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An Interview with George Koob, M.D.

The following is the edited transcript of an interview by Bill Moyers with George Koob, M.D., on the neurochemistry and neurobiology of drug addiction. Koob is a professor in the neuropharmacology department at The Scripps Research Institute in La Jolla, California. Portions of this interview appear in the CLOSE TO HOME series.

Moyers: What is the heart of your research?

Koob: I want to understand the neurochemistry and neurobiology of emotional behavior. That's my original interest. I started out exploring the neurobiology of stress. But I've also been very interested in the neurobiology of what we call new stress -- the stress experienced in response to new or exciting stimuli. I study what makes us feel good and what produces pleasure, essentially. That has led to curiosity about understanding the disregulation of pleasure systems and reinforcement systems associated with drug abuse. So, more and more, my work involves trying to understand the neurobiology and neurochemistry of drug addiction.

Moyers: What's the most exciting thing you're working on right now?

Koob: Understanding how the reward system becomes compromised during the course of drug addiction and how that makes people vulnerable to drug addiction.

Moyers: Talk about the reward system.

Koob: Think of it as a circuit which begins in the middle of the brain, projects to the forebrain and then back again. Jim Olds and Peter Milner originally discovered it in the fifties when they stimulated rodent brains and found that the animals kept returning to the place where they were receiving the stimulation. The rodents liked what had happened there. It turns out that activation of this system is intensely rewarding to animals and to human beings, but the research basically stopped there because no one really understood how to explore it in greater detail. Then, much later, our interest in drug abuse led to a new view of the reward system from a neurochemical and drug perspective, and we discovered the neurochemistry of how drugs produce their highs. We began to wonder, What happens during chronic exposure to drugs and what does that mean for the concept of addiction? That's one of the most important aspects of our current work, and there are several fascinating parts to it. The first is that the same neurochemical systems which are affected when someone takes a drug to get high are the neurochemical systems that become compromised during addiction. That may sound like an obvious statement, but it really isn't because of the nature of the way the brain works. Secondly, we've come to believe that the stress systems in the brain and the pituitary hormone stress systems become activated during drug addiction, as well as the reward system. And the third part of the story, perhaps the most interesting, is that we have come full circle and are beginning to realize that the neurochemical systems affected by drugs of abuse are the ones that form our natural reward system.

Moyers: OK, what does that mean to a layman?

Koob: Basically, it means that we have so much money in the bank in terms of pleasure in our lives, and we can expend that money over the course of a single weekend's binge on cocaine or we can expend it over a two-week period in the normal pleasures of everyday life. If you spend these pleasure neurochemicals in one lump sum such as a crack binge, you use up your supply of pleasure for a certain period, and so you pay for it later. The system has to self-regulate.

Moyers: Spoken like a good Calvinist. There's only so much pleasure in life you can have.

Koob: Exactly, but it's really a biological Calvinism.

Moyers: In other words, I just have so many pleasure experiences in my mind, in my brain, that I can sustain at any given time?

Koob: Yes. Our bodies are built, in my view, to experience a certain amount of pleasure. We obviously need this system for procreation, to motivate us to do what's good for the continuation of the species. We have to seek nourishment and shelter and we have to procreate. All of those are associated with pleasure. On the other hand, we can't be out copulating all the time, because if we are, we're going to get eaten by whatever predator happens to come along while we're distracted. So something must regulate our behavior. Why aren't we copulating all the time? Why aren't we always overeating? Why aren't we overindulging in any of these things that we need to survive as a species? I believe that just like temperature regulation, the body's hedonic system has ways of self-regulating.

Moyers: Hedonic system?

Koob: Pleasure system. Reward system. Reinforcement system. There are many ways to characterize the system, but I see it as a motivational system in our brain which gives us a tendency toward organized activity and guides us in our everyday lives, causing us to seek things that we need while avoiding those which might be dangerous.

Moyers: So there's something in the original blueprint that wants pleasure and at the same time regulates exactly how much pleasure we can actually achieve?

Koob: In a sense. As I've said, there is a control mechanism which regulates body temperature. You and I don't think about regulating our body temperature. It's an autonomic or automatic function in our bodies. Now, as everyone who's had children knows, if a child's temperature spirals up past 104, 105 degrees, then it's necessary to treat them, otherwise the system becomes too disregulated. It can't fix itself without help and the child could have convulsions and even die. The same thing can happen to hedonic systems. They can spiral out of control until it's very difficult to bring them back into a normal range.

Moyers: Give me a practical example of that.

Koob: A binge of cocaine would be a situation where this system spirals out of control.

Moyers: So what are you doing to your brain when you put that much cocaine into yourself? What's happening up there?

Koob: Well, the first thing is that you're having a massive release of dopamine in the region of the brain that we call the basal forebrain, up toward the front of your brain. Dopamine is a transmitter involved in activation, in initiating movement in normal function -- it is also probably involved in helping initiate thought processes as well. When you take cocaine, it just exaggerates that effect. You get a sense of power, a sense of being able to do things, an immediate feeling of pleasure associated with moving and getting going and being unusually capable. This comes from the powerful release of dopamine.

Moyers: "I feel great."

Koob: "I feel great. I can do anything. I can even whip Wall Street if I need to." That's what stimulants do. For years, amphetamines and cocaine have been used for those purposes. They were used during World War II. They were used in other areas by the armed forces to sustain performance. And you can see how that type of effect would produce a very powerful reinforcing action.

Moyers: By reinforcing, you mean it makes you want to do it again?

Koob: Well, it's pleasure, so yes, we tend to repeat things that make us feel good. In other words, cocaine use increases the probability of more use.

Moyers: The pleasure escalates the desire which in turn escalates the use which increases the pleasure which . . .

Koob: Yes. It keeps escalating. And this pleasurable effect can be sustained for long periods -- up to several days. But eventually tolerance develops to this powerful effect. What's interesting is that some clinical investigators actually report that some users say they can't understand why they are still using because, even without coming down, even with a constant supply of drug, they are already starting to feel some dysphoric responses.

Moyers: The drug is making them feel bad?

Koob: Yes. They feel paranoia, agitation, discomfort. And then when end a cocaine binge, there is suddenly a dramatic crash in the mood state -- in many cases a feeling of total abjection and despair. That's probably due to decreases in dopamine function. But also, more recently, we have evidence of profound decreases in serotonin, which has been linked with clinical depression. That's interesting in itself, but even more recently -- and these data are only now beginning to be published -- we've discovered increases in a stress neurotransmitter in the brain called corticotrophin-releasing factor, a chemical which is released during behavioral responses to stress in particular emotional areas of the brain. We're finding now that during acute drug withdrawal, that chemical is augmented. So we have at least two things going on. The immediate response to the drug is this release of rewarding neurotransmitters. But over the long term those pleasure neurotransmitters become compromised. By using chronically, you are, in a sense, recruiting the bad guys. You're exciting and activating a system of transmitters that exist to regulate -- to minimize, in this case -- pleasure.

Moyers: With what consequences?

Koob: Well, in animals, we see behavioral signs of intense stress and discomfort. During cocaine withdrawal, human beings often report stress, anxiety, and depression. In treated addicts, we also see a vulnerability to stress that's even more prolonged and can outlast any acute withdrawal stage. So one of our passions right now -- an area which we really don't know much about yet -- is trying to understand how this cycle increases vulnerability to future relapses and future drug addiction. That's pretty much where the action is. What we need to do is understand how this sequence of events can lead to relapse. Why do people go back to using? Eighty percent of individuals who detoxify within a year go back to drugs. The good news is that twenty percent don't -- twenty percent attain stable abstinence. But why do the eighty percent go back?

Moyers: We all know smokers who sincerely proclaim this is the last cigarette.

Koob: There are many reasons why it's so hard to quit. One has to do with the fact that there are a lot of cues -- previously neutral items in the environment, which have, over time, become associated with cigarette smoking. It's incredibly difficult to rid your everyday life of events linked with smoking. You associate a cup of coffee with smoking a cigarette. You associate getting up in the morning and reading the paper with a cigarette. There are lots of puffs on the cigarette and there are lots of cigarettes and those all become conditioned to your environment, so they become an integral part of your life.

Moyers: The body learns that.

Koob: It's what defines a habit.

Moyers: For years, the first thing I did when I went to my office was to have a cup of coffee. After my heart surgery, my cardiologist said I had to give it up. And I have, but the first thing that happens now when I get off the elevator and turn down the corridor to my office is this rush of desire for that cup of coffee. Are those the kind of associations you are talking about?

Koob: Yes. And it's very persistent for smokers. Also, some investigators believe -- and they actually have some data to support this hypothesis -- that a lot of people are actually self-medicating with cigarettes to a small degree. In other words, it's very easy to control mood state with cigarettes because they hit you very fast. You're smoking something -- it gets in your lungs, gets to your brain very quickly. When do people smoke during the course of a day? Well, they smoke in the morning to wake up and get going. They smoke when they have to calm down before they meet their boss. They smoke when they're falling asleep at the computer trying to do some report or term paper. Now, all of these are fairly mild situations, but you can see how someone could become dependent on that sense of control over emotions which smoking can bring. You raise a very important issue here, because work in this area not only provides information about what happens when people start doing drugs and get into the addiction cycle, but about what conveys the vulnerability in the first place.

Moyers: Why do you think we start using for the first time?

Koob: Well, not only why do we start using in the first place, but why do some people become addicted from using? Remember, large proportions of people who use drugs do not become addicted.

Moyers: Right, most people who drink don't become alcoholics. Most people who take cocaine don't become addicts.

Koob: And a large proportion of the people who use heroin don't become heroin addicts. No one ever talks about that issue, but there are estimates that for every one heroin addict, there are two or three "chippers" -- individuals who simply use opiates on the weekend or even less frequently. They have developed elaborate behavior control mechanisms to limit their intake of the drug. Well, what differentiates chippers from addicts?

Moyers: Why can I have two glasses of wine and want no more, and yet my friend can't stop with six. Is that what you're asking?

Koob: Yes. We believe that the same neurocircuitry, the same chemicals in the brain which are compromised once a person gets addicted, are probably the ones that in some way convey the vulnerability in the first place. We can only speculate at this point, but maybe someone has higher endogenous levels of stress hormones. Maybe someone has a deficit in dopamine function or over-active dopamine function. We don't know. That's going to be the real challenge for future work.

Moyers: Trying to identify who's at risk.

Koob: Who is at risk and how to translate the information that we gain from the animal studies to humans. Great advances are going to be made in the next ten to fifteen years, because of the innovative new work with PET scans and the ability to visualize the neurochemical activity of the brain.

Moyers: Let's go back to this reward system we were discussing. It started with rat research.

Koob: Yes, the work of Olds and Milner, which I've mentioned, found this brain area that rats liked to have electrically stimulated, and then there was a great deal of research devoted to identifying how psycho-stimulant drugs like amphetamines work. The earliest work was done by Dave Roberts and Chris Fibiger at the University of Vancouver and by Susan Iverson Neuman and a group in Denmark, showing that the basal forebrain part of the brain, which was the area identified by Olds and Milner, had this neurotransmitter, dopamine, in it. If you injected a rat with amphetamine or cocaine, it would become extremely active and run around its cage. If you removed the dopamine in this mesolimbic dopamine system, the rat would stop responding completely to the stimulant drugs.

Moyers: And what did that suggest?

Koob: Essentially, that that part of the brain and that dopamine system were important for the psycho-stimulant actions, for the activation and "speediness" associated with amphetamine and cocaine. And then subsequently, a number of laboratories began to explore the same question but directed at the rewarding effects of the drugs. Again, remove this mesolimbic dopamine system and rats will stop taking cocaine. They simply quit, as if the cocaine has no effect. The work in rodents has focused in on an area called the nucleus accumbens, which is up in the basal forebrain, but also on an area called the ventral tegmental nucleus as well as the amygdala. The name "amygdala" stands for almond or almond-shaped, and it's in the temporal lobe in human beings. It's an area which has long been associated with how we process pleasure and how we link pleasure to everyday life.

Moyers: All right. When you put cocaine in the tiny brain of a rat, can you actually see something happening?

Koob: If you lower a probe, a tiny, tiny probe, down into these areas of the brain, with a semipermeable membrane at the tip, and you run liquid through that, you can pick up the dopamine being released during drug-taking behavior. The animals pressing the levers which inject cocaine intravenously into them show this huge release of dopamine.

Moyers: And as the dopamine is released, the pleasure in the creature is increased?

Koob: There's a direct link between the amount of dopamine being released and the self-administration of the drugs. Something very operational about it.

Moyers: It must be that the brain is saying, "I like that. I like that, " and going to work to get more.

Koob: Right. And dopamine is one of the common elements associated with most drugs of abuse. My personal view is that the brain wasn't constructed with only one reward transmitter. There are also the endorphins, the opioid peptides which you've heard about -- it's the receptors to the endorphins that are presumably activated by opiates like heroin and morphine. Alcohol probably activates opioid peptide systems as well as dopamine, and so do opiates. So there are at least two major neurotransmitters that are implicated in the rewarding effects of drugs, and that would be dopamine but also opioid peptides. Thankfully, there's some redundancy in the system. Animals do not take cocaine when their mesolimbic system is removed, but they do seem to be able to navigate in everyday life. It's not as if they've been completely cut off from all pleasure. Which is what you would expect because many other brain systems are redundant. And which is important because, say there were long-term irreversible effects of addiction on one part of the reward system. If there's redundancy, something else can take over so you can still feel good.

Moyers: When you have a rat pressing a lever for cocaine, can you see a smile on its face?

Koob: You can see a smile on the face of the rodent and you can see the dopamine being released in the accumbens all at the same time. Actually, rodents don't smile, but they do look peppier. Presumably they're getting some form of pleasure. I mean, it's very difficult to say whether a rat feels pleasure or not, but let's put it this way: when my assistant goes to put these rats into the chambers for their self administration session, they are very active and very appetitive, they're jumping up on the front of the cage because they know it's coke time and they're ready to have their dopamine released. It's almost an impossible question to ask in animal research. But, in the same sense that your dog shows an appetitive response when it's dinner time, the rats show appetitive response when it's time to have a cocaine session or an alcohol session.

Moyers: So how would you define addiction?

Koob: To me, the best real definition of drug addiction is that your behavioral repertoire has narrowed such that drugs become the focus of your whole life. Your pleasure centers have been usurped, taken over by the drugs. In other words, you no longer seek out natural pleasures because the drug is driving the system.

I remember once giving a lecture to lay professionals -- drug counselors and others -- on the neurobiology of drug addiction. I showed some slides of my animals taking cocaine and there was an individual in the front row who was sweating profusely. Beads of sweat were coming off of him. He was all red and he was starting to tremble. At the end of the lecture he came up and said, "Dr. Koob, I'm a physician and I had a cocaine problem three years ago, and I really thought I was over it until I heard you talking about cocaine, and, boy, I really want cocaine!"

Moyers: Just from listening to you?

Koob: Just listening to a scientific lecture on the actions of cocaine and how it works in rodents elicited this incredible craving response in him. Now, there's another powerful stimulus associated with relapse and drug-taking which is often overlooked by basic researchers and that is negative mood state. Clinical researchers know it well because they see that most relapse in human addicts happens not because they experience cues like seeing someone get high, but because they are in a bad mood or an uncomfortable situation. Some stressor infringes on them. It could be a big deal like the illness of a family member or the loss of a job. Or, it could be much milder than that. They could simply be dissed by somebody, someone could cut them off on the freeway or make an obscene gesture towards them and that could trigger a series of negative feelings about themselves. And when they get in to work, someone could say something even slightly negative and now the whole tone for the day has been set and they're thinking, "It's only going to get worse." Those kind of negative mood states are very frequently associated with relapse to drugs. There's more than one determinant of vulnerability. It's my belief that not only are the brain reward systems involved in vulnerability, but also, as I've said, brain stress systems. More has to be explored in this regard, but we have identified basically three common elements so far associated with chronic drug use, and this involves all the major drugs: cocaine, heroin, alcohol, nicotine and, more recently, the active ingredient in marijuana, THC, in our laboratory. One is that we can measure increased reward thresholds, which means that it's harder to get any pleasure, with or without drugs, during withdrawal and afterwards. Second, we've seen decreases in dopamine function associated with chronic administration of these drugs. Third, we've seen activation of this brain stress system during withdrawal from all of these drugs of abuse, including THC and nicotine.

The main question for me is, "What is common to the drugs of abuse?" Clearly opiates are different than alcohol and alcohol is different than cocaine, but my interest has been what are the common elements that convey the vulnerability to drug addiction. You've interviewed Dr. Leshner, Director of the National Institute on Drug Abuse. He talks about a "switch" which exists between the state of "addicted" and "not addicted," and what causes that switch to flip. Now, he acknowledges that it is too simplistic to think of an ordinary switch because that implies that it's either open or closed, on or off. But if you think of it as a very slow moving switch -- like a dimmer -- that's gradually gaining power and control over the individual through a biological mechanism, and, as with a dimmer switch, the exact boundary between very dim and off is hard to see, then he and I are basically talking about the same thing.

Moyers: Something turns use into addiction. What's your theory on that?

Koob: Well, I believe that there can be genetic vulnerability, you can be born with that. And taking the drug itself can convey that vulnerability, something that I think is often overlooked.

Moyers: Wait a minute. Taking the drug itself can change the brain?

Koob: Right. It's a vicious cycle. Once the change is established it's very hard to get out of the cycle. Both of those factors, genetic and pharmacological, can be in effect at the same time.

Moyers: But then something else must be going on, too, because you said a person can want a snort or a shot because he got dissed on the road or in the office. Is that biological? Or is that psychological?

Koob: You get into a very interesting philosophical issue there . . .

Moyers: Or is it the environment?

Koob: Well, it's all of those things. Remember, psychology is biology. Whatever changes occur in the way we think and the way we do things are ultimately conveyed by some neurochemical change in the brain. Let me give you a very powerful example. My colleagues up at UCLA, Jeffrey Schwartz and Lou Baxter, have been studying Obsessive-Compulsive Disorder, which is generally considered to be an anxiety disorder but has some similarities to addiction. They can do PET scans on people with Obsessive-Compulsive Disorder and show deficits in certain parts of the brain. They can reverse those changes in the obsessive-compulsive patients by treating them with Prozac. But they can also reverse those changes completely with a behavioral therapy that they have developed to treat the condition without drugs. So both the behavioral therapy -- a form of psychotherapy -- and drugs, when they treat the patients effectively, make the same change in the brain. Is it psychological or is it biological? It's both. And it doesn't matter. You can get the same results either way.

Moyers: Do you believe that group meetings like those of AA, that talking about addiction at a meeting can change the brain?

Koob: Yes, I do. I think it can change the brain ultimately. I don't think you can do it just in one meeting, but yes, a full course of the equivalent of Alcoholics Anonymous has proven to be effective. There was a recent study sponsored by the National Institute on Alcohol Abuse and Alcoholism showing that the equivalent of Alcoholics Anonymous was an effective treatment for alcohol dependence and preventing relapse. And I would argue that, while there's no evidence yet, the same brain systems which are helped by naltrexone perhaps, are also helped by Alcoholics Anonymous. It remains to be determined.

Moyers: It's fascinating to me to think about the fact that you can change the brain by injecting something in it -- a foreign substance -- and then change the brain again by talking about what's happened to you under the influence of that particular drug.

Koob: I firmly believe that that's true. Some of the best experiences of researchers occur in taxis. And I remember leaving the Addiction Research Center in Philadelphia and taking the taxi to the airport. The taxi driver found out what I did for a living, and he told me that he used to have a problem with heroin. He said, "There's this little guy in my head and every once and a while he pops up and tells me I should be taking heroin, but I can sit on him, I can really sit on him and I can control it. " And I think that's an example of someone who has learned behavioral techniques to prevent himself from relapsing. And I would argue that if we can find the key to the vulnerability, we will be able to find the key to the treatment as well and develop better behavioral therapies.

Moyers: You're working on a vaccine for cocaine. Tell me about it.

Koob: The cocaine vaccine is an example of one of these beautiful collaborations in science. It's not even clear to those of us who began the collaboration how it happened exactly, but I remember these immunologists asking me whether I could test some analogs of cocaine that they had for efficacy and I said, "Certainly." I told them we have rats taking cocaine, so we'll just give them an injection of your drug and see if it substitutes for the cocaine. It turned out that these people were working on catalytic antibodies and immune responses to different agents and they were trying to develop an assay, or a test, which would let you know, through use of one of these antibodies, if something was or was not cocaine. It would, in essence, measure cocaine in the blood of a human being. We all sat around talking and decided, "Well, if we can use an antibody in an assay, why couldn't we do this in a living animal and simply immunize a rat against cocaine?" If that would work then presumably when the animal took cocaine the antibodies would act like a sponge and basically just take the coke out of the system. And so that's what we did.

Moyers: You've actually done it with a rat.

Koob: We have actually done it with a rat. The vaccine is basically a large protein with cocaine molecules stuck on it. It looks like a satellite. And that's injected into the rat followed by several boosters. Normally, when you inject a rat with cocaine, it will run round and round for 90 minutes and look like the stock market had just gone through seven thousand five hundred, but the animals that have been immunized with this vaccine show no response. It's like they didn't get the drug. Now, this is an interesting and fun experiment, but the question is: What importance does it have, does it have any real value? There are ethical issues that it would raise. For example, someone could test to see if you had these antibodies, an insurance company or something, and they might find out that maybe you were an addict at one time, or in a child, maybe you came from a bad neighborhood where parents would want such immunity. Or, what if you immunized a child and then later needed to use cocaine for anesthesia or something?

Where we think it would be most useful is as an adjunct to treatment. So that if someone did have a relapse and took a snort, there is no effect. It doesn't get into the brain; has nothing to do with the brain. In effect, it's an immunological sponge in the body to soak up cocaine.

Moyers: Is it conceivable that the day could come when we can vaccinate every child against potential cocaine addiction?

Koob: I don't know whether you'd want to get into that. I mean, that would raise a lot of, I think, ethical issues.

Moyers: Such as?

Koob: I just don't know all the implications.

Moyers: Couldn't the addict bent on relapse try to use over the vaccine? Increase the amount of drugs, so he could actually "pole vault" over the barrier?

Koob: Yes, the addict could do that. We've seen that happen, the rats can do it. If we turn them loose with unlimited access to cocaine, they can pole vault over it, as you say. Our hope is that would not be the use of the vaccine. It wouldn't be useful to someone with unlimited access, or someone who really, really doesn't want to stop. It would just make it cost more for them to pursue.

Moyers: Or, they could use amphetamine, switch to another similar drug.

Koob: That's certainly an issue, and probably they would do that in many cases. But there's also no reason we couldn't produce a cocktail vaccine which would immunize against all stimulant drugs, for example.

Moyers: Have you tested rats for alcohol?

Koob: Yes, in fact, one of the major effects that my colleagues here have observed is in anticipation of the self-administration of alcohol. While the animal is waiting for the lever to become available to press for a drink, we can actually see dopamine released. We see dopamine release in response to the alcohol as well, but we actually see a small release anticipating the drink, and this is very fascinating.

Moyers: The rat knows it's going to get something good and gets excited just thinking about it?

Koob: Well, something like that, and we think this may also be another common element associated with drugs of abuse. The dopamine system can anticipate, in a sense, the actual drug delivery, so there's a kind of a priming effect -- the animal itself releases some dopamine when it anticipates the drug. It's probably associated with cues in the environment like the smell of the box, the sight of the levers, the lights that are used to trigger the infusion of cocaine or the infusion of alcohol. And this anticipatory release of dopamine is not seen unless an animal has an experience in self-administering. It's not something that they do without a history of drug use.

Moyers: They have to have learned that drugs make them feel good?

Koob: They have to have experience, exactly.

Moyers: What's the significance of that to your research?

Koob: I believe that this anticipatory release of dopamine may actually be something that's associated with vulnerability to relapse. In other words, a cue in the environment could, superimposed on a negative motivational state in particular, produce a whetting of the appetite that might lead to the craving that is associated with relapse.

Moyers: What happens when you take the drugs away from the animals?

Koob: That's actually a very interesting question. One of the things we've been studying recently is that if an animal has a history of even limited access to drinking, and you remove the alcohol for three or four days and then put the animal back where it drank, it will drink approximately 50 percent more than it did before. We discovered this serendipitously in our own laboratories by not testing them on the weekends, and finding that on Monday morning all the animals drank more alcohol. Then we subsequently found out that other researchers had already observed this. It's a well-known phenomenon in the human condition known as the abstinence violation effect.

Moyers: Explain that, please.

Koob: Well, alcoholics who have quit, who are on the wagon, when they relapse, they overshoot and tend to binge -- almost as though they are making up for lost time. So once the relapse has occurred for a variety of reasons, cognitive and perhaps emotional, they drink to excess as opposed to just having two drinks. They don't restrict themselves, as they probably told themselves they would this time. They overdo it and end up in a binge situation.

Moyers: So having used and then abstained, the thirst seems to be greater.

Koob: Yes. We don't really understand the basis for this abstinence violation effect. But we're trying to understand the neurochemistry of that phenomenon. One of the things that we've discovered is that we can reverse the effect with naltrexone, an opiate-blocking drug which is currently being used to treat alcoholism in the U.S., and with acamprosate, another drug being used for treatment in Europe to prevent relapse in alcoholics. We find that chronic administration of both these drugs doesn't stop alcohol drinking, but it does stop this overshoot, which is fascinating because it means that it can't be totally eliminating the rewarding effects of alcohol, but it isn't supporting overdoing it. And there's a correspondence between this behavior in the rodents and what happens in the humans.

Moyers: What is the most brain-damaging drug?

Koob: Alcohol. Unlike other drugs, it actually destroys neurons and it destroys not only your brain, but your liver and your pancreas in the process. And the toxic effects it has on many parts on many organs in the body ultimately can result in brain toxicity. There's a syndrome called Korsakoff's psychosis where you get holes in your brain from chronic alcohol use, and it's usually combined with malnutrition, which makes it even more toxic. Alcohol will destroy neurons in your memory areas of your brain, in your hippocampus, and also in your thalamus.

Moyers: Literal holes in the brain?

Koob: Actual holes in the brain.
 

Koob: My favorite occupation when I'm not doing science is growing fruit trees, oranges, lemons -- we grow every kind of fruit you can imagine here, blackberries, peaches, nectarines. It's fun to go out and do things with your hands. I have to travel a lot, so I enjoy planting the seeds and then coming back to see how they have been doing. I find a great deal of pleasure in gardening, particularly in growing things that I can eat. There's a reward in it. Take these peaches here -- I'm salivating thinking about what they're gonna taste like in about a month when they're ripe.

Moyers: This raises an interesting point. You eat your fruit because it tastes good, those honeybees over there go to the nectar because it tastes good; it's pleasurable to them.

Koob: Right. Right.

Moyers: Are we talking about the same things when we talk about the pleasure and rewards of drugs?

Koob: A lot of people think so. In fact, there have been a number of articles suggesting it. The neurotransmitter, dopamine, we talked about is certainly involved in pleasure-inducing stimulant actions, and it is probably released throughout the animal kingdom to help animals choose between different stimuli. In honey bees, the neurotransmitter is octopamine, but it's similar to dopamine. And so, even in honeybees, that octopamine is released in anticipation of a change from one flower to another with more nectar in it. When the bee has to make a switch, why does it go from flower A to flower B? Well, flower B has more nectar in it, and what initiates that switch is, in fact, the activation of octopamine or a dopamine-type neurotransmitter in the honey bees. Yes, the process throughout nature is very similar.

Moyers: So what happens in the bee's brain is the same thing that happens in the rodent's brain, the same thing that happens in our brain when we take drugs?

Koob: To some extent, I think so. I often tell students that a drug doesn't do anything that we're not capable of doing on our own. But when you take a drug, the response is condensed and intensified over time. We release dopamine when we anticipate switching to some new hedonic stimulus. Bees presumably do the same thing. So I believe that drugs have a way of interacting with the natural substances in our brain to produce the effects that they produce. Even if the drug is a synthetic agent, it is acting upon natural receptors, natural neurotransmitters that we have in our own brain. Of course, it's hard to make the dopamine equivalent of a 30-minute cocaine binge with my gardening. But if I were able to do that I would think that the pleasure that is derived under each circumstance would be more or less the same. With the coke, it's just condensed into a very short period of time. And that obviously explains why cocaine is such an unbelievably powerful, reinforcing stimulus.

Moyers: It gets to the reward system very quickly.

Koob: It gets there very quickly and it activates those dopamine neurons much more quickly, presumably, than natural stimuli would do. Or at least in the sense that it's much more intense of an action. I remember sitting on an airplane once next to an executive who said to me, "I don't understand what's so special about cocaine, what's all the hoopla about cocaine?" And I said, "Well, think about the pleasure you get when your stock quadruples on the stock exchange because you've just released a new product and it just catches on like wildfire and your stock just soars. Think of the pleasure that you experience over a several-week period of your stock climbing, and condense that into one 12-hour binge and that's what cocaine does."

Moyers: And yet I've had one addict after another tell me that after a while they don't take it for the pleasure; they take it to escape the pain.

Koob: Exactly. I was visiting France and I happened to catch a French talk show and they had some alcoholics on. And they asked them, "Why do you drink?," and they said, "For pleasure, but more to feel better inside my skin." That basically captures it all for me. There are two major sources of reinforcement with drug dependence. There is the pleasure that got you there in the first place, but after a while the system has become so compromised that you are taking the drug to return yourself to a normal state. In my view, the essence of drug addiction is that you have created an artificial but negative state. In effect, you spend most of your time not trying to get some extra bliss, but just trying to feel normal. Because your brain's reward system is depleted, you get no pleasure from anything except drugs, and even the drugs don't do it anymore. So you have bankrupted the system. There's no more pleasure in your account. We're back to the notion of just how much pleasure you have available at any given time.

Moyers: If the pleasure principle is so embedded in us -- for some people, fruit-growing, for some people, drugs -- won't we always look for another way to satisfy that desire? Right now in California methamphetamines are trendy; there's always some drug craze, it seems.

Koob: Yes. And my perspective again is a biological perspective. From that position, if you limit access to drugs, you can limit dependence. And you can limit access in many ways. You can limit access through interdiction, like our government has tried over and over and basically failed. You can limit access through education and learning, teaching people how and what are the untoward effects of drugs, so that they know what they're about to engage themselves in. You can limit access by the route of administration. If smoking a drug like cigarettes is banned, most of the toxicity associated with nicotine is eliminated and most of the dependence is eliminated. Not all of it because there are obviously oral preparations of nicotine that are also addicting. But basically the faster it gets to the brain, the faster you get high and the most likely you are to get hooked. Smoking cigarettes gets nicotine to your brain extremely fast -- they are just like crack cocaine in that regard. Now, eliminating smoking nicotine doesn't solve the problem entirely because there are the odd ducks that actually can become addicted to codeine, for example, a very weak opiate, through the oral route. But they're much less likely to become addicted to that than to smokeable heroin. So I think there are a combination of ways that one can limit access to drugs. Everything from education to interdiction to understanding the biology. Unfortunately, very few of us really understand how drugs work and what they do, and I think that is one of the major deficits in our policy. There's a lot of misinformation associated with drugs. For example, no one gets addicted the first time they taste drug x, y or z. That's pretty much a fallacy. There are occasionally individuals who like it so much that they never stop once they get started. But the fact is, in most cases, addiction doesn't take place until chronic use has taken place.

Moyers: Is your 3-year-old son, Cameron, at risk?

Koob: I think all people are at risk. There is obviously a genetic vulnerability. I hope my child doesn't have that. But there's also the environmental vulnerability. If you grow up in an environment where crack cocaine is everywhere, how can you avoid getting involved with crack cocaine? I think all of those things contribute.

Moyers: So what do we do for the kid at risk? We don't even know who's most at risk.

Koob: Well, hopefully, through more research -- yeah, let's hear it for research -- we will be able to know when someone is at high risk. But another issue comes up -- people ask me, "What do you tell your child who you suddenly discover is smoking marijuana?" My answer is that you do what you would do if you found them with a small bottle of scotch in the car. You wouldn't want your son or your daughter drinking alcohol on the way to school in the morning. You wouldn't want them taking hits from a bottle during recess. You wouldn't want them taking a snort on their way home at night. So what's the difference?

Moyers: So Cameron's a few years older, he comes home from school, and he says Dad, a kid offered me a joint today, I took it, it was really sweet, it was nice. What do you say to him?

Koob: I don't know. [LAUGHTER] What do I say to him? That's the real dilemma. I think what you have to say is that there are major problems with smoking marijuana and you have to outline what those are. What are the liabilities? What is the danger? And you have to set limits and say that until you are old enough to make your own decisions, you have to follow the law. This is an illegal drug and it should not be partaken of.

Moyers: Would you tell him this drug could change him in ways he would not find good?

Koob: Absolutely. But for young people, especially teenagers, you have to tell the truth. You have to level with them. You can't exaggerate because they will check it out, they have ways of verifying what's true. If you tell them that they're gonna get their chromosomes broken by smoking marijuana, they're going to go look it up in a book and find out that you're blowing hot air because there is no evidence that marijuana breaks chromosomes. I think you have to tell the truth. That driving while high is just as bad as driving while drunk. And that going to school stoned is just as stupid as going to school drunk -- you aren't going to learn much either way.

Moyers: From what you've learned through research, is the brain of the addict different than that of a non-addict?

Koob: I think the answer is yes. We have to qualify it slightly and change the question slightly and ask, "Is the brain of someone vulnerable to drug addiction different before they start drugs, or is it different after they have become a drug addict?" I think it's clear that after they become a drug addict, their brain has changed. And it's probably changed forever. A good example is that, once exposed to opiates, even in animals the response then to opiate antagonists is exaggerated dramatically. And that lasts up to six weeks just in animals. It's hypothetically possible that in humans similar things take place. The real question is, "Is the brain of a potential addict different than the brain of a non-potential-addict?" Now that's an issue that's still being explored. Clearly, there is often a different response to alcohol in those who have a family background of alcoholism.

Moyers: Do addicts lose control of their drug use, or are they simply doing what seems irrational to outsiders like you and me but is very rational to them from inside the drug experience?

Koob: That is also a very important question, and it gets into a lot of controversial issues on how we define addiction precisely. From the perspective of society as a whole, they have lost control over their drug use because, in effect, their lives have become completely centered on the drug experience. In other words, they don't do anything else -- the whole focus of their life is on getting and using drugs. But if you were to actually look at a heroin addict, you would say that within that world, he is regulating the amount of heroin he's taking because he has to get a certain fix and get it by a certain time or he will go through the withdrawal stage, which most addicts find incredibly aversive. So it's a very difficult issue to define. You can't simply say loss of control. You can say loss of control in the sense that they cannot stop. You can say loss of control in the sense that they do it to the exclusion of other normal activities. But you can't say loss of control in the sense that they're just going to continually take more and more and more. They do with some drugs, but even there, not always. Alcoholics and heroin addicts can maintain functioning at very high levels of use for very long periods of times. In fact they can titrate themselves down. They sometimes -- or used to in the old days anyway -- check themselves into treatment programs and go through withdrawal deliberately just so that they can have a cheaper and more manageable habit when they get out. But it's a loss of control relative to other activities and relative to what we would consider in society a norm.

Moyers: What about gambling, where the addiction can be as compulsive and as devastating as if a drug has invaded the brain, but in this case no substance is involved?

Koob: We're currently exploring that in one of the courses that I'm teaching. I firmly believe that gambling fits the addiction model very well.

Moyers: I can see that the behavior does, because they go on gambling despite losing everything, but no drug has entered the brain, how can the pleasure system get disregulated?

Koob: Ahhhh. Well, actually, no drug is needed. The reinforcer is powerful enough and the history of how that reinforcer is delivered, the way it's delivered, can also contribute dramatically to how that stimulus is perceived by the human being.

Moyers: And the reinforcer is?

Koob: In this case money, winning. Not so much the money itself, but the act of winning.

Moyers: But I've known addicts who are addicted who never win.

Koob: It's the excitement associated with the possibility. Oddly, the most addictive things are not situations where you get what you're after every time -- where each high is predictable and good. It's the situations where you don't know if you're going to get it, where you might, but then, you might not. What we call intermittent reinforcement. And presumably it's the same neurotransmitters with gambling that we see with coke or other addictions. This is untested, but presumably it's those same neurotransmitters.

Moyers: The pleasure-giving dopamine?

Koob: And the opiod peptides, presumably. And the stress system probably gets activated as well.

Moyers: But in this case not triggered by a drug.

Koob: Not triggered by a drug. And one can speculate further. This gets a little bit out of the realm of normal addiction medicine, but the issues of compulsive eating, compulsive sex, compulsive exercise raise important questions.

Moyers: Somehow all of these are exciting the dopamine, the pleasure agent, the little thrill seeker.

Koob: Presumably. The hypothesis would be that they are disregulating the same neuro-chemical systems that get usurped and disregulated by drugs.

Moyers: It all runs through this reward pathway.

Koob: Cocaine is just a short-cut, in my view.

Moyers: It happens in a hurry.

Koob: It happens in a hurry and with more intensity, making it more likely that more people will get in trouble with coke than with gambling.

Moyers: I'm told it only takes eleven seconds for smoking to get the nicotine into the brain. That's pretty fast.

Koob: Absolutely. Cigarettes are very addicting, there's no question about it. And they create a tremendous dependency. The difference between crack cocaine and cigarettes is that crack cocaine delivered by smoking is much more powerful in its initial effects. And so that kind of addiction presumably can happen quickly and more effectively than perhaps other addictions. By and large many young people smoke cigarettes more or less in a chipping-type fashion. For several years, they aren't dependent on it -- they can take it or leave it. Anyone who's been a cigarette smoker will tell you that they passed through that phase. But then the time comes -- something happens, it's not clear exactly what, but they can't go without it or if they try to quit they find themselves back at it. There's been some change.

Moyers: How do we get at the relationship between the environment and brain change? Have you been able, in your studies with rodents, to examine how the environment affects their behavior?

Koob: Well, it's clear that if you change the availability of reinforcers in the environment and you provide equally pleasant things to rats such as sucrose, which they like a lot, then that will actually reduce drug intake. That hasn't been one of our main lines of inquiry. But there is data in an area called behavioral economics, where people have studied the elasticity of reinforcers. In other words, if you pair, say, heroin with the availability of food and you make the animal hungry enough, heroin loses and food wins. On the other hand, if you've made the animal dependent on heroin so that it has become a major dependency, there are circumstances where presumably heroin would win and the food would lose. We still need more research in this area.

Moyers: Yes, but clearly environment plays a role. You take that famous study of those veterans who came back from Vietnam who were heavy users of heroin during the war. When they got back, they didn't get re-addicted, even those who used a few times, the study shows, unless they had actually used before they went to Vietnam. So take them out of the environment and the stress of war and they stop using.

Koob: Yes. That's true. And those kind of environmental questions can be asked in a laboratory. We do that here. We can take animals and expose them to an anise smell and a tone during opiate withdrawal and a month later when they're completely detoxified they will avoid that smell and tone.

Moyers: What do you take from that?

Koob: There's a memory of the aversive effects that have been conveyed by the drug, and it persists indefinitely, more or less. And you can do the same with the positive side. You can train an animal by pairing a light or a tone with delivery of cocaine. And that tone or light becomes a priming stimulus for seeking cocaine.

Moyers: Would this help to explain why some women who have been heavy smokers or cocaine users will stop when they find out they are pregnant -- just stop, without help or treatment?

Koob: Actually, in my way of thinking that's an example of what is called transcendence. As humans, we can look to the long-term, not just to what's happening now. So while the mother-to-be's immediate desire is to have a cigarette and feel good, she can also consider the potential of having a healthy baby -- all the warmth and affection and love you expect from having a healthy baby, and that's a much more powerful reinforcer than the hit of a cigarette. Maybe for those Vietnam vets, the goal of being home with their families and away from the trauma of the war was enough to keep them from returning to heroin addiction. I don't think rodents necessarily could do that. But human beings can. We have the ability to transcend the acute pleasurable effects of some of these drugs if we want to. Other things can be more important to us.

Moyers: So values and goals are reinforcers in their own right?

Koob: Yes, I think so.

Moyers: Does that have implications for treatment?

Koob: Yes. With goals and ideas and support and hope we can change the brain. We can recover from addiction.

Moyers: Given the importance of values, how do you see the addict?

Koob: I believe that addiction basically meets the criterion for disease, the way I think of disease. I think it is a medical problem and there are medical solutions. But I always emphasize that this in no way obviates a person of responsibility for the disorder. I see addicts as individuals who have a disorder that is treatable, and they should seek treatment. If you're a diabetic it behooves you to seek treatment and take your insulin on a regular basis if it's that severe. It would be irresponsible not to take your insulin or maintain your diet. And I feel from the point of view of addiction, it's the same thing. If one is an addict, it is irresponsible not to seek treatment, and to the best of your ability.
 

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