She Studies How Addiction Hijacks Learning in the Brain
Erin Calipari, an addiction researcher at Vanderbilt University, works to understand how drugs alter learning circuits in the brain.
Laura Partain for Quanta Magazine
Introduction
Erin Calipari comes from a basketball family. Her father, John Calipari, has coached college and professional basketball since 1998, leading six teams to the NCAA Final Four, and her brother coaches men’s basketball at Vanderbilt University in Nashville, Tennessee, where she now works. But when she joined her college team as an undergraduate, she realized her strengths lay elsewhere. “I was fine. I wasn’t great,” she said. “It was pretty clear to me a couple years in that it was not a career path.”
Off the court, as a biology major she gravitated toward hormones and neurotransmitters. She grew fascinated with the neurobiology of how and why drugs such as cocaine and opioids are addictive, as she learned about the effects of ecstasy on the serotonin system. “I thought drugs were so cool because they hijack the brain,” she said. “Drugs essentially take the normal systems we have in our body and drive them in a way that makes you want to take drugs again.”
After pursuing graduate work in neuroscience, in 2017 Calipari set up her lab at Vanderbilt to explore how addiction is connected to the ways the brain learns and makes decisions. “Deciding what to do and what not to do is really fundamental to everything we do,” Calipari said. “You put your hand on a hot stove, you learn really quickly not to do that again.” Addiction can diminish a person’s ability to learn that drug use is hurting them, and also their ability to learn anything at all.
Her world still collides with sports, for instance when she gives talks to athletes about the dangers of substance use. Athletes can be vulnerable to addiction when they are prescribed pain medicines, such as opioids, for injuries. There is a risk of dependence if opioids are taken for long periods of time, even when patients follow doctors’ orders — a fact that has led to a nationwide public health emergency. Tennessee is an epicenter of the opioid epidemic. In 2022, Nashville had the second-highest rate of overdose deaths in the country.
Addiction is challenging to study because it shows up differently in different people: Even which neural pathways rewire vary from person to person.
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Calipari therefore leads research to unravel the mechanisms of addiction in a city where many people suffer from it. The fact that her work could help the people around her motivates Calipari, although addiction is not a problem she, or anyone, can easily spot.
“When you think of addicted people, you’re thinking of these stereotypical images we have of people injecting drugs and passing out,” she said. “But that’s not the biggest population of people suffering from substance use disorder. They’re nurses. They’re teachers. They’re doctors. They’re athletes.”
What makes researching addiction and finding treatments for it particularly challenging, she said, is that it appears differently in different people, depending on what they’re addicted to (a substance or a behavior), their motivations, their genetics, their sex and their access to resources. Which neural pathways rewire because of addiction can also vary widely among individuals.
Quanta spoke with Calipari about the role of the well-known, but not well-understood, molecule dopamine in addiction and learning, how different sexes experience addiction differently, and how her years growing up around sports influenced how she approaches science today. The interview has been condensed and edited for clarity.
Dopamine is better understood as a “learning” molecule than as a “pleasure” molecule, Calipari said. “Everyone has to have a favorite neuromodulator in the brain, and dopamine is mine.”
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What does learning look like in the brain, and how do drugs interfere with that?
Our brain is wired to help us see things that are important and respond to them. It determines whether we need to do something again or not. Do we need to move or stay? Is this good or bad? Is this something I need to pay attention to?
Drugs are convincing our brains, “Yes, this is important. This is something we need to do again.” Drugs drive not only decisions about the drug itself, but also decisions about non-drug stimuli in our environment. They change how we learn.
How does that work at the molecular level?
Drugs like opioids act on dopamine. Most people think of dopamine as a “pleasure molecule,” but that’s not the whole picture. Yes, dopamine is released by rewarding stimuli like chocolate or sugar. But it’s also released by aversive stimuli like stress or pain. It fires when things are new or different, whether they’re good or bad. And in that way, dopamine is critical for helping you learn.
Drugs basically continue to push dopamine even when things are no longer new or different. The brain continues to think that something is important, signaling you to keep paying attention. But while drugs increase dopamine in the moment, long-term drug use depletes it. So with more and more drug use, there’s less and less dopamine in the brain, which means you have a hard time learning anything new.
Should dopamine be redefined as a “learning” molecule rather than a “pleasure” molecule?
Yes. Understanding dopamine as a molecule that guides how effectively we learn is much more accurate.
Using optical and genetic tools, Calipari’s team manipulates brain cells and circuits to see how drug exposure hijacks the neurobiological learning system.
Laura Partain for Quanta Magazine
How do you study this complicated system?
In my lab, we use different strategies for recording and manipulating different cells in the brain to try to figure out what cells and circuits help us make adaptive decisions. And then, once we’ve identified these circuits, we go in and we say: How does drug exposure change how the system works? We do this work at the physiological and epigenetic level. The goal is to understand basic biology — how drugs hijack the circuits — and then figure out if we can reverse the process. We can use CRISPR tools, for example, to reverse some of the plasticity in specific brain cells.
Can understanding how dopamine works eventually help us to develop treatments for addiction?
Understanding what dopamine does to help the brain learn is really important. But targeting it will be very difficult. You can’t just block dopamine: If you do, people won’t be able to move, they won’t be able to pay attention to anything. There’s a lot of work coming out on different ways to fine-tune the dopamine system instead of just turning it on or off. I think that’s what we’re going to have to do.
What’s it like working as an addiction researcher in one of the epicenters of addiction?
Nashville is bad. At the height of the opioid epidemic, Tennessee had one of the highest rates of opioid prescriptions. In recent years it has fallen, but the opioid problem hasn’t. And it’s not just opioids for us; methamphetamine is a big one, too. And so Vanderbilt is in this unique space as one of the biggest research hospitals in the region at a hub of substance use disorder.
Sometimes it’s exhausting to not be able to solve addiction tomorrow. That’s overwhelming in a not-great way. Sometimes it’s sad to talk to people who are suffering from substance use disorder, and I don’t know how to help them. They’re asking me questions as an expert. But I’m an expert on the specific neurobiological changes that occur. It is hard for me to understand the impact of this disorder on the day-to-day life of an individual since I have not personally experienced it.
Mentorship from her father, a star college basketball coach, has influenced the way Calipari leads off the court.
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Are we getting closer to understanding and eventually finding a cure for addiction?
Curing addiction is difficult because addiction is not one uniform disease. Some people suffering from addiction have comorbid disorders like anxiety and depression. Some people are taking drugs because they are trying to avoid pain. Some people have compulsive behavior, and some do not.
Just understanding what is similar and different in the brains of individuals with each of these unique symptoms will be critical to understanding how to approach treatment in the first place. In my lab, for example, we’re looking at the differences between males and females.
What are you finding?
When you look at why people take drugs, women are more likely to report taking drugs to avoid or escape negative consequences, like stress and anxiety. Men are more likely to take drugs impulsively, to get high and to hang out with friends. Both sexes are taking drugs, and some percentage of both will develop substance use disorder. But they’re doing it for different reasons.
Hormones have a lot to do with this. We found that estradiol, which is an ovarian hormone that circulates with the menstrual cycle, changes the way that nicotine works in the brain by changing the functions of its receptors.
We also found that if you give animals unlimited access to drugs, males and females take the same amount of drugs, and their behavior looks identical. But when we looked at what proteins in their brains changed, males and females were totally different. A lot of those proteins have similar cellular functions. What we think is happening is that this drug increases dopamine in both males and females and drives behavior in the same way, but the molecular pathways used by each sex are very different.
Beyond scientific curiosity, Calipari is driven to study addiction to help people who are suffering. “Addiction affects the lives of everybody,” she said. “There’s people suffering from substance use disorder, and then there’s their family, their friends.”
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Why would the brains of different sexes use different pathways to get to the same point?
If you had a system where you require one neuron to encode one piece of information, that system would be susceptible to failure. Everything would have to work perfectly every single time for you to be able to navigate the environment. But the brain has a lot of redundancies, which means you don’t need everything to work perfectly. There are a lot of ways to get to the same end. Why males and females have different ways of coding for behaviors is probably based in evolution and the survival of our species.
This must be a heavy field to work in. What keeps you motivated?
The thing that brings me in every day is that these are important questions. Learning about the next thing and solving hard problems is in and of itself super satisfying. Then when you take a breath and take a step back and realize that those hard problems you’re solving really impact people — it then makes it even kind of more meaningful.
But where I really get my motivation is in mentoring the next generation. When I went into research, my goal was to affect the most people I could. The way I was thinking I’d do this was by discovering something important and changing society, which is obviously the ultimate goal. But then when I got here and set up my lab, I realized that what you do is teach students that they can do this job. Empowering them to figure out what they’re good at and what they love keeps me going, even when the science isn’t always going the way that I want it to.
You’re kind of like the coach of your own team.
When you end up running a lab, you realize it’s a lot of science, but it’s also a lot of not-science. It’s getting people to work together and creating the right environment for each individual, which can be challenging. It’s like putting a team together. If they work together, it’s less hard for each individual. And if you do it the right way, then everybody wins.
To Calipari, heading a scientific lab is like coaching sports: She wants all her students to succeed individually and as a team.
Laura Partain for Quanta Magazine
You’re also an advocate for women in science. Where did that drive come from?
Nobody in my family had a graduate degree before me. Because my dad’s in sports, there wasn’t a huge emphasis on academics. Then I ended up in a space that — I don’t want to say I had no business being in, but I was around a bunch of people who I felt were smarter than me. They knew what they were doing. They knew what path they were supposed to be on. And I felt like I was flying by the seat of my pants.
I happened to have amazing mentors that helped me stay on a path I didn’t know I was on. And then, as I got older, I started to realize that I belonged here. I was just as smart as the people around me. That alone made me realize how much it matters to have people feel like they belong.
Instead of asking women to act like men to fit into a system built for men, maybe we should be changing the system to reinforce the things that we’re missing, which are things that women bring to the table — how they navigate the world, how they perceive things, how they support students. We benefit enormously from creating space for women.
You have played sports your whole life, including basketball in college. Do you think that has had any influence on your career today?
The biggest things you learn in sports are how to push yourself to get better each day, how to come back from failure and how to rely on your teammates. When I was younger, these experiences taught me how to come to work after an experiment didn’t work and how to ask for help when I needed it.
During my training, I was the athlete playing the game. However, when I became faculty, I was all of a sudden the coach. My job is different now. It is focused on how I can get my team to get better. I have to figure out what each person’s strengths are and put them in a position to succeed. I am also here to help them fill the gaps with great teammates that are good at things they may not be good at. Sports have given me the skills to focus on working hard and being motivated, and they have given me a framework for how to create an effective team and motivate them to be their best.
Your dad, John Calipari, is a professional basketball coach. Was he a mentor to you?
He was an amazing mentor, but more with the things he did than the things he said. When I was in middle school, he got fired. Watching him get fired but then come back and say, “You know what, it’s fine; I’m going to get up and do this again” — that was really important for me, to realize that even when things feel like huge failures, sometimes it’s the beginning of something new.
