Cocaine addiction is the use of compulsive cocaine despite adverse consequences. It arises through epigenetic modifications (eg, via HDAC, sirtuin, and G9a) and transcriptional regulation (mainly through the FosB AP-1 complex) of genes in the nucleus accumbens.
Video Epigenetics of cocaine addiction
Mekanisme transkripsi dan epigenetik
Peran inhibitor HDAC dalam kecanduan kokain
Histone deacetylase inhibitors (HDAC inhibitors) have been implicated as potential treatments for cocaine addicts. HDAC is an enzyme that can predict histones associated with genes. This can activate genes for transcription. Several experiments have shown that inhibiting HDAC involved in histone H3K9 deacetylation reduces drug-seeking behavior.
It is well known that epigenetic regulation, such as H3K9 methylation, has a key role in the mechanism of addiction. Recent research has shown that the administration of HDAC inhibitors may help reduce the desire for cocaine in mice. Trichostatin A (TsA) is a HDAC inhibitor associated with reduced cocaine-seeking behavior; it inhibits HDAC classes 1, 3, 4, 6, and 10. Because these HDAC inhibitors have a significant effect on cocaine search behavior, scientists speculate on their ability to reduce the risk of cocaine addicts to recurrence in mouse modeling systems during rehab.
After several tests in which rats were exposed to cocaine followed by HDAC inhibitors or placebo, it was found that HDAC inhibitors had a significant effect on the decline in cocaine-seeking behavior. It also shows the epigenetic mechanisms involved in HDAC chromatin regulation. Data is essential to prove the hypothesis that trichostatin A can break down the chromatin structure and prevent behavioral changes after cocaine exposure. The test also revealed that HDAC inhibitors can not only prevent addiction, but also help reduce the risk of recurrence of cocaine addicts in a mouse model system.
The role of HDAC5
As previous findings suggest, the use of chronic cocaine leads to both changes in the chromatin remodeling activity of HDAC and drug-seeking behavior. Renthal et al. a special focus on histone deacetylase class II, HDAC5, as it is known to have activity-dependent regulation on neurons. In fact, they found that HDAC5 is a central regulator of chronic cocaine use and contributes to behavioral adaptation with deacetylase activity. Chronic cocaine injections increase HDAC5 phosphorylation in Ser259 in nucleus accumbens (NAc) in 30 minutes. It provides a docking site for 14-3-3 proteins, which mediates the export of HDAC5 out of the nucleus. They also found that CaMKII was required for depolarization-induced HDAC5 induced deposition in NAc tissue, highlighting its role as a kinase for HDAC5. Experiments with the mutant proteins and HDAC inhibitors show that HDAC5 acts are mediated through the catalytic histone deacetylase domain. Rapid phosphorylation and HDAC5 exports from the nucleus after cocaine use are likely to lead to increased acetylation of pulses, targeted gene activation, and behavioral adaptation to long-term cocaine exposure.
The second experimental group rented by Renthal et al. showed that chronic cocaine use induced an increase in the regulation of NK receptor protein 1 in HDAC5 knockout mice, which was associated with H3 hyperacetylation in NK1R gene promoter. The NK1R gene promoter has been associated with increased responses to cocaine prizes, which means HDAC5 in the normal genome may decrease the gift of cocaine by exposure to chronic cocaine. They also found key pathways involved in neural plasticity and reward behavior, which include DA-receptor signaling, ATF2/CREB, NF- signaling? B, NFAT, cytoskeletal remodeling proteins, and ion channels. Their data involve chromatin remodeling as a mechanism that encourages changes in gene activation and behavioral response to cocaine. Using this they can conclude that in the normal (wild type) genome, the response to chronic cocaine includes HDAC5 phosphorylation and deacetylase exports out of the nucleus to activate the downstream target genes. Between exposure and 24 hours later, HDAC5 returned to the cell nucleus to limit the expression of this cocaine-regulated gene with histone deacetylation. Their experiments with HDAC5 knockout mice provide additional support for this hypothesis. Because HDAC5 is not there to limit gene expression, it begins to accumulate with recurrent cocaine exposure, with the end result of increased susceptibility to cocaine gifts.
Changes in critical H3K9me3 modification
Modifications to histones such as methylation and acetylation can alter gene expression patterns by enabling or deactivating a DNA region for transcription. The position of H3K9 has been shown by several studies to be altered by the use of chronic cocaine.
The observed addiction behavior of long-term cocaine users can be caused by changes in gene expression profiles in the brain reward circuit. Much of the research has focused on the active region of the gene associated with the rewards, but Maze et al. focusing on what happens to the heterochromatic region. Maze et al. shows that the heterochromatic region in nucleus accumbens (NAc), the major brain reward circuit, is significantly altered in the H3K9me3 position. Acute cocaine exposure causes a rapid increase in H3K9me3 within half an hour and decreases back to normal levels within 24 hours. Chronic cocaine exposure causes a slower increase in H3K9me3 within an hour (although it reaches the same level as the current acute) and a 50% decrease from the normal baseline level within 24 hours. This chronic exposure is proposed to reduce heterochromatization in this brain region in patients given recurrent cocaine exposure, which implies that long-term addictive behavior is affected by this epigenetic sign. They used ChIP-seq to provide supporting evidence that H3K9me3 modifications were primarily localized to intergenic areas. In this genomic area, 17 repeating element areas (SINE, LINE, LTR, etc.) experienced significant H3K9me3 status changes in chronic cocaine exposure mouse models. They used quantitative PCR to determine that from these important elements, the LINE-1 region showed a significant increase in expression levels. LINE-1 is a retrotransposon, so expressing it improperly activates the transposon to insert itself into important genes and destabilize DNA. They concluded their findings by suggesting that insertion of LINE-1 retrotransposone causes inappropriate or impaired gene expression that leads to addictive behavior.
G9a's role in change to H3K9me2 modification
Like Maze et al., Studies by Covington et al. focuses on histone modification in nucleus accumbens. They argue that the modification of H3K9me2 in this area of ​​the brain plays a role in the pathways of stress and depression. Their idea is that cocaine modifies this epigenetic sign and that it increases an addict's susceptibility to stress and depression, leading to the addictive effect of this reagent. A methyltransferase, G9a, was found to have reduced expression in the nucleus accumbens in cocaine addicts, causing reduced H3K9me2 levels. Unililized genes through acute heterochromatin acetilism express the genes involved in the BDNF-TrkB-CREB signaling pathway. This leads to an increase in downstream CREB phosphorylation in the pathway. CREB causes an increase in acetylation and dis-regulation of stress and depressive signaling pathways.
Cocaine induces epigenetic changes that cause neuronal morphology and behavioral changes. Most of the changes are related to heterochromatin disturbance caused by the reduced methylation rate in histones, ie H3K9. This reduction is mediated by G9a repression, a histone-lysine N-methyltransferase administered by? FosB. Fosb is a transcription factor caused by cocaine that accumulates in the nucleus accumbens (NAc) and acts to suppress G9a. When? FosB is expressed, G9a levels are reduced, and dimethylation levels of H3K9 are reduced in NAc. Maze et al. interested in determining how reduced rates affect cocaine user behavior. Several studies were conducted on mice and it was concluded that G9a overexpression, and thus the presence of H3K9 dimethylation, led to a decrease in preference for cocaine in mice. The researchers then looked at the nuclear volume of mice exposed to cocaine and found that the G9a down regulation increased the number of dendritic spines in the nucleus accumbens leading to increased cocaine-seeking behavior.
It should be noted that only in nucleus accumbens, G9a levels are important for cocaine addiction. Studies have been conducted where G9a and H3K9me2 levels are altered in other areas of the brain, but these other sites have no effect on cocaine-seeking behavior.
Study of gene expression in mesolimbic path
The role of sirtuin deacetylases has also been shown to play a role in mediating cocaine addiction. To determine their role, the two previously mentioned transcription factors, Fos FosB and CREB, must first be analyzed. It has been stated before that? FosB improves user behavior looking for cocaine. This is because FosB has a unique stable structure that allows it to survive and accumulate in the body. Unlike? FosB, CREB is responsible for reducing the sensitivity to cocaine causing negative symptoms during the withdrawal period. Each of these transcription factors increases the behavior of addicts who are looking for cocaine. Once a link between transcription factors has been established, researchers want to know if other genes cause addictive behavior as well and explore those who are significant markers for cocaine addiction, one of them, is the family of sirtu genes. Sirtuins are Histone deacetylases that depend on Class III NAD. Not only sirtuins deacetylate histones, but also responsible for deacetylation of tubulin, p53, and NFKB. Several studies have explored the role of sirtuins played in cocaine-seeking behavior. In one set of experiments, it was found that a significant increase in? FosB in nucleus accumbens cause? FosB binds SIRT2 promoter. This increased binding causes acetylation of H3 associated with an increase in Sir 2 mRNA. It was also found that acetylation of cocaine-induced H3 increased Sirt1 in the nucleus accumbens. Thus, the use of recurring cocaine causes an increase in both Sirt1 and Sirt2. Scientists are then interested in determining how the increase in Sirt1 and Sirt2 affects nuclear volume because it has previously shown that cocaine use repeatedly. Scientists studying Sirt1 and Sirt2 also found that these transcription factors led to an increase in nuclear volume. Therefore, it has been concluded that? FosB, CREB, Sirt1 and Sirt2 all play an integral role in cocaine search behavior.
Kumar et al. focuses on how exposure to acute and chronic cocaine affects the striatum, which is another area of ​​the brain involved in the reward and locomotor pathways. To study the molecular action of cocaine in the region, the researchers studied histone modifications from three different promoters: cFos , BDNF , and Cdk5 . They see that cFos , which is usually expressed immediately after a nerve fire action potential, has a high H4 acetylation level in 30 minutes of cocaine injection - but no histone modification is seen with chronic cocaine use. These results suggest that this promoter is activated by the use of acute cocaine and may mean that neurons rapidly regulate fire during acute cocaine exposure, but are unaffected by long-term use. BDNF has been involved as an important regulator in drug dependence, and Cdk5 is involved in the regulation of cell proliferation genes. Both of these promoters are induced by the use of chronic cocaine (hyperacetylation of H3). Changing the natural acetylation state of this promoter to acute and chronic cocaine users alters locomotor responses and prizes for cocaine. This suggests that behavioral activity observed by cocaine users can be attributed, in part, to histone modification at this promoter site.
McClung et al. discuss the CREB gene expression profiles previously mentioned and? FosB because they are involved in cocaine use. This transcription factor has been shown to play a role in short-term and long-term adaptive changes in the brain. CREB has been involved in learning, memory, and depression and enriched in cocaine users in the nucleus accumbens. CREB appears to increase many genes in its path within the brain reward area and appears to reduce the valuable effects of cocaine and lead to depressive behavior instead. Gene expression changed by CREB was induced by short-term cocaine treatment and eventually returned to normal. They also focus on? FosB, which is in the FosB protein family. While most of these proteins have been implicated in changes in short-term gene expression genes, McClung et al. show that? Changes in the expression of the FosB gene in NAc are induced by short and long-term cocaine exposure. Short-term cocaine exposure leads to the same expression profile of the regulated gene because CREB does not create the noticeable reduced beneficial effect. However, long-term exposure leads to different expression profiles leading to increased beneficial effects. They suggest that? FosB acts as a repressor and somehow interacts with the CREB pathway and indirectly leads to the same visible short-term effects, but over time, acts to increase the gene in its own path that leads to increased beneficial effects. It is not known how these two paths interact, but they have shown that there is some overlap.
Modified gene expression pathway dopamine receptor
Also involved in the CREB-Fos protein pathway is dopamine D1 receptor (DRD1), expressed in neurons in the nucleus accumbens and caudate toamen regions. Zhang et al. focuses on this receptor, as it is known to mediate the effects of cocaine. When stimulated, it increases the cAMP level, in turn leading to CREB activation. They have observed cocaine injection before causing a direct increase in the sensitivity of D1 receptors. Through the mutant mouse line the D1 receptor has also been involved in mediating both locomotor sensations and the valuable effects of cocaine. Acute cocaine injections induce c-fos and CREB expression through D1 receptors and recurrent cocaine, associated with long-lasting AP-1 transcription complex containing? FosB. Persistent? The expression of FosB in D1 receptors in nucleus accumbens led to a significant increase in the locomotor-inducing and beneficial effects of cocaine. In contrast, the increase in CREB has been shown to reduce the effects of cocaine. Zhang et al. also used microarrays to identify specific genes induced by the use of chronic cocaine, which depends on the functional D1 receptor 24 hours after the withdrawal of cocaine. There are 109 identified genes that rise or fall are set at 1.2-fold or more in C1-receptive D1 mutant mice after repeated injections. This gene expression is completely normal in mice with functional D1 receptors, suggesting the use of chronic cocaine has a direct influence on the mediation of these genes through functional DRD1 receptors. They found genes belonging to a number of functional groups, and selected six candidate genes from three of these functional groups to verify their differential expression in caucass tournaments. For each gene, researchers verified the dependence of their expression on D1 receptors after cocaine treatment using Trichostatin A or other receptor antagonists. In particular, they focus on genes that encode extracellular factors, receptors, modulators, and intracellular signal molecules. This can be regulated by the treatment of chronic cocaine through D1 receptors, and all genes contain transcriptional complex binding sites AP-1 in the promoter region. For extracellular signal molecules, they see the expression of genes IGFBP6 and SDF1. Both are induced in caudate tobacco in wild-type rats, but are attenuated in the D1-receptor mutant. This suggests that IGFBP6 and SDF1 may be induced by recurrent cocaine administration, and also that this interaction is partially dependent on functional D1 receptors.
Direct changes to functional groups
Zhang et al. has previously seen that chronic cocaine administration leads to increased dendritic branching and spinal density in middle spinal neurons and pyramidal neurons of the prefrontal cortex, which may contribute to cocaine-induced neuropathy. When investigating the receptor and modulator genes, they found that the expression of sigma receptors 1 and RGS4 was not regulated after recurrent cocaine in the DA D1 receptor mutant, suggesting functional Dopamine D1 receptors necessary for induction. These receptors have been seen to modulate the beneficial effects of cocaine, and receptor antagonists have blocked the effects of acute locomotor stimulation and decreased the sensitization of behavior. Sigma 1 receptor changes have been shown to modulate the release of dopamine, so a shift in its expression can change the behavioral response to cocaine with the influence of pre and post synaptic. They know that RGS4 protein can modulate the function of G-protein-coupled receptors, and since levels of RGS4 may increase or decrease in response to D1/D2 receptor stimulation, it may be involved in the change of signal transduction path after activation of D1 receptor from recurrent cocaine stimulation.
For genes that encode intracellular signaling molecules, Zhang et al. focuses on the Wrch1 genes. After experimentation researchers found Wrch1 was regulated by recurring cocaine injections in caucass tournaments in the D1 receptor mutant. There was no change in wild-type rats, which led them to believe that Wrch1 could inhibit cocaine-induced receptors and D1 receptors mediating behavioral changes. A key member of the Wnt signaling path ,? -cathenine, is thought to be induced by chronic cocaine (which is correct in the nucleus accumbens) but acute cocaine reduces expression in caudate tooth while chronic cocaine injection decreases expression even in NAc in the D1 receptor mutant. This line affects Wrch1, so it can also affect cocaine-induced neuroadaptations. Lastly, they found that CaMKII-? not regulated as expected, and CD2 is lowered in the D1-receptor mutant after chronic treatment. These results suggest that gene expression change is obviously caused by chronic cocaine exposure through D1 receptors and most on the AP-1 binding sites.
Changes in mesocorticolimbic system
Contrary to most studies focusing on nucleus accumbens, Febo et al. suggest that prize brain circuits are not the only systems involved in addictive behavior. Previous knowledge has suggested that stimulants induce changes in gene expression in the main part of the mesolimbic circuit (including ventral stratum area, ventral striatum/nucleus accumbens, and prefrontal cortex) and play a major role in the development and maintenance of the country's addict and chromatin remodeling. They apply this knowledge to investigate whether these gene expression changes are involved in cocaine-related behavioral and molecular adaptations. They found an unexpected pattern of brain activation in wakeful mice exposed to sodium butyrate, a HDAC inhibitor (or HDACi). Acute doses result in extensive activation of BOLD (depending on blood oxygen levels) in the forebrain and midbrain, but cocaine-induced activation is significantly attenuated after repeated exposure. Sodium butyrate co-treatment with cocaine restored pronounced BOLD activation after successive cocaine treatment. This suggests that the brain's initial response to repeated exposure to cocaine triggers a reversible desensitization mechanism with pretreatment with sodium butyrate. The neural circuit for epigenetic modification contributing to cocaine sensitivity is not limited to the mesocorticolimbic dopamine system ("reward system") as they had hoped. Instead, they see corticolimbic circuits (involved in emotion and memory) have a greater role in HDACi-related changes in reward behavior. Evidence that HDAC-mediated elevations of a stimulant's sensitization effect is a specific context, and involves associative learning.
Maps Epigenetics of cocaine addiction
Treatment
In May 2014, no pharmacotherapy was effectively approved for cocaine addiction. HDAC inhibitors have been implicated as potential treatments for cocaine addiction.
Current cognitive behavioral therapy is the most effective clinical treatment for psychostimulary addiction in general.
References
Source of the article : Wikipedia
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