Not only is cocaine a highly addictive drug, but it also comes with an incredibly high chance of relapse even after someone has abstained and experienced symptoms of withdrawal. A new study is illuminating the epigenetic changes made to DNA during the withdrawal stage for those trying to rid themselves of the drug and offers new hope for more effective epigenetic-based treatments for drug addiction.
According to researchers from McGill University and Bar Ilan University, the genes found in your brain, specifically in the nucleus accumbens, may be reprogrammed following cocaine withdrawal and perhaps withdrawal from drug use in general. Their results were published recently in the Journal of Neuroscience.
Professor Moshe Szyf, from the Faculty of Medicine at McGill University, explains that the genes that we get from our parents do not change throughout our life. These genes are then inherited by our children and there is little we can do to adjust or reverse any unwanted genetic changes.
However, Professor Moshe Szyf indicates that epigenetic marks can be adjusted by certain drugs. “Epigenetic marks such as DNA methylation act as switches and dimmers of genes- they can be switched on, off, or dimmed — by epigenetic drugs inhibiting DNA methylation and removing methyl marks from these genes.”
The team of investigators set out to determine if they would be able to put a halt to addictive behavior. By adjusting the epigenetic marks that occur as a result of cocaine withdrawal, it could be possible to treat those struggling with drug addiction with epigenetic drugs. For instance, RG108 a DNA methylation inhibitor, is able to change epigenetic marks on DNA in this way. Specifically, RG108 is known as a DNA methyltransferase (DNMT) inhibitor that interacts with DNMT to inhibit DNA methylation.
Cocaine addiction in a rat model
The researchers utilized a rat model to induce cocaine craving. The team trained rats to self-administer cocaine whenever they were exposed to a certain sound or light. Similarly, humans often come in contact with cue-induced cocaine cravings, which intensify and persist over extended periods of time after withdrawal. The rats were then tested after short- or long-term (one or 30 days) cocaine withdrawal.
After long-term withdrawal, the rats aggressively sought out the drug whenever they experienced the stimulus of the specific light or sound. The epigenetic changes were even more evident after a lengthy period of time without the drugs.
Epigenetic treatment of drug addiction
Szyf indicated that the rats actually stopped seeking out the drug once they were injected with the DNA methyltransferase inhibitor RG108 just prior to their exposure to the light or sound. Not only that, but it was effective for a long time. Szyf thinks that this evidence suggests that a single treatment using RG108 could actually reverse or cure one’s addiction to drugs. Additional evidence has even demonstrated it may be capable of reducing cancer growth.
In addition, the researchers found that methyl donor S-adenosylmethionine had the opposite effect compared to RG108 in regard to cocaine-seeking behavior.
Withdrawal sets the stage for success
The most significant alterations in DNA methylation, they found, occurred during withdrawal and not during the exposure to the drug. Gal Yadid from Bar Ilan University said that, “During this period of withdrawal, hundreds of genes changed their state of DNA methylation including genes that were known before to be involved in addiction.”
New epigenetic avenues for treating debilitating drug addiction experienced by humans may be pursued in light of this research. Although this study was done using rats to model human addiction, the epigenetic effects of RG108 as a DNA methylation inhibitor has been demonstrated and the nucleus accumbens is a well-known area of the brain linked to motivation, reward, and pleasure.
The failure of current drugs
Current approaches that we use to treat drug addiction may actually aggravate it, according to Yadid. “Our research suggests that because the changes in addiction involve numerous genes, our current approaches will continue to fail if we target one or few targets in the brain, but more research is needed to confirm if these new avenues hold promise.”
Massart, R., Barnea, R., Dikshtein, Y., Suderman, M., Meir, O., Hallett, M., Kennedy, P., Nestler, E.J., Szyf, M., Yadid, G. Role of DNA Methylation in the Nucleus Accumbens in Incubation of Cocaine Craving. Journal of Neuroscience, 27 May 2015.
McGill University. Cocaine addiction, craving, and relapse. McGill Newsroom. 26 May 2015.