Why are some people more vulnerable to drug addiction than others? Why is it possible for a person to use a drug once and be able to put it down forever, whereas another person becomes hooked and cannot stay clean, no matter how hard they try? These questions are far from being completely understood, and the answers may lie in several different factors, including environmental, societal, and genetic. Yet, understanding the interplay among these factors is difficult, since they vary from person to person. New research using an animal model, however, may shed light on these complex interactions by examining the possible epigenetic influence on drug addiction.
In a study that was published in Proceedings of the National Academy of Sciences, researchers at the University of Michigan Medical School found that differences in the expression of specific genes and epigenetic marks, particularly histone modifications, could influence an individual’s likelihood for developing addictive behaviors and a predisposition to relapse.
According to the National Institute on Drug Abuse, an estimated 22.7 million Americans needed treatment for a problem related to drugs or alcohol in 2013. Researchers are trying to find out why these individuals may be more prone to addiction than others and whether there are specific underlying genetic and epigenetic reasons. They discovered for the first time that an epigenetic histone modification, specifically histone methylation, is able to influence addictive behavior. In addition, they were the first to selectively breed rats to demonstrate that differences in gene expression in a specific brain region is connected to the rats’ likelihood for addiction.
The group of scientists investigated a specific brain region known as the nucleus accumbens core, which has been previously implicated in addiction-related behaviors. In the study, the team focused on two selectively bred rat lines that differ in temperament – high responder and low responder rats. High responder rats demonstrate behaviors similar to human addiction, such as impulsivity and novelty-induced locomotion. Low responder rats demonstrate addiction-resilient behaviors and do not engage in these behaviors as much as high responder rats. The rodents were raised for numerous generations in the U-M Molecular and Behavioral Neuroscience Institute lab belonging to the senior author, Huda Akil, Ph.D. They assessed the expression of fibroblast growth factor (FGF2) and dopamine D2 receptor (D2), two molecules that have previously been implicated in what causes the differences between the rat lines, and the epigenetic regulation of FGF2 and D2. The D2 “pleasure” receptor enables brain cells to receive brain chemical signals, specifically dopamine, which is involved in addiction.
The rats were first trained to expect to find cocaine, an incredibly addictive drug, in a particular place and “self-administer” the drug by placing their nose in a hole to receive a controlled dose. They were also taught to expect the drug when the scientists shone a light. Even the low responder rats learned to take the drug. The difference, however, was in the way the two types of rats repeatedly sought out the drug, in other words, their addictive behavior. The high responder or addiction-prone rats were significantly more likely to continue searching for cocaine even when the researchers stopped providing it.
“Because we had access to these rats that were bred for certain traits, and were able to control for environmental factors, such as the amount of drug exposure, we could assess differences in the brain both before and after the rats became addicted,” said Shelly Flagel, Ph.D., lead author of the new study and an assistant professor of psychiatry at U-M. “By studying their gene expression and epigenetics, as well as their response to drug availability and drug-related cues, we can link these differences in the brain to addiction-like behaviors, such as relapse. This allows us to hone in on the biology of addiction even further.”
At the outset, compared to the addiction-prone rats, the addiction-resilient rats had “lower FGF2 mRNA levels and an increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter.” This genetic and epigenetic difference between the rat types persisted even after the rats self-administered the cocaine. The addiction-prone rats, on the other hand, had lower D2 mRNA levels and a “greater association of H3K9me3 at the D2 promoter”, which did not persist after cocaine self-administration. The low D2 mRNA levels in the area of the rats’ brains were likely mediated by this epigenetic modification, according to the researchers, which “may render individuals more susceptible to cocaine addiction.”
Overall, this histone modification, H3K9me3, was more likely to be carried by the addiction-prone rats, which kept their brain cells from reading the gene for D2 receptors. Histone modifications play a role in chromatin structure and gene expression and histone methylation involves the addition of a methyl group to histone proteins. Although histone methylation can be associated with either transcriptional repression or activation, the epigenetic mark H3K9me3 is well-characterized as a mark of transcriptional repression.
After the addiction-prone rats became addicted following self-administration of cocaine, they were found to have levels of D2 similar to the addiction-resilient rats. These addiction-prone rats were also more likely to relapse to addictive behavior after the cocaine was removed for a period of time as a result of the suppressive epigenetic tag. After a month without the drug, the addiction-prone rats were much more likely to seek out cocaine when the light previously associated with receiving the drug came on again. Similarly in humans, this craving is often reported by those trying to recover from addiction when they are exposed to drug-related items or locations that they associate with using the drug.
The evidence gained from this rat model could be used to improve our understanding of addiction from a human perspective. Flagel hopes that options for treatment and drug-related public policy can improve as a result of unveiling the biological basis, particularly in regard to genetics and epigenetics, which may be passed on through the generations or perhaps increased after taking drugs.
“It is likely that the propensity to seek drugs and become addicted to them involves numerous genes. Moreover, factors beyond novelty-seeking including stress and depression can lead to substance use in some individuals,” Akil said.
The researchers are now utilizing broad-based genotyping to identify various genes that may contribute to drug abuse and addiction. Potential biomarkers and novel epigenetic influence may help progress us towards targeted treatment therapies and strategies for substance use disorders.
Source: Flagel, S.B. Chaudhury, S., Waselus, M., Kelly, R., Sewani, S. Clinton, S.M., Thompson, R.C., Watson, S.J., Akil, H. (2016). Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model. Proceedings of the National Academy of Sciences, early edition.
Reference: University of Michigan Health System. Who gets hooked on drugs and who stays clean? Study in rats finds genetic markers that influence addiction. University of Michigan. 27 Apr 2016. Web.
