is later retrieved in the presence of a drug-related cue (Henikoff & Greally, 2016). The memory is associated with a rewarding or learning circuitry within the first exposure. Subsequent interactions between the cue and the drugs become the foundational basis of the memory. Any exposure to the cue and drugs evokes cravings, increasing its consumption, leading to tolerance, withdrawal and finally addiction (Henikoff & Greally, 2016).

Epigenetics in Addiction As mentioned, epigenetic modifications make the chromatin accessible, hence activating or repressing the transcription of particular genes. By regulating gene expression, the physiological state and functioning are also altered. The role of epigenetic mechanisms has been largely experimented in animal models, providing insights into the environment's interactions, genetic and the resulting addiction. Most studies have established that epigenetic mechanisms translate environmental signal into the transcriptional process, hence causing gene expression changes (Feng, 2017).

10 Methylation and phosphorylation processes result in a repressed histone state, limiting the chances of abnormal DNA code alteration. Other studies have also demonstrated that methylation results in activated gene transcription state similar to other epigenetic modifications such as acetylation. Nonetheless, the modifications contribute to the expression of diverse behaviors and diseases including drug addiction. This is influenced by the impact the epigenetic mechanisms have on the chromatin structures.

The chromatin has three states; open, intermediate and closed. At these stages, they are accessible, intermediate or inaccessible respectively. Acute drug exposure to drugs leads to reversible change characterized by an increased histone acetylatransferases and acetylation hence increased DNA accessibility which promotes learning and memory-related gene transcription (Walker & Nestler, 2018). With continual exposure to drugs, the changes in the chromatin become less reversible. This deregulates histone enzymes, transcription factors and the entire transcription process. Histone modifications occurring at this point have a greater influence on behavior and functionality, which also shifts regulation of gene transcription from learning and memory to adaption. At this point, the chromatin state is altered, making it accessible to altered gene regulation. This change leads to increased tolerance and maladaptive behavior, which are some of the significant factors associated with addiction (Feng, 2017).

The alterations resulting in addiction result in deregulation of gene regulation, which is largely irreversible. Abstinence from drug use results in brief and reversible change characterized by increased histone methylation and histone deacetylases hence reduced DNA accessibility and gene transcription. This attempt to balance an already deregulated transcription hence causes withdrawal symptoms, forcing one to relapse back to addiction (Werner et al., 2020). Sustained abstinence without any relapse finally results in a closed chromatin state, rebalancing the

11 deregulation. Histone enzymes repress and gene transcription, through positive feedback mechanism, attempts to correct the epigenetic changes caused by addiction. Normal and highly regulated gene transcription can be finally achieved with long term abstinence, hence rebalancing the effect of deregulation caused in addiction.

Future Research The current evidence on epigenetics and their impact on gene regulation and subsequent involvement in drug addiction indicates a better understanding of epigenetic mechanisms in addiction. However, most of these researches are conducted in rats and animal models hence their limitation. Epigenetic changes are often specific to tissue type and cell type, hence can be different in humans. This may require the study of post-mortem human brain and epigenetic related changes for precise understanding of its role in addiction.

Furthermore, there is need to understand how demographics impact the epigenetic mechanisms.

Less has been explored in terms of age and sex, and how these factors interact with environmental exposures in the development of epigenetic changes in addiction. The same way, most drugs of addiction have not been utilized in the study of epigenetic changes. In most instances, drugs such as cocaine, opioids, and heroin take most of the studied drugs in addiction, oblivious that other drugs of addiction exist and could have different impact on epigenetics or mechanisms of causing addiction. This has contributed to recent attempts in understanding epigenetic mechanisms in alcohol addiction among others.

There is also need to understand the epigenetic changes that occur outside drug addiction and potentially lead to altered chromatin state. For example, long lasting histone methylation caused by depression in rat models. Understanding these changes, how they compare or differ with

12 changes in addiction and how they interact is important in understanding the behavioral impact of epigenetic mechanisms.

Conclusion Epigenetic mechanisms involves the change in genetic expression that are inheritable but do not result in changes within the DNA sequence. Essentially, epigenetic mechanisms are beneficial in cell proliferation and general human development. However, the disruption of normal epigenetic mechanisms results in potentially harmful conditions, as seen in the development of drug addiction. Through epigenetic studies, ways in which epigenetic modifications contribute to the development and persistence of drug addiction have been understood. Frequent exposures to drug substances result in epigenetic modifications that alters gene expression through activation or repression. Histone modifications, DNA methylation and microRNA, are majorly involved in influencing the change in gene expression by impacting the transcriptional process, which eventually causes behavioral changes depicted in addiction.

Understanding epigenetic mechanisms in addiction provides a strong basis for the formulation of better diagnosis, treatment and prevention of drug addiction. It can also be utilized in mediating the progression from recreational drug use to addiction.

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