2002 LECTURE SERIES

Drug Addiction: Why the Brain Loses Control

Dr. Nora Volkow
Associate Director for Life Sciences Brookhaven National Laboratory and Professor of Psychiatry, SUNY Stony Brook
January 30, 2002

Thanks for that very nice introduction and I want to really thank all of you for the opportunity to come to UC Irvine and give this presentation. Now, to start with, I'm going to start with a complaint. I hate dark auditoriums because darkness puts your brain to sleep and I don't want anybody to be asleep, so is there any way that we can increase the light a little bit. I think that we can still see the images.

I think one of the most complicated problems, and at the same time, one of the most fascinating, is the problem of drug addiction. And why is it that I think it's one of the most fascinating? Because it entails the loss of control and we as humans with our complex brains love the concept of thinking, at least, that all of our actions in many ways are voluntary and we are here--we have a clear-cut example where they are not. I've never, ever, ever, in my life, in my professional life, come across a single drug addict that told me that they wanted to be addicts, but basically all of them wanted to stop the drug. They end up coming for treatment and yet what happened was, they could not control it, even though they consciously said, I don't want to take the drug. These people are paying an extremely high price at all levels for taking the drug, so something very, very powerful is driving them to take the drug. And so if you think about it, it provides a real challenge to try to understand what happens in the brain that makes you lose control.

Now, if you take a drug--I mean traditionally and classically, there's been a lot of prejudices against drug addiction, and I come from the psychiatry field and we are responsible for some of that -- well, it has to do with the person cannot control the drugs because they have a weak personality, whatever that means, or because they don't have the moral standards and there was always this connotation and judgmental view about the process of addiction. And then people started to see well, people take drugs because it's pleasurable. They seek pleasure. The thing that's interesting is that what happens with a lot of drug addicts is that the drug stops to be pleasurable and they'll tell you, Doc, I really don't even know why I'm taking the drugs. It's no longer pleasurable. So then why are they taking it? What's happening in the brain that makes them engage in this behavior that's so intense that they are actually sacrificing a great variety of other structures that they have as humans?

Well, I mean if you look at the literature, what do we know? Well, for many, many years, it was classically said well, people become addicted because drugs make you feel pleasure, but that doesn't really make much sense because all of us, if we were given a drug of abuse--no, I wouldn't say all of us, but many of us would find the drug pleasurable. And so if we get exposed to it, we may say well this is interesting, it's pleasurable, it's an interesting experience. But if you're addicted and you were to be exposed to the same drug, the difference would be you would find it pleasurable, but immediately, you would have this strong urge to take the drug, and if you had the drug in front, you would be unable not to take it. So that distinction between the person being able to perceive the drug as pleasurable, but saying this is an interesting experience, verses that of the loss of control is what we call addiction and the notion is what goes on. And clearly from that experience is like all of us can drink alcohol, can find it pleasurable, but only if we are alcoholics do we lose control. But it's not the fact we are not alcoholics, we are not receiving the pleasure, so it's not inability, which was believed for many, many years, that the person that was addicted to drugs because they were more pleasurable, where there's evidence that that's not the case. In fact, the drugs may be less pleasurable. So then why are they taking it?

Well, in studying addiction, and I would say the same for any type of behaviors of the brain, you're dealing with a very complex set of phenomenon that ultimately account for the process of addiction -- and in the talk, I wanted you to realize that, that I'm going to be focusing very much on the biology, not because I think that the biology's the only thing, or actually you have to start to disengage the puzzle to then be able to put it together and understand it. Addiction is complex. If you do not get exposed to the drug, you will not become addicted, but it's certainly clear that our environment is very, very important. We know, for example, that stressful conditions favor drug administration. We also know that genes are very important. We know that from epidemiological data that, for example, has been documented again and again and again, that if you're born out of a parent--that is a father that's an alcoholic, you're at the higher risk of becoming alcoholic. Moreover, we know that genes are very important in drug addiction because we can actually now engineer animals where you mutate one gene that you can naturally make them to self-administer drugs much more rapidly. Or the same thing, you can manipulate a gene and make those animals never want to take the drug, so we know that genes are important. So, ultimately, the whole concept in the process of addiction is that interaction of your environment, your genes, your past history, your biology, what I call, and then ultimately, the drug itself.

Are there changes that are produced by the drug, and then produce addiction? Well, with this complex picture, where do you start and where do you start in terms of--I mean the question that I was after is to understand the biochemical changes in the brain that lead to the loss of control, that's what I'm after. So, where do you start with something like that? It's quite ambitious. Well, in science, what you do is--actually, science is a wonderful thing because it builds on knowledge, so you take the information that has been previously available and you set to design your experiments. Now, I work with humans, but there's an enormous amount of new territory in animals actually documenting the effects of drugs in the brain. And the most important finding, I should say, in terms of the effects, why do people take certain drugs and not others? Well, the reason why drugs of abuse are perceived-drugs that produce addiction and are perceived as what we scientists call reinforcing [inaudible] is because they have a unique effect in the brain. They increase the concentration of a chemical that we call dopamine. So they increase the concentration of dopamine in pleasure centers of the brain and this ability of drugs of abuse to increase dopamine is--appears to be crucial for its reinforcing effects. And all of the drugs of abuse do it-- alcohol, cocaine, heroine, marijuana, you name it. They increase dopamine and that's presumed to be the reason why they are addictive.

So, people were saying okay, then that says dopamine is important for the rewarding properties of drugs. But how does it work then? What is the role of dopamine in addiction, because we say you can perceive the pleasure of the drug and the drug is increasing dopamine in your brain, but you are not addicted. So then what happens? What is really the drug of dopamine in the process of addiction and the loss of control, and that's what we aimed to study when we did that imaging study, strive to understand it. Now, how do you look at dopamine in the human brain? It's producing in a very small area in the deep areas of the brain called mezacelaphone. A few, actually, a very small nuclei, and it sends projections, like fingers, touching different areas of the brain and one of the fingers that it touches is this area here, which is called the nucleus. It's not that unique to remember, it's just one of the most important pleasure centers of the brain, so this area up here. So, the dopamine cells go and regulate it. So, the way that it works, in a simplified fashion, is that dopamine cells sends a projection like a finger, which we call a terminal, and if I had a better pointer, a visual can give me a better point, this is very, very weak. So, this is the dopamine terminal. Dopamine is liberated, so the chemical is liberated and this acts like the messenger activating this area here, this cell here, to these molecules that we have here, which we call the receptors. So, dopamine is liberated, it activates the receptors and this produces a signal and if you see this in this area here, it's a pleasure signal.

Now, we use imaging technologies. With imaging technologies, the ones that are used is called positive emission [inaudible], PET scanning, and the thing that PET scanning allows you to do is actually, it just measures the concentration of radioactive compounds. These are radioactive compounds that have very short lives, 20 minutes, so they are very benign. You can use it in humans. But the beauty of the technology is that you can use these radioactive compounds to label specific molecules, so you can create a compound, a radioactive compound, that will, for example, label the protein here, which are the ones that are sending the messages, the receptors. And this is the image that actually reflects the concentrations of these receptors, these molecules that are transmitting the pleasure centers into the brain, so you see it here and the colors represent different concentrations and in this case we'll use a rainbow scale. I'll be using the rainbow scale all along, so the areas in red are the ones with the highest concentration. Now, this image here that looks very similar to this one, actually, is targeting a very different protein. Here, we're targeting this blue protein here. This is the receptor and we can target this protein here, which is a transporter, and a very interesting one. I don't have time to get into it, but you see, the images look very, very different, but they are I--very similar, sorry, but they are actually looking at the completely different proteins and that's absolutely very powerful because it allows you to see, for example, are there changes with drug addiction here or are there changes here? And on top of that, you can also look at--if you see a changing of protein, to me, I can say a changing of protein, well, that's academic curiosity. The important aspect is how does the change in that protein effect the way that the brain functions, because ultimately if you are going to understand the process of addiction, you need to understand how it changes in function, so with pet technology, what you can do is actually measure the consumption of glucose in the brain and glucose is the main source of energy in the brain, so, when an area's very active, it consumes more glucose, but when an area is dysfunctional, it consumes less, so you can actually look with this technology at different types of proteins involved with dopamine signaling. That dopamine cell sends a message, interacts with these receptor and this produces a signal, which you can measure with brain glucose metabolism. And because these radioactive substances have very short, half-life, you can do multiple tests in the same individual. Also, you can test transporters, receptors and metabolism in the same person and try to understand what are the consequences, for example, of changes in receptors in brain activity. We can do that.

Now, what happens, what I'm going to do here is my strategy in understanding addiction has been not to understand, per say, okay, an addiction, but to understand the process of addiction in general. So, I've taken the notion of studying multiple substances sequentially, so I've studied alcoholism, cocaine, heroine, methamphetamine, and what I'm going to be presenting to you is not the specifics on one addiction, but actually, I'm going to concentrate uniquely on the things that they have in common. Because ultimately, there is a skeleton on the process of drug addiction that is similar across the different drugs and it's understanding what that skeleton is all about, or actually, my view provides a slide of what's really going on with the loss of control.

So we are going to, for now, forget about the dopamine transporters, because while certain drugs do change these cells, it is not a common finding. The common finding across all of the drugs of abuse is these molecules here, the dopamine D2 receptors. And these proteins are very important because they are key elements in transmitting the pleasurable signals associated with drugs of abuse. So, if you generate--now, I said you can generate, engineer animals, that don't have specific genes. If you can generate animals that don't have the genes that [inaudible] for this protein--and interestingly what happens with these animals, they will not take alcohol. They will not perceive morphine as pleasurable, so you completely manipulate the ability of drugs to be reinforcing by getting rid of these receptors.

So, what happens when we measure these receptors in people? And this is a very consistent finding. It's the same in cocaine or alcoholics or heroine abusers and these are the images. These are actually images that were obtained many years ago. I think I published this story almost ten years ago, but it's a classical one because we've replicated it since. Let me guide you as to what you're seeing. These are four levels of the brain. It's a horizontal slice. It's like they're slicing an orange of sequential plains. This is your scale, the rainbow scale, and the concentration of the receptors, which is marked here in red, is very much toward the center area of the brain and this level, which is lower, and it's exactly where you have a pleasure center in the brain. This is a normal subject. This is a cocaine abuser tested one month after large doses of cocaine and this is the same subject tested after we've hospitalized him for four months to ensure that they don't take the drug. And what you can clearly see is that there is a significant reduction in the levels of dopamine D2 receptors, which in this case, you'll see by the fact that actually you see the concentration going down and you can see just by the color scale. And what was interesting is that these reductions in dopamine D2 receptors is long lasting and it's certainly present at four to five months after the patients have been detoxified for long periods of time.

Now, when you look at data, one of the things that's very tricky, but I want--I mean, you are--I mean part of the notion is for you to realize what are the tribulations that all scientists face, and I'm not complaining 'cause I like tribulations, but one of the tribulations that we face is that nothing in biology--almost nothing is black and white, so it's not like everything is yes or no, and I want you to get exposed to it because that's one of the difficulties that we face. So, when I show you an image, I'm going to follow you--here is an image of a subject.

Well, how frequent is this abnormality? I'm always going to follow it with individual data. So, what you see here--let me get back--these are images. Now, images are actually generated by matrixes of numbers, so you can actually draw--you can draw a circle here and quantify how many receptors are there, so you can transform this image into a number and that's actually what I'm interested. I'm not interested just in the fact that they're very nice looking images, but what are the numbers like? So, what I'm going to show you is the individual data for one of the stories. We've replicated this in three different groups of cocaine abusers and one--this is one of the groups of cocaine abusers. So, what you see here in this axis here, is the levels of dopamine D2 receptors and here, I'm plotting it as a function of age for two groups, normal controls and cocaine abusers. These are cocaine abusers that are hospitalized to ensure they don't take the drug. And I'm plotting it against--there's a function of age because as we grow older, dopamine D2 receptors go down. And when you look at the data, you can clearly see that the cocaine abusers have lower levels than the normal controls. So this is statistically significant and as a group, cocaine abusers are lower levels and we've replicated these in three different groups. It's not specific for cocaine. We've seen it in alcoholics. We've seen it in heroine abusers and we've more recently seen it in methamphetamine abusers. There's the reduction in receptors, however, I want you to also pay attention to the notion that it's not a black and white finding and what you see here is, for example, you have these cocaine abusers that look like controls, but in the brain, even more important, are these normal controls that look like cocaine abusers. Look at that one. And to me, that actually is something that has never--that has haunted me all throughout my studies because you can either ignore it or to try to understand it, and I'll come back later to this. So, this is what we've found, decreases in dopamine D2 receptors. And this was very interesting because it documented for the first time that there are biochemical changes in the brain of drug addicts, cocaine addicted people.

The question that I was after was not just to identify that there are biochemical abnormalities, but what I was after was to understand how do these biochemical abnormalities lead to the process of addiction? And by themselves, they don't, per se, tell me much, because what about if there is decreases in D2 receptors, but as we know, there's an enormous amount of redundance in the brain, so maybe we can compensate. So, if we have decreases in receptors, that function doesn't change, who cares? So, the question though was, are there changes in the function of the brain of these people, and are these changes in any way associated with these reductions in dopamine D2 receptors? Well, the way that we approached that problem was by measuring, as I was telling you before, brain glucose consumption, because it's a very sensitive indicator of brain activity, so when you have this function, one of the things that happens is glucose consumption in the brain goes down. And these are the images for the same subject that you saw before, for D2 receptors, the same cocaine as you observed on the normal control, except now you are looking at the different parameter. You are looking at glucose consumption, so, of course, the images look different and it's only three images. This is the same levels, three different levels, on a normal control, in a normal control. These are actually people. We test them. They are awake. They have their eyes open. You see they have their eyes open because just to get you an idea of how neat this concept is, this is the visual cortex, so if you study the subjects with their eyes open, it gets very active. You have them close their eyes, this area becomes decreased activity. This is the frontal cortex. This is a normal--these are actually--I think it's a medical student and you see the high activity in this area here, which is called the single [inaudible] very famous area because it's very important for attention.

Now, what happens with a cocaine abuser? This is a cocaine abuser and no cocaine for ten days. They have this dramatic reduction in glucose consumption, so their brain is much less active than that of a normal person and what's interesting is the notion that it's actually widespread and it's long lasting. There is some recovery of activity. This one looks better than this one, but you can clearly see that even at the 100 days, post last use of cocaine, there's dramatic reductions in glucose consumption. And the other thing that's interesting is while the changes in metabolic activity consumption are central of the brain, there are some areas that are more affected than others, and I'm actually putting them with these arrows and I'm pointing it out here. Look at this area here. There's basically no activity. That's the prefrontal cortex. You don't want your prefrontal cortex not to be active. You don't want your single [inaudible] not to be active because then you cannot pay attention and that would be really terrible. Just compare that single [inaudible] with this one on this person here. Look at this here. There's basically almost no activity to the prefrontal cortex, so, what we see is that there is a decreasing in activity, but it's most accentuated in the frontal cortex.

Now, we were trying to understand, are these changes in activity of the brain in any way related to the changes in the receptors that we were seeing? And because we had the measures in the same subjects, you can actually ask the question, are they in any way related? And let me tell you the question--the answer, actually, before I go any further. The answer is yes, they are related, but that relationship is not throughout the whole brain, it's on very specific areas and I'm going to show you where it is. So, I'm going to show you that these right here shows you the brain areas where activity was--as the decreases in activity were associated with a reduction in receptors. And this other area here, in this diagram, this area, which we call the single [inaudible], the one that I was telling you, very important for attention, prefrontal cortex, very important for a lot of cognitive abstraction processes, orbital frontal cortex, this area of your brain just on top of your eyes, very intriguing area and I'll get back to it because it's a fascinating area. Nothing related to the classical areas, the limbic areas, the pleasure centers, no. The reduction in receptors were associated with reductions in the frontal cortex. And this was a very intriguing phenomenon, but I think, before I get into that, because it was intriguing because nobody had really documented that the frontal cortex was important in drug addiction.

We always thought of drug addiction as that addiction, a disease of the primitive parts of our brain, the limbic parts. And here, the frontal cortex, which epitomizes the higher levels of our human brain, appears to be involved in drug addiction. And I--before I get into the story of why I think this is intriguing and how it helps us to understand addiction, I want you to look at the individual data, because actually, what you are seeing here is for you to see--we investigators like to show you images and results, but I like to challenge you all to see what the data really looks like, so I'm taking this area here, the areas with the strongest association between D2 receptors and [inaudible] the ones in red, single [inaudible] and orbital frontal cortex. So, the next one shows the orbital frontal cortex, and what it shows is the data, now numerically, activity in the orbital frontal cortex, as a function of the levels of receptors and you see that it is the subjects with the low levels of receptors that have decreased metabolic activity into these areas of the brain. So, what it is telling us is that yes, there are specific biochemical abnormalities in the brain of people that are addicted that are functionally significant, that are associated with a reduction in activity of frontal areas of the brain and that association is strongest for the interior single [inaudible] and the orbital frontal cortex. And these, as I say, was something that was unexpected, completely unexpected and, and because it was completely unexpected, than you are in a little bit of a vacuum of how do you make it, how do you understand it and it had a lot of implication.

So, before I wanted to jump into the water full of the implications, because it really changes the way that we look at the picture, I said is it something just to cocaine, because we replicate it on cocaine, or is it something that is present in other types of addiction? So, here is the latest data with methamphetamine abusers, actually methamphetamine is a serious problem of drug addiction in California. A lot of the work on methamphetamine, and I'll touch on that a little bit later, has to do with toxicity, very toxic drug, but we really do not understand the process of why is it so addictive. So, we did the same study as with the cocaine abusers and these are two levels of the brain on a normal control. You see the concentration of the dopamine D2 receptors here, and this is a methamphetamine abuser, the classical reduction in the D2 receptors, in methamphetamine abusers. Those, like I said, were the cocaine abusers, and this is the individual data for you to look at, exactly showed like before, as decrease is a function of age under normal controls, and then you see as a group, methamphetamine abusers have reductions in D2 receptors.

Are these changes in D2 receptors also associated with changes in the functions of the frontal cortex and the answer is yes, they are. They just recently, very recently, like I think one month ago, published this. As for the cocaine abusers, it is the subjects that have the low levels of receptors that are seeing the marked reductions in activity of these frontal areas. Now, let me tell you and explain to you why I went to the obsession of trying to replicate this in two groups of cocaine abusers and now in methamphetamine abusers. I did it because it basically, to me, it was an eye opener. All of us saw then--were documenting that this area here, orbital frontal cortex, on top of your eyes, is important for drug addiction, so I'm going through the literature and of course there's zero, no information about the orbital frontal cortex in drug addiction, none.

Now, how do we make sense out of it? Well, neuron-atomically, it makes sense, because the dopamine cells, which I told you are in the deep part of the brain, send projections that go ultimately and regulate the orbital frontal cortex, so just--it makes sense that the drug, drugs of abuse that are activating the dopamine [inaudible] ultimately with repeated administrations, are going to affect the functions of this area of the brain.

Now, why was I intrigued? Why was I so intrigued? Well, I tell you, there was nothing in drug addiction and this was ten years ago, however, ten years ago, there was some really classical work being done in the imaging community documenting that this same area, the orbital frontal cortex, was abnormal in patients with obsessive compulsive disorder. So, there I am one day presenting grand rounds in the department of psychiatry and I say well, they have similar abnormalities and my chairman gets offended and says Nora, are you pretending to tell me that obsessive-compulsive disorders and drug addictions are the same disease? And I said to him no, I'm not pretending to say they're the same disease, but I'm pretending to say that they have destruction of the same sequel. I said furthermore, if you think about it, what do these two disorders have in common? What do they have in common? The compulsive quality of the behavior, the obsessiveness. In the obsessive-compulsive person, it is to wash their hands at nausum. And if they don't wash them, they have the compulsion to do it. They end up washing it. In the drug addict, is to take the drug, even when the drug is no longer pleasurable. If you think about it, then yes, of course, both of them have the compulsive and then the--what the data is telling me--I mean I have no prejudgments. This was a surprise to me as much as it was to my chairman, was the notion that here, drug addiction is disturbing an area of the brain, the orbital frontal cortex, that we know when disrupted, leads to compulsive behaviors. And of course, that completely changed their perspective because it leads from the notion that you are taking the drug because it is pleasurable to the notion that when you've been exposed to the drug for a certain period of time and you've become addicted, what characterizes addiction is the compulsion, and it may be that it is the ability of chronic drug administration to change the function of this area of the brain that ultimately leads to the compulsive behavior. And, in fact, there is--well, there was no data on the role of this area of the brain in addiction. There's really elegant work in the field of food consumption. The orbital frontal cortex is an area of the brain that's absolutely fascinating because it's the area of the brain that allows you to assess the value of something as a function of its context. So, something that's appealing to us is appealing under certain circumstances, but not certainly on their [inaudible].

And what do I mean by that? You take a monkey, or monkeys--and you give them a piece of lettuce, so then--and they are recording orbital frontal cortex. The cells go very happily because it's rewarding, so the orbital frontal cortex gets activated, but then you take the same monkey and you put a piece of apple and the piece of lettuce, the orbital frontal cortex no longer fires in front of the lettuce, but it will fire in front of the apple. So the ability to change the reinforcing value of something as a context, is the role of the orbital frontal cortex. Now, you haven't disrupted--and what drugs are doing is they basically are making all of the other competitive stimulus bail down in the addictive person, so the main drive is the drug and nothing can compete with it, and that's basically modulated by the orbital frontal cortex.

So, for example, what happens--and these things you can do in animals, you can destroy the orbital frontal cortex in an animal. So what happens when you destroy an orbital frontal cortex in an animal? Something very intriguing happens. You have an animal, a normal animal. You teach the animal to press a lever and every time that the animal presses the lever, he gets food, okay? Then you withdraw the food and the animal initially presses it a lot to try to see what am I doing wrong and then gives up. It's like when you go and you put your dollar in the can machine and it doesn't come and you may kick it to try to see if you can get your can, and after kicking it two or three times, you say this is ridiculous and you leave. Well, the animal does something--it tries it and then just gives up. If you destroy the orbital frontal cortex, the animal presses the lever and continues to press the lever even when it no longer is delivering food. It cannot change the ability to see that that's no longer reinforcing and that's exactly reminiscent of what your drug addict tells you, I do not know why I'm taking the drug. It's no longer pleasurable. I just cannot stop it.

So, what this data brought to us was basically a completely different perspective in the notion of addiction. It brings the notion that the drugs, through their effects on the dopamine system, are basically interfering with the function of two areas of the brain, orbital frontal cortex, the single [inaudible], so I don't spend so much time because I don't have--it's not so clear in my brain yet how important is the interior single [inaudible]. The orbital frontal cortex is key because it's such an important area on valuing the relative value of things, and on motivating, this is actually things that are valuable, motivations, to go and try to achieve them. So, this area of the brain is keying the motivational [inaudible]. So, what's happening with the drugs of addiction is they're actually not only affecting the pleasure centers, but they actually fundamentally modifying your ability to perceive other stimuli as reinforcing, and to have those stimulis be able to actually stimulate you, and in the drug addict, that's what happens. The individual is no longer able to perceive pleasure in other things, and as a result of that, the main drive becomes the drug. And this, of course, has caused a lot of therapeutic implications because one of my perspectives is how can we develop strategies to make those other reinforcers valuable again so that the subject can have more than one behavior so that there are competition between them. And so that's one of the therapeutic implications of these findings. However, having said this, that the drug abusers, whether it's a cocaine abuser or in alcoholics, they have decreases in D2 receptors and this is, in fact, associated with disruption in the frontal cortex. You could come back to me--and this was actually pointed to me, probably one of the first lectures, they said, well, how do you know that these changes that you have there were not there before the person became addicted? How do you know? You study them, they are addictive, but you cannot imply that this is the function of the drug exposure. And my answer is I don't know. I don't know. These people are cocaine addicts. They studied them when they are already addictive and yet it's a very important question because it implies--it actually touches on an aspect that's very, very relevant. If, in fact, these changes in D2 receptors were there before the person becomes addictive, then could it be that they, in some way, have to do with the vulnerability, the predisposition to take drugs, which we said varies from person to person.

Environmental circumstances and people get exposed to drugs. Why do some people become addicted and others do not? A very, very important question. So, that question of how do you know that those changes were not there? It pertains to the issue of predisposition, but how do you study it? Well, you say, I am not a scientist. If you are not a scientist, this is simple, just study your person before they become addicted, then follow them and see if their receptors changed. And yes, of course, that's a way of doing it, but that would be so expensive to do, because you don't really know who's going to become addicted, right? You can judge just as well with select family members, et cetera, et cetera, extremely expensive, very, very difficult study to do. No study section of the NIH would fund you. So, I'm not so grandiose to say I'm going to propose that, so I couldn't, but I'd love to do it, but I cannot. So, you have to be clever and creative in these things. If I give a presentation like this, I actually, I benefit a lot from questions like that. It just raises my curiosity. So, I said well, let's move the table around. Let's approach the problem from a completely different perspective, and I'll tell you what I mean by that.

This is another story just like the two that you've seen before, another one, it's replicated at nausum, looking at dopamine D2 receptors, again, in normal controls in cocaine abusers, this is, as, again, the similar findings, normal controls, decreasing in age, cocaine abusers look at them, lower, lower, lower, but the thing that I was telling you, that it's actually astounded me, look at the overlap. Look at these, look at the subject here. Initially, the subject has values completely undistinguishable from drug abusers. And so forget now about the drug abusers, because that's the approach I said, just let's focus on the normal thing. And the thing that impressed me about the normal controls is that tremendous variability in the levels of D2 receptors. So we have this subject here, for example, that has almost 50 percent lower receptors than this subject here, and while some of these variability in the levels of receptors is accounted by age--as we grow older, we have less receptors. You can see that for subjects of the same age, you still have tremendous variability. So, I said why is that significant? And that's where you sort of say, or, and you can ignore it and say no, I'm not seeing that. It's statistically significant, let's publish it, or you can look at the data and say what does it mean? If we claim that lower levels of dopamine D2 receptors are in some how involved in the process of addiction, that they are important, then we cannot have it both ways, ignore them in the normal controls that are not addictive.

So the strategy that I said is if we are claiming that dopamine D2 receptors are important in the process of addiction, what does it mean to be a normal person having low levels of dopamine D2 receptors? This would be the way that you'll respond to drugs of abuse. Was it effective? And it's a very valid question, so that's a factor in the study that we need. We took normal controls, a very simple study, we measured dopamine D2 receptors, 23 subjects, quality controls, not taking drugs, and we gave them Ritalin. Ritalin is a stimulant drug that we use for the treatment of Attention Deficit Disorder, but, however, it's a stimuli like amphetamines. An interesting thing about stimulants is that some people like them and some people hate them. It's a very interesting concept, very valuable responses. In general, you see a lot of variability in the responses to drugs, but with stimulants, it's very marked. So we took advantage of that and said if the perception of the drug in the pleasurable/unpleasurable dimension at all related to the levels of receptors, because if we claim that receptors are important in the way that you respond to drugs of abuse, then you could predict that they may and we did that experiment. We measured D2 receptors and then we gave them Ritalin and we asked them do you like the way that the drug makes you feel or not? We gave them a hectic--a fairly high dose of Ritalin, by the way. And what happens is roughly 50 percent of the subjects liked it and 50 percent disliked it. And when they dislike it, they dislike it. They hate it. They say I hate it. So, this is a subject, that like the--that did not like the way that the drug made him feel. He reported it as unpleasant and on the contrary, this is a subject who liked the way that the drug makes him feel. These are dopamine D2 receptors and you can see this subject here that liked the drug, as he reported it as pleasant, has much less receptors than this subject here, and you're going to see the individual data, since I've been promising you that I will do that for every single finding and here is the data. Twenty-three subjects, two--these two subjects were very bizarre, fascinating, and I have a story. Now I understand it, but I don't have time to go into it. They don't respond to anything, nothing, nothing. You measure their heart rate. This is a very high dose and they--their heart rate doesn't even go up. They don't feel anything. Now, but I tell you, I know why. I know why. There's a reason to most of the things that happens with drugs. Pleasant--much lower levels of receptors than those subjects that reported it as unpleasant. So, what I'm saying is that your response to a drug is not just a function of that drug, but actually of the unique biochemical characteristics of the brain. Of course, it makes a lot of sense, but you have to--inside, is you have to prove things even when they make a lot of sense. So this was, in fact, the first demonstration in humans that the unique biochemical characteristics of the brain of the subjects in this case, the levels of these receptor molecules predicted the way that they responded to a drug in the liking/disliking phenomenon. People just reported the effects of methylphenidate as pleasant, Ritalin--reported it as pleasant because it make them feel higher, full of energy, more expansive. People that reported the effects of them as unpleasant, which said I hate the drug, hated it because not only it decreases--it make them feel more depressed and it make them feel out of control and very, very restless.

Now, what explanation do you make out of these findings? And I like a simple explanation, and I like always to take information that's out there and use it to try to explain a phenomenon. And in the field of drug abuse, it has been known and in pleasure, in the study of pleasure, and the perception of pleasure, it is known that there's an optimal level of stimulation at which things are pleasurable. So, if you do electrical stimulation on displeasure centers--if you do a very high--very low frequencies, that's not enough. But then if you do very, very high frequency, those responses become aversive, so there's an optimal window at which the stimuli is pleasant. So to me, the easiest explanation of this finding is in these subject with low levels of receptors, we give them Ritalin, methylphenidate, a high dose, it's massive link with dopamine. They have lower levels of receptors, so that serves a little bit to [inaudible] the signal and to produce the optimal transmission. In the subjects with very high levels of receptors, they are producing a massive increase of dopamine and that just becomes aversive. They have many receptors, but they all get stimuli that it becomes aversive. And so what we postulate is that perhaps what's going on here, and this is the way that it may relate to vulnerability, is that if you have a high levels of receptors, they may be protecting you against taking drugs because drugs produce a much larger increase in dopamine than normal psychological reinforcers because I must tell you--I forgot to tell you this--but normal reinforcers like food or sex are pleasurable, in part, it's mitigated by the fact that they also increase dopamine in the same areas that drugs do it, but they do it at a much lower level. So could it be that in these people where they already have high levels of receptors, they get very much stimulated by normal things, but then you give them a massive swab and it becomes aversive, whereas in this individual here, with low levels of receptors, the stimulation of the drug is optimal.

So, this was--if that were the case, and it's a hypothesis, of course, just sort of say, these people here, in which it wasn't pleasant, we gave them a very high dose, but the question is, if it was [inaudible] actually, I think that that's the answer. If we had given them a lower dose, one-tenth of the dose, we gave them .5 milligrams. That probably doesn't tell you anything, because it's just a number, but it's a big dose. So, we gave them one-tenth, would it have been pleasurable? Again, use the experiment to do--I go through the IRB Institution, I review report, to ask permission. Can I call my subjects back and give them a low dose of methylphenidate because I predict that there's going to be a low dose at which these people will feel the drug as pleasurable. So, after weeks of going through the IRB, I get permission. We call the subjects. They refuse to come back because the experience was very unpleasant. So, I don't know the answer, but I predict that my thinking was correct, but I don't know. So, I think--so, we publish this data and we sort of say this is preliminary evidence, which [inaudible] you also have to be very cautious, or I should sort of say, this is preliminary evidence that the dopamine D2 receptors may play a role in vulnerability. Call it preliminary evidence--in the fact that in as much as having lower levels of receptors will make you perceive drugs as pleasant. If you approach a drug and you feel it as pleasant, the likelihood that you would take it again if you were exposed to it, is much higher, and this has been demonstrated, than when you take the drug for the first time and it's very aversive. So, that initial response to the drug actually does play a role in vulnerability. So we publish it. It sort of says, this is preliminary data, but when you do these studies in humans, human brain tells you a lot of things. It tells you--it points you, the way that I view it, is doing studies in humans that are addictive, it gives us a way of which are the pertinent variables. But the problem with is these studies are an association, so we have an association between having high levels of receptors and having an aversive response.

It's an association, but how do I know that they are linked? There's a [inaudible] a causality between having--that the subject disliked the drug because they haven't high levels of receptors. It's an association. It's suggestive, but it really doesn't prove it. For me to prove it--and that's why I was so timid in my discussion on the paper--for me to prove it, the way that I'd like to prove it--again, I tell you, just aside, I can fantasize how I'd like to do it. These people that have low levels of receptors, I would like to do something to them so that the receptors go out and then I want to give them methylphenidate and then I predict that they are going to hate it. But how the hell do I increase dopamine receptors in the human brain? I have no way of doing it. There's absolutely no way I can do that, so that is why, basically, this is an example, but what I started to do--normally, in science, you take the data from the mice and you go to the humans, but here, now with these very powerful technologies, where we're finding things in humans, but we cannot completely answer it, you can test it in an animal. In an animal, we can actually increase receptors and see that, and that's what we did, and it's actually--a study done by one of my post-doc, Peter Donalds, who actually, what he did was he made animals self-administer alcohol, so he make animals alcoholic. Not all animals become easily alcoholic, but there's a group of them that do like it and they start to drink a lot. And what he did to these animals, and these little creatures, is he actually injected them with a adenovirus here, and in the adenovirus, inside of the adenovirus, he puts the DC receptor G and the adenoviruses are these wonderful things. They are terrible also, but the viruses are very scientifically interesting because they are fantastic syringes for the cells. So, you put that gene into the adenovirus. The adenovirus attaches to the cell and liberates the DNA inside. So, it's a way of delivering genes, in this case, into the brain. So, we injected these adenovirus with a D2 receptor into the nucleus [inaudible] is that area that I tell you, the pleasure center, where drugs increased dopamine. When you do that, you inject here, you measure a percent change in dopamine receptors. Dopamine receptors go up. They go up, not dramatically, interestingly. In this case, we'd see an increase of 50 percent, which just say--I mean just by pure chance is in the range of the viability that we're seeing across people of the same age, so this is very physiologic. The maximal changes occur at four days. With the adenoviruses, if you inject the gene and the gene doesn't incorporate into the DNA, so the exposure is very temporary. It just lasts a few days. Your body sets up an immunological reaction that destroys the adenovirus, so ultimately, the effects are very short lasting. So, the gene--the receptor goes up 4, 6, 8 days, but around 10 days, it actually goes back to baseline. At this point, we injected the animals again and then we measure again, the receptors go up. So, what happens if you increase the number of receptors in these animals that are self-administer alcohol? And the answer, do you change the alcohol intake? And the answer is yes, and you change it dramatically. And this is the data. This is percent change in alcohol intake. This is day zero, so this is their baseline and this is their reduction, almost 80 percent less alcohol. It does not completely eliminate it, or it markedly, markedly reduces it and the decreases in alcohol, unfortunately, are short lasting and mimic, more or less, paralleling the short duration of the effects of the adenovirus in increasing the concentration of the receptors. So, around day 14, 17, you are back to baseline. And this--on day 20, we injected again the animals, we get the adenovirus and again, you see that the lack of reduction in the alcohol intake. And this is just a [inaudible] but we injected the adenovirus without the gene and you see it has no affect. So, what we showed with this study is that increasing the concentration of dopamine D2 receptors markedly, markedly reduced the alcohol intake and we have now replicated these findings for cocaine administration. So, if you increase the levels of dopamine D2 receptors, you can actually, markedly reduce the consumption of cocaine in animals that have been made to self-administer cocaine. So, documenting in fact that the levels of dopamine D2 receptors do regulate administrations of drugs, are involved, and by so doing, may be one of the variables involved in predisposition to drug addiction.

Now, having said that, I want you to also be critical. In our studies, the normal controls--there were a group of them that had low levels of receptors that were very similar to those that we see in cocaine addicts or alcoholics, that none of them was addicted. What it tells us then is that while the dopamine D2 receptor is important in vulnerability, it is not sufficient to produce addiction, and this is a non-trivial distinction because it brings to light the notion of the other variables that are required for the presentation of the behavior. So, this is the story with the dopamine D2 receptors and it's potential role. Now, what the term is whether you have low levels or high levels of receptors, it's very likely that a component will fit these genes, but I also have to tell you that there is new data coming out showing that stressors, in fact, effect the expression of receptors. So if you are subjected to stress, it can decrease the levels of dopamine D2 receptors and this may be one of the mechanisms by which, under circumstances of stress, people become much more easily addictive, so, it's not just a thing that the levels are just a function of the genes. Genes play a role, but the environment also plays an important role and this is basically the simple--simplified notion, if you have high levels of receptors, what happens is that normal things that are supposed--like this required center, these pleasure centers, are not for us to take drugs, they are there to actually drive us to do things, so we--it's the way that the brain, nature, ensures that you are going to do behaviors that are important for survival, so you tie them to a pleasurable response. So, normal things that are supposed to produce pleasure, actually, if you have a lot of receptors, dopamine has liberated the probability of dopamine having an interaction with our receptor is much higher than if you are unfortunately born, or for whatever reason, have low levels of receptors, so then natural reinforcers are much less likely to drive you and that makes you in turn much more vulnerable to the use of drugs.

Now, having said that, one of the things that's very intriguing, I basically started with a series of studies to try to see are the brain of people that are addicted differently and we've documented that they are and they are different in a very specific way that involves the dopamine system, but [inaudible] involved with motivation drive. But the very important question is how do we know--do drugs, which this is a question that is very much in the general public--do drugs--do we know--these things we don't know if that's the drug. I said it could be genetic. It could be environmental, but are there--do we know if drugs affect the way that your brain functions, black and white. Do they? I do not know.

There's some evidence that they do--but it's also likely to be genetics, but do we have an example documenting that drugs effect the brain, and I'm going to give you an example, drugs modify the way that your brain works. And I'm going to give it to you clear, not like the other one where it can be other things, and I'm going to give it actually for one. I love this image, because it's in many ways, politically incorrect. It's a 100-year-old woman smoking, right? I shouldn't do this, but I love that image, but I'm going to demonstrate it and show you the data that we have for smoking. Why? Because interestingly, anywhere between 85 to 95 percent of people that are addicted, smoke and we don't really understand why. Smoking--everybody--what we know about smoking is that nicotine is very addictive and a lot of the effort of--in understanding cigarette smoking goes to nicotine. The other thing that we know is, of course, it's very bad for your lungs. It produces cancer and that's why this is politically incorrect because it defies our knowledge and I shouldn't be showing this, but I think that she's a wonderful woman there, so I like her. So, we were actually intrigued, not on nicotine, because everybody and their neighbor has been showing studies in nicotine, but there was a study, a very interesting study, looking at the different thing in smoke and they took little rats and they put them in a machine where they just put smoke from cigarettes. They didn't give them nicotine. It was smoke. And then they measured two proteins, actually one protein, here. This protein here called monar manoxidize B--very flamboyant name. Don't get intimidated by it. What this is is an enzyme. It's a protein. What it does, it degrades, it destroys dopamine. So it's a very important protein because if you have very high concentration, it destroys dopamine. If you have very low concentration, then you have more dopamine in your brain and this study done in rats showed that when you put them in a box full of cigarette smoke and then you took their blood and then the enzyme in the plackets in the plackets in the blood, was lower. So, one of my colleagues, Dr. Joanna Ferric, was the one that pushed this particular experiment, said, well, why don't we test this in humans because the question is that who really cares about monar manoxidize being the plackets to [inaudible] I wouldn't even know what to do about it, but I would be very intrigued if it happens in the brain, nor do I care about the rat in the little box because that's very unrealistic. I care about the concentrations that people smoke.

So, is it effecting the concentration of this enzyme? You're going to see--I tell you, in biology, and imaging, nothing is black and white. This is a black and white. There's always exceptions in life. This is a non-smoker. This is what you're seeing here is an image where we're actually measuring the concentration of the enzyme, monar manoxidize B. The highest concentrations in the center here is the talons, very, very high concentration. It's one level. This is a smoker. By now, you've become experts on images. You can clearly see the dramatic reduction. There's no difference between--I mean there's--it's not the same age, the same gender, there's nothing that we can add to it. It is the smoking.

Smokers have a dramatic reductions in the enzyme and, well, the first people--the thing that people said, oh, it's genetic, that's why they are smokers. Well, we took four former smokers, heavy, heavy smokers, who had not smoked for two years, and this is their brain. It is not genetic. It completely recovers and it's a function of the chronic administration of the cigarettes. We've done the experiments. We took ten normal people that were not smokers. We gave them a cigarette, measured the enzyme, it's not inhibitive. You need to give chronic administration. So, it inhibits the enzyme or it can recover when you stop. How long it takes to recover, I do not know because these are people that have stopped for two years and it's very difficult to convince your smokers to stop smoking, so we wanted to design that study, but it was a complete failure. We didn't get volunteers that were successful.

So, here we have a clear-cut documentation that a drug, cigarettes, markedly changes the biochemistry. It inhibits an enzyme that's a key enzyme in regulating the concentration of dopamine in the brain and by now we know that dopamine is key, among other things, for pleasure, but it's also key for movement, I mean concentrating on pleasure. If you destroy the dopamine cells, what happens? You become Parkinsonian. You cannot initiate movement. You are basically enslaved in your body. You cannot move. So, dopamine is important for pleasure. It's also important for movement. It's also important for attention. Here we have a drug that inhibits the instruction of dopamine and what do we postulate happens? It has multiple implications. The first implication was, you know, that there's been a series of studies showing not everything is black--I mean bad and good. I mean we know that cigarettes are very bad, but there's some interesting series of epidemiological studies showing that people that smoke have a much lower incidence of Parkinson's Disease and people didn't know why.

Monar manoxidize B destroys dopamine and it produces in the destruction of dopamine, the metabolism produces radicals that then damage the cells, the dopamine cells. So, if you inhibit this enzyme, you don't produce these radicals and then you don't destroy the dopamine cells, which is what's producing Parkinson's, so these provide a potential mechanism of why they are seeing these much lower incidence of Parkinson's in people that are smokers than are non-smokers. Of course, there are ways that you can inhibit the enzyme without having to smoke. Immediately, the cigarette companies immediately wanted to find those, right? It's not a bad thing that it's inhibiting the enzyme, so immediately, the cigarette companies jump into it, but we didn't accept their money because we didn't want any conflict of interest, but through that whole concept, you know, it's--what's interesting, because it also happens of the notion, we traditionally think of cigarette smoking as nicotine, but here we have a completely different thing. Why do people that are addicted smoke? Well, nicotine is likely to be an important variable, but it's--this is where we postulate. Also, dopamine gets liberated, interacts with our receptor and part of the dopamine goes back, but part is destroyed by this enzyme. So the net amount of dopamine here is a function of how much you are synthesizing, producing, versus how much you are destroying.

Well, suppose you are a cigarette smoker, you have these enzyme inhibited, so the dopamine that is liberated is not destroyed and it gets back into the terminal, so then what happens when you get stimulated--I tell you, all of the drugs, nicotine, alcohol, they increase dopamine. So, what happens is by having this enzyme destroyed, the effects of these drugs are going to be accentuated, that's what we postulated, so more dopamine is liberated and dopamine is the signal that transmits the pleasure, so it actually amplifies the reinforcing effects of these drugs. Again, this is a hypothesis in humans. We did our studies in animals to demonstrate it. We inhibit the enzyme, not with cigarettes because politically incorrect with--to make these poor creatures smoke, but you can give them drugs that inhibit the enzyme, like what we can do in people, and why not? It's not a bad thing to have your enzyme--don't ask me why it's bad. It's not bad to have the enzyme inhibited, it's actually quite beneficial, but what happens is that we inhibit the--where it says naïve, we gave two weeks off, plus civil to animals and then actually four weeks, and then it read we gave the animals four weeks of deprenyl. This is a drug that inhibits monar manoxidize B and we challenged them with cocaine and we measured how much dopamine goes out.

So, let's look at the naïve animals. Cocaine increases dopamine approximately 300 to 200 percent. It goes up and down. And in these animals where we have the enzyme inhibited, look at their response. It's markedly, markedly accentuated, so they are taking--that's one of the reasons why probably these drug addicts are taking the drug. It's making the drug much more powerful. In this case, it's like giving them the double dose, so, not that they know about it, they just feel that the drug is more powerful. And it's not completely a negative effect, because what happens is that we're speaking about the effects of drugs increasing dopamine, but I told you, those pleasure centers are not just for drugs. And what happens is one of the things that we want these drug addicts to be able to do for treatment is to perceive other things as pleasurable, so these may in fact help them to actually perceive other reinforcers, but as I say, there are other ways of doing it.

And finally, I want to touch on another aspect of drug addiction that brings up the whole complexity of the issue where, for concentrating a lot on the notion of why do people become addicted? How do genes play a role? Do drugs change the way that the brain functions? But a question that's actually paramount throughout our society is are drugs toxic? And we have that question--trying to address that for years and years and drugs are toxic to a different extent and for some drugs, we don't really know how toxic they are, like marijuana. For others, like cocaine, we actually show that they are toxic, because they can produce a stroke or hemorrhages. But then there are other drugs who actually go in there, by animal experiments we know, and actually destroy specific cells, so, in animal experiments, so there's--that's another aspect to the notion of addiction that you may be taking drugs that are damaging specific systems in your brain. And I want to actually--that question of toxicity is one that I was personally very much interested [inaudible] that a drug that's very problematic here, methamphetamine. And the reason why I was very intrigued about it was if you look at the literature, there's an extensive, extensive amount of work started by really the classical work of Syden, in which when you gave animals methamphetamine, actually also amphetamine, a few doses, you actually appear to be destroying the dopamine cells, damaging the dopamine cells. Now, this is not a trivial effect, because if you damage the dopamine cells, you can end up with Parkinson's, which is quite a severe nero-degenerative disease. So there's an extensive amount of literature showing that methamphetamine, a few doses, can produce marked damage to the dopamine cells. As I said, these cells are very important, they're important movement, but also important for reward and pleasure. It's what drives us to do things. It's the excitement of life [inaudible] so, if you destroy them in animals, does that happen in humans? And I was intrigued about it because we are unfortunately at the face of epidemic of methamphetamine. And to me, the perspective is that we need to give information to the people and I was particularly interested if, in fact, methamphetamine is as toxic as it's shown in the animal, the people out there taking the drug should know it, then they can make the decision do they want to mess with their brain like that or not?

But it's not always evident, because when you take an animal experiment, you do it under very different conditions from the way that people take the drugs, so it was a very pertinent question and that's why I actually engage in doing the studies because they actually wanted to get that information out there. And the patients [inaudible] were brought from UCLA. We flew them to [inaudible] national laboratory. This is where methamphetamine abusers--it was a study that I did in--jointly with Dr. Linda Chang, and the way that we approached the problem is looking at the dopamine terminal, now, which is the projection of the dopamine cell, it's the part that touches, and you can actually measure it by labeling this protein here, which we call a transporter. And when you do, for example, studies with these radioactive compounds that bind here in patients with Parkinson's Disease, you see a marked reduction in their brains for the concentration of that protein. So, we did methamphetamine abusers and you're going to see it by yourself. Normal controls--this is a [inaudible] that measures transporters that--which we used as a marker of the dopamine terminal. Normal control, two different levels, the same color [inaudible]. Look at the methamphetamine abuser. Look at this. And this is something I have never ever seen with cocaine abusers. I have never seen it with alcoholics. I tried. I thought, initially, I thought--ten years ago, I thought that cocaine was damaging to the terminal, well, it's not, with methamphetamine, it's a dramatic effect. Here is the individual data. Now, we've done studies in--now we've extended it to 19. In normal controls, methamphetamine abusers, very significant and if you look at it, it's an interesting phenomenon. I want you to look at it. It's an average, 24 percent. Now, the thing that's intriguing about it, these images are not very similar to what you see in Parkinson's Disease, except that in Parkinson's Disease, it's more severe, but if you look at the normal data, the data of the methamphetamine abusers, it's average 24 percent. In the Parkinson patients, it may--depending on the severity, it can range between 45 to 80 percent. But if you look at the range, you have a couple of them here that are 40, 45 percent on the range that you see in mild Parkinson's Disease. And yet these people were not Parkinsonian, because it was an exclusion right there. If they were Parkinsonian, they couldn't participate.

And so the question is what does it mean? Why can we have such low levels of transporters? Are they affecting the way that the brain functions? Again, the same question. If you are destroying your terminals, well, it doesn't seem to matter. Who cares? So, while there were no Parkinsonians, what we were seeing in the subjects, we were actually doing a series of tests to actually assess whether the changes in the transporters, the loss of the terminals, in fact, was associated with changes in function and the answer is yes, it was and here is the data. What we found was that the losses of the dopamine transporters in these methamphetamine abusers were associated with disruptions in two functional tasks. One of them was motor tasks and the other one was memory tasks. Motor tasks, here, time gauge, this is one of the tests. We did several tests, but this is a simple test. You ask the subject to walk as fast as possible, very simple. The longer she takes them, the slower they do her. And what you see is that the subjects with the lower levels of dopamine transporters are the ones that were the slowest and this correlation between having low levels of transporters and being very slow was not unique at this gross motor function, but if you have them doing something that requires fine motor coordination, you see exactly the same thing, that it takes a long time for the subject with very low transporters to do these precise movements. So, they--the losses of these transporters in these methamphetamine abusers is associated with decrease in performance.

The same thing with [inaudible] memory. This is a simple memory task. I give you a list of words. I tell you, I want you--I'm going to be asking you which ones you've heard and which not. I ask you immediately and then I work--I'll wait a period of time and what here is the more words as you can remember, the better your performance and again, you see that it is the subjects with low transporters, the ones that are unable to remember the words that they've already heard. So, what this data showed was that methamphetamine, at the doses abused by humans, appears to be now a toxic to the dopamine cells, not as dramatic as the animal studies. The animal studies show double the amount of damage, or three times the amount of damage, but nonetheless, it is damaging. It doesn't show for the first time that not only is it damaging to the terminals, but this appears to be associated with disruption in function.

Now, this was very interesting and, of course, we published it. I mean I wanted, I wanted the data to be out there, for if someone wants to take methamphetamine, let them know what the drug does, let them have knowledge. But the question that was in that paper that we published that we said well, these patients are not Parkinsonian. These subjects are not Parkinsonian, but you have to realize something about the brain. The brain is very redundant, fortunately for us. As we grow older, we lose some of that redundancy. In the dopamine system, it's classical. For example, as we grow older, we lose something like between 5 and 6 percent of the transporters. So, in these subjects, we have 24 in average, 24 percent average loss. That's forty years of aging, 4-0, 40, so, the question was now they are young and that's probably why they don't have Parkinsonian symptoms, because they are young, but what would happen when they grow older, and as part of becoming older, they lose some of the activity of the dopamine cells? Are they at high risk of Parkinson's Disease? This is not a trivial question, a very important question. Well, the answer, of course, depends on what happens to this damage. If the person stops, will they still be at risk? It's like with cigarette smoke and you just stop, you really decrease your chances of getting lung cancer.

So what happens with the methamphetamine abusers? If they stop, well, they recover. Well, I must be honest with you, I thought it didn't and I thought it didn't because we were seeing the damage of the terminal months after these methamphetamine abusers stopped taking the drug and if I were reported in that first paper that we did, we think that this is long lasting, well, it was long lasting because it was present in people that had stopped the drug for a long period of time, but the question was, well, what would happen if these people--if we follow them, even though they have a lot of losses, will they be able to recover? So, we started with 15 methamphetamine abusers. A very difficult drug to treat, very, very addictive. We started with them. Now, you have to realize these are people that smoke or inject, which is different from taking the drug orally. Under those conditions, it's highly addictive. So, we took people that were under a legal system, they either go through rehabilitated or they ended up in jail, which gives you the best chances of getting them clean. So, we have started with 15 and we said, okay. We did the PET scans. We brought them to [inaudible] We followed them and then we said we are going to re-scan them nine months later, and they've been clean. Well, even with the legal system, we started with 15. We ended up only with five subjects, which is not bad if you think about how addictive the drug is, but we were successful at that level, because, in fact, this was a legal problem, otherwise, forget about it. We wouldn't have got the five subjects and I was actually--in my brain, I always have prejudices initially, but the good thing about my brain is that it can be changed. So, if see the data, it does change, so I was looking at this data, my researcher gave it me. I say no, I was going to one of the meetings in Puerto Rico, of all places and I was in the plane and I was looking at the data and I couldn't believe it. The data is the following. This is the image, normal control, methamphetamine abuser. Look at that--this particular subject, marked, marked reduction, one-month intoxifications. This is two years later. Now, you see that recovery, sort of--now, look at the data. This is two areas of the [inaudible] first study, second study, first study, second study. It's only five and yet it's highly significant. In this area, all of the subjects recovered the dopamine transporters, not completely back to normal, they are still slightly lower, but significantly better and in this case, all but one of the subjects in this area of the brain recover also the transporters, so I was amazed. I was in the plane and I couldn't believe it and so to say ultimately, the data--'cause otherwise, why would we even want to do the studies if we're not going to follow the data, so we were documenting for the first time in humans, that even though methamphetamine is toxic, if you stop taking it, there's significant recovery.

If you look at the data, you look progressive at it. You cannot just manage it and I was sort of in the [inaudible] and then someone asked me, well, what happens to the function? Well, you see, actually, that this decreases in transporters were associated with this function [inaudible] and then the study's not so great. This is the data. Is there a parallel recovering in brain function? Okay. I read too fast. Well, this one, this is the time it takes them on second, four of the subjects seem to recover and this one did not. So apparently, it was not significant, but you can start to see that, that there is some recovery there. And this one, this is the fine motor coordination, no change, no recovery. The memory task--this one here--no recovery. Some go up, some nothing. This one here, a [inaudible] there was some recovery, but nothing significant. Whereas in the biochemical measures, we're seeing a clear-cut improvement--in the function, we are not. So, what it tells us is, I think, if this--from two perspectives, yes, it's good news in the sense that if you stop taking the drug, your brain will improve. The bad news is that the improvement will not lead you to normal function, at least not right away, and this wasn't [inaudible] right away. I mean some of these people were detoxified for two years. It may take longer, but you may be able to recover some of that function.

And it brings to light, also, the mechanisms. Why are we recovering? One of the things that's so fascinating is this is our brain. Well, it may be that our brain has ability of recovery, contrary to the classical notion that once you lose anything in the brain [inaudible] is gone. Well, new data is showing that that may not be necessarily the case. And in this data--points into that direction, but the brain, even it cannot recover completely in function, it's able to exert some level of recovery.

So, I've tried to get you a full picture of the whole process of drug addiction and the [inaudible] importance--we've shown that drugs directly can affect the brain. We've shown that genes and your biology, your past experience, can also interact with the drug to affect addiction and now there's data showing that the environment affects the biochemistry. We think that the challenge right now ahead of us is not only helping integrate that, but very much to understand, for example, how genes are effected by the environment to ultimately lead to the process of addiction, 'cause one of the things that's very, very interesting is, well, we know that there is predisposition. Predisposition does not necessarily mean predetermination and understanding that distinction, which does not seem to be very much modulated by your environment, is what will make us as humans, whether we are from the health providers or from the general community, be able to deal with the issues of drug addiction. And with that, I want to end and, but before I do that, I want to just actually give credit to my colleagues at Brookhaven National Laboratory, with whom this work would have not been possible. In particular, I want to basically note the contribution of Dr. Joanna Fowler, who is the head of the pet group and she's the one that did--very much the idea of the studies of cigarette smoking. Youshing Ding, she's our chemist that does the labeling of a lot of the compounds. Dr. Gene Jackwan, who actually is my nuclear medicine physician that does the hands-on work on doing the imaging studies. These two guys here, John Godly and Steven Dewey, that do all of the animal work behind the experiments and, of course, I want to thank the founding agencies and I want to thank you for your attention.