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
"This is a fascinating concept, that a single protein, the D2 receptor, can have such a powerful effect. One single protein."
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.
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.