Addiction is an incredibly powerful force that affects many people all over the world. It’s a debilitating, lifelong disease that is difficult to combat. Cocaine addiction is a particularly challenging obstacle because it’s an immediately rewarding drug, delivering a high quick and easy. This trait, paired with drug-associated cues such as location, experience, or certain people is what makes the possibility of relapsing so likely for addicts.
But what if there were other factors on a genetic level that cause such a high rate of relapse? Researchers from the University at Buffalo sought out to determine the reasons why beating cocaine addiction seems like a nearly impossible uphill battle, and why cravings continue after stopping usage. It turns out that the answer may lie within a person’s epigenetics.
In a study published in Science Advances, Drs. Craig Werner and David Dietz trained a group of rats to self-administer cocaine at different times and accessibilities, and then put them through different periods of abstinence—ranging from 1 day to 30 days. They measured the effects of cocaine addiction on the brain, particularly in the nucleus accumbens (NAc)—a crucial part of the brain’s reward system. They specifically focused on epigenetic molecules called chromatin remodelers and how addiction directly affects gene expression in the brain.
Chromatin remodeling is a process involving the rearrangement of chromatin from a condensed, tightened state to a looser, more accessible state that makes DNA available to transcription factors.
Their particular chromatin remodeling gene of interest was INO80, which regulates gene transcription by histone exchange. INO80 is a part of a complex network called the ubiquitin-proteasome system (UPS), and it is involved in mediating response to cocaine use in the NAc. UPS also helps to regulate epigenetic mechanisms like histone modification and DNA methylation.
During the first day of abstinence, there was no change in INO80 expression. By day 30 however, there was a significant increase in INO80, resulting in intensified cravings for cocaine.
The team confirmed their findings by performing chromatin immunoprecipitation (ChIP), which is an antibody-based method used to determine the locations of different DNA binding sites on the genome. They paired the ChIP with DNA sequencing, which revealed that the gene INO80 is responsible for regulating the pathway that controls the response to cocaine use in the NAc.
Dr. Werner highlights the importance of their discovery: “INO80 affects some combination of target genes”. He continues, “In the future, we want to find out which of those downstream genes are contributing to drug-craving behaviors. This would be a big first step into this really new territory of how gene expression maintains relapse vulnerability.”
In addition, they found that a gene called TRIM3 forms a complex with INO80 which regulates it’s effects by labeling it to be degraded by the cell, limiting the expression of INO80. Normally, this mechanism is responsible for curbing cravings for cocaine, but they determined that the presence of TRIM3 was drastically reduced on day 30 of abstinence, which left INO80 unregulated, thus increasing cocaine cravings.
Though the research team set the goal to determine new targets for treatment, they also wanted to further understand addiction in the brain. “Part of the problem with addiction is that we don’t know exactly what has changed in the brain,” said Dr. Dietz. “Yes, we have found a potential therapeutic target but the target itself is being modified by the addicted state. Until we have a better picture of what has changed with any one aspect of addiction, we will be stuck in terms of developing better treatments. This finding shines a light on the muddy waters of the neurobiology of addiction.”
Source: Werner C.T, Dietz D.M et al. (2019). Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving SCIENCE ADVANCES, 5(10)
Reference: University at Buffalo. “UB study reveals how drug abstinence changes gene expression, making relapse more likely”. UBNow Research News. 11 Oct 2019. Web.