One of the major challenges of cocaine addiction is the high rate of relapse after periods of withdrawal and abstinence. Now, new research from McGill University and Bar Ilan University reveals that changes at a DNA-based level during drug withdrawal may offer promising ways of developing more effective treatments for addiction. The data findings show that withdrawal from drug use results in reprogramming of the genes in the brain that lead to addictive personality. The study is published in the Journal of Neuroscience.
The team explain that genes are inherited from parents and these genes remain fixed throughout the person’s lifetime and are passed on to their children; there is little that can be done to change inherited adverse genetics changes. In contrast, state the researchers, epigenetic marks such as DNA methylation act as switches and dimmers of genes. These epigenetic tags can be switched on, off, or dimmed by epigenetic drugs inhibiting DNA methylation and removing methyl marks from genes.
The team state that they wanted to see if they could stop addictive behaviour by influencing the epigenetic markers that were triggered by withdrawal using epigenetic drugs such as the DNA methylation inhibitor, RG108.
The current study used a rat model of incubation of cocaine craving, in which rats were trained to self-administer cocaine which was cued by a specific light or sound. This drug craving or addictive behaviour was tested after either 1 day or 30 days of withdrawal from cocaine. Following the long withdrawal, the rats developed an intense drug seeking behaviour when exposed to the cue. It was after a lengthy period without the drugs that the epigenetic changes were most evident.
The results showed that the biggest changes in DNA methylation occurred not during the exposure to the drug but during withdrawal. During this period of withdrawal, hundreds of genes changed their state of DNA methylation including genes that previous studies have shown to be involved in addiction. The researchers state that the data findings may point to new avenues for treatment of addiction in humans.
The team surmise that the mainstay of current approaches to treating addiction might actually aggravate it. They go on to add that the current study results suggests that because the changes in addiction involve numerous genes, current approaches will continue to fail if too few genes are targeted in the brain, however, more research is needed to confirm if these new avenues hold promise.
Source: McGill University
![Regulation of chromatin remodeling by drugs of abuse. Cocaine and amphetamine increase levels of cAMP in the nucleus accumbens (NAc) and activate protein kinase A (PKA). PKA then phosphorylates cAMP-response-element-binding protein (CREB), which allows for the recruitment of the histone acetyltransferase CREB-binding protein (CBP). Examples of this are shown on the fosb and c-fos genes. Chronic cocaine or amphetamine is also known to elevate levels of ΔFosB, which can recruit histone deacetylase 1 (HDAC1) to the c-fos promoter and inhibit subsequent induction of the gene. This desensitization of c-fos also involves increased repressive histone methylation, which is thought to occur via the induction of specific histone methyltransferases. It is not yet known how cocaine regulates histone demethylases (HDMs) or DNA methyltransferases (DNMTs). Cocaine also activates the mitogen-activated protein kinase (MAPK) cascade, which through MSK1 can phosphorylate CREB and histone H3 at serine 10. In addition, stimulant drugs regulate Ca2+ levels in NAc neurons (perhaps via regulation of glutamatergic synapses from cortical regions). This activates CaMK (calcium/calmodulin protein kinase) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5. This results in nuclear export of HDAC5 and increased histone acetylation on its target genes [e.g. the NK1 receptor (also known as the neurokinin 1 or substance P receptor)]. Several other genes have been shown to display increased acetylation on their promoters after cocaine or amphetamine exposure, including cdk5, bdnf and npy. In addition, acute ethanol has been shown to reduce histone acetylation by increasing HDAC activity, whereas withdrawal from chronic ethanol increases histone acetylation by reducing HDAC activity. Epigenetic mechanisms in drug addiction. Nestler EJ. et al 2008.](https://i0.wp.com/health-innovations.org/wp-content/uploads/2015/05/cocaine-addiction-craving-and-relapse-neuroinnovations.jpg?ssl=1)
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