Discovering new addiction genes

By Maggie Moore

Why are certain people more vulnerable to addiction than others?

This is the question that Assistant Professor Vivek Kumar, Ph.D., is working to answer every single day, through his research on the genetics behind behavioral abnormalities like addiction.

In a TED-style talk at the Cumberland Club in Portland, ME, Kumar shared how he and his laboratory are using mouse models to research the individual differences that make people vulnerable to addiction.

“Most of us are going to use a drug with some abuse liability, but only a few of us are going to escalate drug use and become addicts,” said Kumar. “And the question that geneticists and researchers are trying to answer is, why are certain people more vulnerable than others?”

Ultimately, Kumar wants to discover how certain genetic variants change brain structure, and therefore alter brain functioning – and how these variants can be targeted for treatment.

A Chronic Brain Disease

Addiction is a chronic brain disease, said Kumar, similar to other chronic conditions like diabetes, hypertension, or kidney disease. Kumar noted three important similarities between addiction and other chronic conditions:

1. Prevalence: the prevalence of addiction – how often we see it in the American population – is in line with what we typically see in prevalence of heart disease, kidney disease, diabetes, and cancer, said Kumar.
2. Genetics: between 20% and 80% of the phenotype (a phenotype is a measurable trait like weight, height or eye color) for addiction is controlled by genetics. This is in a comparable range to chronic conditions such as diabetes or hypertension.
3. Relapse: the relapse rate of addiction is also very similar to the chronic conditions described above, but an important distinction is how we tend to view the relapse of an addict. For example, Kumar explains, a diabetic who has been on a particular treatment plan for 10 years and maintains their blood sugar properly by taking the medication may have an incident, and their blood sugar goes up. That patient would go to the doctor, who would consider 10 years of having the disease under control as a successful treatment, and adjust the medication.

However, an addict who may have a similar relapse and reinitiate drug use will often be seen as having “fallen off the wagon.” The treatment plan of 10 years – despite a decade of having the chronic condition under control - may be considered a failure. But if we think of addiction as a medical condition, said Kumar, we should consider 10 years of successful treatment as an accomplishment, adjust medication after a relapse, and reinitiate the treatment.

“I feel if we understand addiction as a neurobiological disease, just like many other mental illnesses or chronic diseases, we will take the stigma out of studying and treating addicts,” said Kumar.

The Addiction Cycle

Three key regions of the brain regulate the cycle of addiction: the basal ganglia (the “motivation/pleasure-seeking” part of the brain that releases dopamine), the amygdala (the “fight-or-flight” response part of the brain that regulates stress responses), and the prefrontal cortex (which is involved in decision-making and other cognitive processes).

“In essence, the three different regions are acting together to cause the disease, but they’re regulated by very different cell types, very different receptors, very different neurotransmitters,” said Kumar. “A person can have many different things that go wrong leading to the disease of addiction.

Because of all of these nuanced differences, personalized treatments for addiction are key. Someone who has a cortical dysfunction, resulting in multiple relapses, may require a very different type of therapy and medication than someone who has a basal ganglia deficit, for example.

“In fact, if you really want to treat someone well, you’ve got to figure out which part of this cycle is weakest in this individual, and you’ve got to then treat that,” said Kumar.

“Everyone’s addiction needs to have specific treatments. It has to be personalized. The goal of our work is to give targets that can allow stratification of patients to give better treatment.”

One Nucleotide, One Major Change

Kumar’s team found out that one nucleotide – out of 2.8 billion - in a single gene caused a difference in cocaine response between two groups of mice that were otherwise identical. One group was less sensitive to cocaine. The nervous systems of the mice in the two groups responded to the drugs differently, and their nervous systems even changed differently given the exact same dose of a drug.

When the researchers swapped the nucleotides of the mice, the change completely reversed their responses to drugs.

Kumar and his colleagues were then able to share these findings, and the new mouse models, with colleagues across the nation who study alcohol addiction, food binging, and nicotine addiction.  By sharing these mouse resources, other researchers have shown that this gene also regulates addiction phenotypes seen with these drugs. 

Looking Ahead

It’s predicted that there are hundreds of genes that regulate the process of addiction, and genetic studies in humans scientists have only identified a handful of those genes thus far.

Using the mouse as tool for discovery can be a powerful resource. Kumar’s lab has leveraged data from JAX to discover cluster of 50 novel genes with behavioral phenotypes that are  predictive of addiction. He is currently in the process of testing these genes for addiction. 

There’s so much more to discover, and the Kumar Lab has only scratched the surface.

“With this understanding, we can begin to recognize the driving factors behind addiction, and to take the scourge and the stigma off addiction as a social construct,” said Gregory Leet, JAX’s vice president for advancement. “We can begin to recognize it for the genomic issue that we have come to understand that it is through the great work of people like Vivek.”