Nora Volkow has never been one to blindly accept convention. As a child in Mexico City, she would hunt down the source material cited in her textbooks and spend hours immersed in the intricacies of the Spanish conquest of Mexico or the geography of Indonesia. Diving deep instead of sticking to her assignments was not the best way to get good grades, she admits. But that curiosity began to pay off when she discovered biology. Volkow was named the best medical student of her class in 1981 at the National University of Mexico, and she went on to break new ground in the field of addiction research. As a young researcher at the University of Texas, she was the first to show that cocaine changes the human brain. A controversial idea at the time, it is now widely accepted. Later, Volkow used cutting-edge brain-scanning tools to pinpoint not only the physical changes wrought by addiction, but also the inherited brain abnormalities that make some people more vulnerable to it. Her work provided a potent rejoinder to anyone arguing that addiction was simply a matter of willpower. (At the time, first lady Nancy Reagan was urging everyone to “just say no.”) Revolutionary ideas are part of Volkow’s heritage. Her great-grandfather was Leon Trotsky, the Marxist revolutionary theorist and Soviet Bolshevik leader assassinated on the orders of Joseph Stalin. Volkow and her three sisters grew up in the Mexico City house where Trotsky lived out his exile and was murdered in 1940.
Volkow, who has directed the National Institute on Drug Abuse since 2003, is still challenging assumptions. In recent years, she has raised eyebrows for proposing that the same neural mechanisms behind cocaine and alcohol addiction also underlie eating disorders that lead to obesity.
Discover contributing editor Adam Piore talked with the 58-year-old in her office in Bethesda, Md. Volkow, a wiry long-distance runner with a lively demeanor and a slight accent, spoke about everything from the implications of her work on the neuroscience of addiction to the nature of evil.
Discover: What was it like to grow up in the house where Trotsky lived?
Volkow: We lived in a group of little rooms that had been used by American students — volunteers — who would come and visit Trotsky. But during the day, we would explore the rest of the house. My father didn’t change it; it was immaculate, and it was left like that for visitors to come see it. It was a fascinating experience because I got exposed to very interesting people of all sorts and of all nationalities, and people who had made a big impact in history, art or science.
One weekend it was my turn to show people around, and I was reading 100 Years of Solitude [a novel by Gabriel Garcia Márquez]. I have been a multitasker all my life. So I’m reading and I’m showing them around. And this man was asking me, “Well, do you like this writer?” And I said, “Yes, I was fascinated.” The man didn’t tell me he was Garcia Márquez. It was only later that I found out. I’ve read that growing up, you were a talented writer yourself, as well as an artist and a competitive swimmer and runner. And your family, of course, has a long history of politics. Why did you become a scientist?
V: Because I’m a very curious creature. Science is the ideal discipline for someone whose brain is basically driven to want to understand things. I spent hours looking at insects in the garden, literally trying to understand their paths and what happened if there was an object that disturbed them and how they interacted with one another. You put something in front of me, and I would become just mesmerized. It can be very disruptive in a lot of activities, but it’s perfect for science.
Your family has endured a lot of tragedy. On your father’s side, besides Trotsky’s death, your paternal grandfather died in a concentration camp. Your grandmother — Trotsky’s daughter — committed suicide. Two of your father’s uncles were killed, and his aunt died of tuberculosis. And your mother’s brothers were forced to flee Spain after the Spanish Civil War. Is there any connection between your family background and your career choice?
V: Absolutely. I come from a family that was persecuted. I lived with the consequences of that persecution and was brought up with the notion that my family paid a very high price trying to create a situation where people have more chances. I was brought up with the sense that we all have a responsibility of making this a fairer world for everybody. And we were taught as very little girls that we needed to do something with our lives that would be helpful for others. How did those past experiences of your family influence the path you decided to take in science?
V: I knew that Stalin actually said he would go after the third generation of the relatives of Trotsky — and that has something to do with it. I am fascinated as a neuroscientist to understand where this hatred emerges from. Why this level of vengeance and hatred of someone? When I got to medical school, I started looking for researchers who were involved with understanding the biochemistry of behavior. And if you’re interested in understanding the biochemistry of behavior — even more then than now — you go into pharmacology. It’s extraordinarily powerful because in pharmacology, you have the ability — by giving a drug — to manipulate [the brain using] that biochemical substance. So I started to volunteer in a research laboratory involved with pharmacology and the responses of drugs in the brain and how they influence behavior. How did that lead to addiction research?
V: Schizophrenia was the first disease that I got attracted to because a schizophrenic person cannot distinguish an inner voice from an outside voice. You also have distortion in thinking and emotions. I was very intrigued by the idea of peering inside the brain using new brain-imaging techniques. When I got my first faculty position, at the University of Texas, I wanted to continue researching schizophrenia. They have a wonderful psychiatric in-patient unit, but they don’t admit the schizophrenics there. I was obviously very, very frustrated. But I was also doing the rounds, and what struck me was there were many patients being admitted with psychosis from taking cocaine. And I basically had had all of that experience of working with drugs when I was a medical student. Immediately I said, “OK, I cannot study schizophrenics, but I can study psychosis in patients who are coming with cocaine substance-use disorders.” So I started to image them with the idea, “Can I use imaging technologies to see if I can also observe a commonality and the patterns that we saw with schizophrenic patients?” During your time in Texas in the mid-1980s, you made one of your first big discoveries with positron emission tomography, which uses radioactive markers to monitor blood flow, among other functions. What was the significance of that finding?
V: In the brain of a normal person, the blood flow is all over the cortex. But I observed in those first images of cocaine addicts that blood flow in their brains was very decreased. There were patches where there was no blood flow. This is what you see when someone suffers a stroke — there is an interruption of [blood] flow into the brain. So when we were getting these images of cocaine abusers, they looked like the brain images of stroke patients. This was a very unexpected finding. It was the first study that ever showed me that cocaine could be damaging to your brain. At that time, it was felt that cocaine was very, very safe. Now we know that cocaine produces lots of constriction, and that’s what decreases blood flow. You’re also known for discovering that the prefrontal cortex, an area of the brain essential to decision-making and our ability to behave appropriately around others, is compromised in the brains of addicts. Why was this an important discovery, and how did it come about?
V: At Brookhaven [National Laboratory] I was doing these studies on cocaine abusers, and after I’d seen a number of brain images, I realized I could distinguish a cocaine abuser from a control. I was very surprised. I said, “Wow, the prefrontal cortex — it’s completely abnormal in people who are addicted to cocaine!” It shifted the whole paradigm because at the time, nobody thought the prefrontal cortex was involved with addiction. I was criticized left and right. Eventually, with all the replications [of the study], people now recognize that one of the main pathologies in addiction is in the prefrontal cortex.
What are the implications of that finding?
V: An addiction has been classically understood as a disease of the primitive limbic brain, not of the cortical areas that are involved in what we call executive function. Executive function pertains to the operations of the brain where you have a committed awareness that requires some level of control — for example, if you want to pay attention. Other examples: if you want to control your anger or if you want to inhibit the urge to eat chocolate.
What jumped out in those brain scans was that the areas of the brain in the lower parts of the prefrontal cortex were hyper, hyper, hyperactive in addicts and were correlated with their cravings. It turns out that if someone is actively craving cocaine, or if you expose an addict to stimuli that remind the addict of cocaine and activate the craving, what you are doing is increasing activity in an area of the prefrontal cortex called the orbitofrontal cortex. It is involved in how you assign value to different stimuli. If you are very hungry and I show you a chocolate and you start to desire it, that is going to activate your orbitofrontal cortex. So what’s going on is the person who is addicted to the drug, if you expose them to an environment with stimuli that for them are salient, those stimuli will hyperactivate — much more than is normal.
What is very interesting is that this is also the area of the brain that is involved in patients with obsessive-compulsive disorders. What makes this particularly relevant is that in both conditions — in addiction and in compulsive-obsessive disorders — you have a compulsive pattern of behavior. One of your biggest discoveries was how addiction affects the D2 receptor, the protein that determines how sensitive individuals are to the release of the neurotransmitter dopamine, a chemical in the brain associated with feelings of reward and pleasure. Does that play a role in the problems in the prefrontal cortex?
V: You need these receptors for the proper function of the human brain. So when the number of receptors you have is decreased, which we discovered happens in people who are addicted to drugs, what results is inappropriate function of the prefrontal areas of the brain that are regulated by dopamine. And one of the consequences is that you cannot exert inhibitory
control — you become more compulsive. At the same time, it also affects the areas that are involved in whether we find something desirable or of value. So addicts in a detoxification unit are much less sensitive to natural reinforcers such as food, sexual stimuli and money. They are very apathetic to the environment, and the only thing that really interests them is the drug. That’s part of the challenge clinically. This is a fascinating concept, that a single protein, the D2 receptor, can have such a powerful effect. One single protein."
And this is not unique to cocaine, right?
V: Right. I was interested in identifying abnormalities that existed across addictions. It was very striking: We found we could replicate what happens in the prefrontal areas and the D2 receptors with cocaine also with alcohol, and then we replicated it in methamphetamine-addicted individuals, and then we replicated it in individuals who come from families where alcoholism is very prevalent. You mean people can have a biological predisposition to alcoholism or drug addiction?
V: Yes. They have fewer D2 receptors; therefore, they are less sensitive to natural reward because natural reward cannot increase dopamine as much as a drug. And there’s increasing evidence that this may be one of the mechanisms by which someone with low levels of dopamine D2 receptors is more vulnerable to taking drugs. This is a fascinating concept, that a single protein, the D2 receptor, can have such a powerful effect. One single protein. You’ve found that a lack of D2 receptors also can predispose someone to obesity. What made you think that the brains of obese people might have similarities to drug addicts and alcoholics?
V: I wondered, “Does the reduction in D2 receptors reflect the fact that these people are taking artificial substances that are changing the biochemistry of the brain, or does that basically reflect the expression of a predisposition to compulsiveness?” So I said, “What is a condition that has the similarities in terms of the behavioral expression?” And that’s why I went to obesity. Because people compulsively eat huge quantities of food, but the food is a natural reinforcer. You’re not bringing anything chemical, but there are similarities. People who are compulsive eaters cannot control — they endanger their lives. My prediction was that they also would have fewer D2 receptors. And the research showed exactly that. You were drawn to neuroscience by the biochemistry of human behavior and, in part, the question of what could drive a person like Stalin to vow to kill every single descendent of your great-grandfather. Have you found any answers?
V: Some. I think that hatred itself can be rewarded and it’s self-perpetuating. Recent studies have demonstrated that falling in love — or the love a mother has for an infant, which is so powerful — is driven by these reward processes, and it actually engages the same [brain] circuit that gives priority of that behavior over anything else, just like in addiction. Just like you can activate those systems with love, for some people you can do exactly the same thing with hatred. People become obsessed about their hatred. All of their activities are aimed toward revenge, revenge, revenge. So there has to be a rewarding component to motivate us. What is it that drives you? Your own drive has led you to a pretty powerful position where you can make a big impact. As the head of the National Institute on Drug Abuse, which spent more than $664 million on research grants in fiscal year 2014, how have you tried to improve addiction treatment?
V: One of my main goals has been to provide the knowledge that will enable us to treat drug addiction as a disease of the brain and to provide the tools that will allow you to be more effective in treating it, but also in preventing it. One way to do that is to provide a much greater granularity of understanding of the changes at the molecular level. We’re funding researchers to investigate how drugs alter what genes are activated such that they modify the function of the cells, and how this, in turn, modifies the functions of brain circuits, and how that modifies behavior. So the work goes into the basic science to understand how genes may make you vulnerable, and how drugs may influence what genes are expressed and what genes are silenced. Once you understand these processes, you can design and develop interventions to basically recover those processes that are disrupted by drugs.
If I could select one biochemical intervention, the one that I think would be most likely to have a beneficial effect is an increase in the level of D2 receptors. But unfortunately, I think we’re still far away from being able to do that. Another focus of your work seems to be the development of medications. Could you tell me a little more about that effort?
V: We have very few medications for the treatment of drug addictions. Based on the knowledge that we have, we should be in a much better position to help people who are addicted to drugs. Our difficulty has been that the pharmaceutical industry has not been interested in developing medications for addictions. So one of my priorities has been to advance the science on such compounds. Now we have partnerships with some of the pharmaceutical [companies]. Addiction is considered an immoral behavior, so many companies don’t want to be associated with those types of applications. But I think that is slowly changing.
