Genetic Markers for Addiction in Rats
Practitioners often have a difficult choice: try to manage the risks of addiction associated with certain pain medications, or try to find alternative treatment options. However, if doctors were able to screen patients for a genetic risk of addiction before prescribing medication, it would reduce the risk of exposing a patient to a potentially dangerous medication.
“In the past, the clinical literature was clear that people are very different in how they respond to abused substances—all we have to do is look at exposure to alcohol, where so many drink but only a small proportion become alcoholics,” Huda Akil, PhD, co-director and research professor at the University of Michigan, told Practical Pain Management. "However, much of that research focused on how the brain reacts to drug exposure, not so much on what makes it vulnerable to drug addiction."
Now, researchers are delving into the genetic and neural underpinnings of addiction. In a new study published in PNAS, researchers out of the University of Michigan may have pinpointed specific markers for addiction vulnerability, details that could reveal many insights about what impacts a patient’s trajectory towards substance use, addiction, and relapse.
New Insight Through Selective Rat Breeding
The study relied on using experimental rats, selectively bred over dozens of generations to be more or less prone to addiction. This selective genetic breeding has been a mainstay focus for Shelly B. Flagel, PhD, lead author of the recent study and principal investigator at The Flagel Lab at the University of Michigan’s Molecular and Behavioral Neuroscience Institute.
During this breeding process, Dr. Flagel and her team split the rats into 2 specific types: bred high-responder (bHR) and bred low-responder (bLR) rats. The bHR rats have several traits related to addiction, such as being more impulsive, aggressive, and novelty-seeking.1,2 This “sensation-seeking” behavioral trait has been of interest for decades,3 since it shows that some rats will readily self-administer drugs if given the opportunity, something eerily parallel to human behavior.
“What’s most valuable about these animal studies is that we have complete control over the rats’ environment, and in this case we had complete control over their genetics, so we selectively bred them based on their traits,” Dr. Flagel, told Practical Pain Management. Because of this selective breeding, the researchers have been able to gain insight into the neurobiological antecedents of addiction, many of which exist in a region of the brain called the nucleus accumbens core.4,5
Genetic and Epigenetic Markers of Addiction
Two specific molecules—fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2)—could play significant roles in the genetic and epigenetic factors that influence addiction.6-8 Past studies have shown these molecules are expressed differentially in bLR and bHR rats.1,9 A specific mark of transcriptional repression called H3K9me3 located at the FGF2 is of particular interest because bHR rats seem to have lower levels of H3K9me3 in the brain, something that can be influenced by administering FGF2 early on in the rats’ lives.10,11
In this new study, the researchers conditioned bLR and bHR rats to self-administer cocaine at an equal rate. Once the cue light was removed, the absence of a drug signal seemed to control the bHR rats’ behavior greatly, as they would only take half the amount of cocaine infusions per minute, compared to bLR rats, which didn’t change their behavior at all.
High-responding rats also showed far more drug-seeking behavior, particularly when the cocaine wasn’t available following an extended period of time of receiving the drug. These same rats were more susceptible to drug-induced reinstatement as well, a surrogate for drug relapse.12,13
The brains of bHR rats also showed much higher FGF2 mRNA levels relative to bLR rats, as well as lower levels of the repressive mark H3K9me3 at the FGF2 promoter.14,15 However, it didn’t appear like these factors affected addiction behavior, but rather that low levels of FGF2 expression could be a protective factor, noted the researchers. It could serve to explain why some people seem almost immune to addiction despite having prolonged exposure to addictive substances.
Future Screening for Addiction
An obvious limitation of the research is the use of only cocaine as the addictive agent. In a clinical setting, doctors deal with other addictive substances, such as opioids.
“What we do know is that for the most part in animals and rats, animals will self-administer almost all of the drugs that are abused in humans,” said Dr. Flagel. However, since opioids act differently than psychostimulants like cocaine, "it’s difficult to put these findings in the context of opioid abuse," she noted.
“But it’s definitely something that we should pursue in the future because obviously opiates are becoming more and more of a problem than other drugs to abuse in other categories these days and it’s definitely something everyone’s pushing to learn more about,” she added.
It’s hard to say if there is a “million dollar marker” that would allow doctors to unequivocally predict a patient’s propensity for addiction. However, epigenetics is a burgeoning new topic, one that has started to break open promising new insights.
The research is currently also ongoing, in parallel with a number of global genetic analyses and other combined studies, which may lead to findings in many other areas, including anxiety and mood disorders.
As to whether neurobiological role-players like FGF2 and D2 receptors could become future treatment targets for suppressing addictive responses to medications is still lofty speculation, though.
“It’s a bit more tricky than administering an agonist or antagonist,” said Dr. Flagel. However, progress is developing in this area. “There are definitely drugs being developed preclinically that we’ve been able to get our hands on to alter the functionality of certain epigenetic markers, but we have yet to be able to do it specifically for a specific gene promoter.”