William Vega, PhD: And now we have a real highlight for our program, which we've been fortunate enough to have really be a highlight every year that we've been having our conferences. And some from actually a very ardent supporter of the National Hispanic Science Network from its inception.

It's Nora Volkow, and she's with us again today to present imaging obesity and addiction. It's our privilege to welcome her, all of us, and we're all very pleased that you're here.

Nora Volkow, MD: Buenas tardes. And I'm very pleased to be here. Hola, quÃ? tal?

I think it's the first time that I'm going to be speaking about something that is not just drug addiction, and that relates to obesity. And I actually, I've been interested in obesity I think now for the past 15 years.

And it happened to be Alan Leshner when I started to work with it. And the reason why I came into obesity was, by using imaging we have started to document a series of changes in the brain across a wide variety of drugs of abuse: alcohol, cocaine, and marijuana. And I was - at that time -- and I was very curious, the fact that there was this similarity regardless of the substance of abuse. And yet, clinically, many of the behaviors that one saw in people that were addicted were also observed in some of the compulsive behavior of disorders.

So I was very curious in my brain to understand whether the changes that we were observing in addicted people were the result of the artificial, of the utilization of an artificial substance, or that they were basically underscoring the process itself that related to the behavior independent of the fact that it was the result of repeated consumption of artificial substances.

And so I said, what is the disorder where you are actually also having this compulsive behavior but you are not getting anything artificial? And that's why, how I started to get interested in obesity.

And I went to Alan, and I said, "Alan, would NIDA consider a study where we're actually investigating the neurobiology that leads to the compulsive patterns of drug abuse and with respect to obesity?" And he says, "Nora, you have to convince the study sections."

And unfortunately, I really never was able to convince the study sections. But because you find ways of doing things regardless of whether NIH funds you or not, that's what I'm going to be speaking to you.

Nora Volkow: So, where does it start? Of course, it is not surprising that the field is coming to converge in terms of addiction and obesity.

It's not surprising because drugs, our brain did not evolve for us to take drugs. It was rather that drugs, just by pure randomness of nature, were able to activate the circuits and systems that were in our brain developed for us to survive to do behaviors that are necessary for survival, particularly those behaviors related to eating and feeding.

And does the way nature ensures that we will eat food is by activating the dopamine system. And when the dopamine system gets activated by food, it basically drives the motivation to eat the food. So you can have a food that's horrible, but if dopamine is activated at the same time of that food, you will eat it.

And this happens, for example, when you are food-deprived. The more food–deprived you are, the more starving you are, the more potent the increases in dopamine that occur when you are exposed to food. Whereas you can have the most extraordinary food that you may think of, say nirvana of chocolate cake, but if you are full and satiated, the chocolate cake will not be able to increase dopamine, and thus you don't have the motivation to eat.

Well, that system that's so crucial on linking the state of the system, "Am I satiated or not," the knowledge that this tastes very good, and the motivation to want to do the behaviors to either procure it and eat it or not, that's dopamine. That's exactly the system that's activated by drugs except that drugs activate this dopamine system.

This is food for a microdialysis study from Di Chiara et al. showing the increases of 50%. Drugs do it in a much more efficient and potent way. And you can see the increase in dopamine that occurs after amphetamine is at least tenfold higher than that, actually it's 20-fold higher than that that occurs after food.

What is the result of that? That the motivational drive that's produced by the drug is much more intense than that produced by food. And the other aspect about it is of course with repeated administration of this drug, because it's supraphysiological, you trigger plastic changes that then are believed to produce the process that we call drug addiction.

Now we all recognize that in the case of food, there are certain foods that more easily facilitate the compulsive eating. And I mentioned chocolate not just arbitrarily, but because chocolate or foods in other ways high in sugar and fat are much more potent, much more efficacious, in generating compulsive eating. And that in turn is associated with increases in dopamine.

So, dopamine. Not all of the drugs are equivalent in their ability to increase dopamine. Amphetamine, methamphetamine, are the more potent. Nicotine, alcohol, are less potent.

Similarly, not all of the foods are equally potent in increasing dopamine. And that increase is just determined by your level of satiety, but it's also determined by the particular of the food. So in that respect, we see a similarity.

Nora Volkow: So in using imaging we can actually in human subjects directly measure the magnitude of the changes in dopamine, which are the ones associated with the motivational drives, produced by drugs of abuse or produced by food. We can do that.

This is a study in which we actually, I am just showing you to demonstrate how we use that technology to measure the changes in dopamine produced by a drug stimulant, stimulant, a drug, methylphenidate, that blocks the dopamine transporter just like cocaine. Cocaine blocks the dopamine transporter.

The transporter is the mechanism by which dopamine that's liberated from the terminal is recycled back, and it terminates its action. So when cocaine, and for the same purpose methylphenidate, block this transport mechanism, you block recycling. Dopamine accumulates.

And when dopamine accumulates, then it binds to the receptors and in the limbic area such as the nucleus accumbens that's associated with reward and the motivational drive to take the drug or to take the food if it's done by food.

The way that we measure it is by using in this case, radioactive compound, a compound that's labeled with a radioactive substance, isotope carbon-11. Carbon-11 is 20 minutes so you can use it in humans non-invasively.

And this compound, raclopride, can only bind to dopamine D2, dopamine D2 receptors, that are free, that is to say, that they are not occupied by dopamine. Right now, I predict that when you are not taking a drug or you are not eating, approximately in average 10-15% of your receptors are occupied by dopamine and 85% to 90% are free.

So if I were to inject you with raclopride, 90% of your receptors will bind raclopride. But then you bring the subject back and you give them the drug, cocaine or methylphenidate, blocking transporters, dopamine gets, is no longer recycled, it accumulates and it occupies the receptors. So that when I inject you with a radioactive raclopride, it can no longer bind because those receptors are occupied.

And when you image it with PET technology you can see the decrease in the binding. This is where you have the receptors. And when you do mathematical modeling, you can actually quantify by comparing these with these, the relative changes in dopamine that are produced by the drug, in this case, intravenous methylphenidate.

And then since these are studies that are done in subjects that are awake, you can then determine the association, the relationship, between the changes in dopamine as it assessed with this PET methodology and the subjective reports of euphoria experienced by the subjects when you give them the drug.

And that's estimated by subjective experience of high or euphoria, and you can see that the subjects that have the largest changes in dopamine are the ones that report the more intense high. And this is the methodology that you can use directly to demonstrate that indeed in humans, just as it had been shown in animals, the ability of drugs of abuse to increase dopamine in limbic areas of the brain is associated with its reinforcing effects.

But that's just the beginning of the story for drugs of abuse and the beginning of the story for compulsive eating. This, in my brain, is exactly what initiates the seduction process. It's the first stage of the dance that is required to produce the repeated changes that would lead to the loss of control that occurs both in addiction and in compulsive overeating and obesity.

The other process that happens, once you get a high, you like the drug very much and that experience is memorized by your brain. But it's memorized in a conscious and in an unconscious way.

In a conscious way because say for example that you can't recall if it was one week ago, where you were doing it and what you felt and who you were taking the drug. But unconsciously, or even perhaps at a certain level even of conscious, your brain has linked and associated that environment with an experience itself.

When dopamine goes up, something extraordinary happens. I mean, it's actually almost magical when you think about it.

The surrounding, the environment associated with that experience, whether it is food or whether it is a drug, becomes linked in what we call a conditioned memory with the experience itself of the drug or the food, if it was incredibly pleasant, or the sex if it was incredibly pleasant. And that's driven by increases in dopamine.

Nora Volkow: And this actually is shown, here. This was the process of the importance of memory both for drug addiction and for food, was first demonstrated for food by Pavlov.

And he shows eloquently, and that, he showed it with no technology, that when you take an animal and you teach them - you don't teach them. You just present the food, the animal salivates with the meat, and at the same time that you present the food, you link it with a sound. You do that repeatedly.

And after repeated administration, you need only show the little sound, and the animal will salivate. There's no more meat, it's not necessary. The animal salivates with the sound.

Now with imaging, you can now look inside the brain and see what's going on. And specifically, you can target the dopamine system. Why? Because the dopamine system is that neurotransmitter that is signaling the motivation to act. When dopamine goes up, I want, I want that particular stimuli. This is a study done in animals with voltammetry in which they did exactly the same thing that Pavlov did: couple an auditory cue, but in this case instead of food, it's cocaine. And in this case instead of looking just at salivation they go inside the brain, look at the nucleus accumbens, and they actually measure the changes in dopamine.

And in this slide here, I just have amygdala and hippocampus because these are key structures that are going to be regulating these responses in the nucleus accumbens. These are the areas of memory that then are going to be activating the nucleus accumbens dopaminergic responses.

What happens when you present these animals, after, there are two animals, the purple animals and the green animals. Green animals are exposed repeatedly to the sound by itself. Purple animals are exposed to the sound with cocaine every time, repeatedly.

Animals are brought back, microdialysis, this is voltammetry, this is not microdialysis. Into the nucleus accumbens auditory cue, here you have absolutely no change. Animals that were presented the auditory cue with the cocaine repeatedly, dopamine goes up with the auditory cue.

In other words, and that's why I say it's almost like science fiction, the auditory cue now can do exactly what cocaine does in your brain. It increases dopamine in the nucleus accumbens. Think about it. A neutral stimuli, a sound, can increase dopamine in the nucleus accumbens.

And in animals, this has been shown to predict the behavioral response, the willingness of the animals, to work in order to get cocaine. The greater the signal, the more the animal is willing to press a lever in order to get cocaine with its conditioned responses.

What about humans?

Nora Volkow: Well, you can do similar studies with imaging, and this is exactly what you have here.

This is a study done in 18 cocaine abusers. There's no drug; we were studying them with raclopride, just like we did with the intravenous methylphenidate. But there's no drug.

We bring them two days into the laboratory. On one day we showed them a control video that it represents nature scenes. And we scanned them. And on another day we bring them to the lab and we show them a video of people procuring and consuming cocaine. And we scanned them.

And these are the average image of these 18 subjects when they watched the video of the nature scenes, versus when they watched the video of someone taking cocaine. They are not given any drug whatsoever.

And you can clearly see the decrease in the binding of raclopride into the striatum. Presumably, just like in the animal, by the fact that the visual observation of other people taking the drug is now able to increase dopamine just like the way cocaine used to do it.

Nora Volkow: And I'm saying used to do it because in these individuals, cocaine, the ability of cocaine itself to increase dopamine has now been attenuated. So what you're seeing is a shifting from the effect, the pharmacological effect of the drug, to stimuli that it has been conditioned in.

And you start to think about how malignant that process is when you're addicted to a drug. Why do I say malignant? Because the moment that you're going to be exposed to conditioned stimuli, dopamine is going to go into your brain.

And when dopamine goes into your brain and goes up with this conditioned stimuli, that is associated with a subjective perception of wanting the drug, the motivation to take the drug.

This is not something that you control. Just like the salivation you don't control, when you get conditioned to a conditioned stimuli, dopamine goes up in the areas of the brain where the message of dopamine is the motivation to procure that particular stimuli.

Nora Volkow: Now, what about food? Well, you do exactly the same studies with [C11]raclopride except that instead of showing them a cocaine video, you show them a neutral situation. Subjects in this case were asked to describe their family genealogy. These are 16 control subjects, and these are the images with raclopride.

And then we bring them back, and we expose them visually to foods that they have told us they like.

Nora Volkow: And when you do that, you don't give them any drug whatsoever. You compare the binding, and you can clearly see, just as for the conditions used for drugs, you can see the decreases in raclopride binding in the striatum.

And just exactly like you saw for drugs that those increases were associated with a desire for the food, so, in these individuals the increases in dopamine are associated with a subjective perception of hunger with a desire for the food.

So it's not that drugs have created a new mechanism. This mechanism of conditioning is crucial on the way that the brain reacts to stimuli that are enforcing, ensuring the, increasing the likelihood that we will be motivated to try to consume those foods that in the past we have associated with pleasurable responses.

But it goes beyond that because by activating that circuitry, it is driving that behavior to eat them. So in my view when I see this, I said, "Oh my God, we're surrounded by multiplicity of visual and stimuli that we've conditioned ourselves." And I sort of said, "No wonder we have an obesity problem in our society. It's almost impossible not to be exposed to highly conditioned stimuli all along."

So this could explain exactly one of the problems of our society. Is that we are bombarded visually and auditorily with an enormous diversity of conditioned stimulus that require that we constantly, constantly inhibit those motivational drive to eat that result as a function of these increases in dopamine.

Nora Volkow: Now, that leads me to the third element. We said reward system involved for both of them, food and drugs, are driving the motivational circuitry, in part through the dopaminergic mechanisms. That the learning memory leads to conditioned responses that motivate and generate a desire to eat this or take the drug.

But also I mentioned the, when we're conditioned, when we want something, there's a third element, our ability to inhibit it. And that's the third system which we know is regulated by dopamine.

So dopamine is involved with reward, it's involved with memory and learning including conditioning, but it's also involved with operations in the brain that we like, that we name executive functions, among which of them is inhibitory control, and that relates to the prefrontal cortex.

So, where is there, what's the situation there in terms of similarities between drug addicted people and individuals that are compulsive overeaters, obese?

Nora Volkow: How do you measure the prefrontal cortex dopaminergic function? You cannot measure dopamine receptors in the prefrontal cortex with PET technology. You cannot do that, and here is an image of dopamine D2 receptors. You can see it in the striatum.

But your signals in the prefrontal cortex are very, very weak, because the relative density of dopamine D2 receptors is, the relative density is very low. So your signal is not strong enough to be measured.

But you can couple measures of dopamine D2 receptors in the striatum, and at the same time in the same subjects, measure brain glucose metabolism, which is an indicator of brain function.

So in the same subject, then, you obtain a measure of receptors and a measure of brain metabolic activity. And then you ask the question. If there are changes in these receptors, which are one of the mechanisms by which you are actually transmitting the dopaminergic signals associated with reward and motivation, how does that affect the function of the human brain?

Nora Volkow: When you do that, then you measure dopamine D2 receptors, to start with what do you see?

You see this picture: normal control, cocaine abuser one month after last use of cocaine, cocaine abuser four months later.

And you see that classical decrease in dopamine D2 receptors that we were the first to report, but since then has been replicated by multiple laboratories, including ourselves.

Nora Volkow: These are the results, not presented as images, but quantitatively, for two different clinical trials. One done in inpatients, using N-methylspiroperidol and another one in outpatients using C 11 Raclopride. Normal controls are in purple. Green is cocaine abusers, and the measure here represents the availability of dopamine D2 receptors, which I'm plotting as a function of age because as we grow older, the expression of dopamine D2 receptors goes down. You see it here, you see it here.

And it goes down whether you're a normal control or a cocaine abuser. Normal control. Cocaine abusers.

However, when you compare them as group, you can clearly see that the cocaine abusers have a significant reduction in the availability of dopamine D2 receptors, regardless of the age of the subjects, regardless of the fact that the subjects are actually inpatient or outpatient, regardless if the subjects are immediately after detoxification, within one week or three months after detoxification.

This is a very consistent finding.

Nora Volkow: And indeed, it's not something that is specific for cocaine. We and many others have documented these decreases in dopamine D2 receptors in cocaine abusers. We have reported decreases in dopamine D2 receptors in methamphetamine abusers, and many laboratories have reported decreases in dopamine D2 receptors in alcoholics.

In fact, there have been not only imaging studies but postmortem studies indicating significant reductions in the levels of dopamine D2 receptors in alcoholics. Heroin abusers also have decreases in dopamine D2 receptors, and a recent study published last year, presented last year actually, at the Society of Nuclear Medicine from a European group, also reported decreases in dopamine D2 receptors in individuals addicted to nicotine.

So these appear to be a very consistent finding across a wide variety of addicted individuals.

Nora Volkow: And what's interesting about it, it's so consistent that it levels to the concept of postulate that the extent to which you have low levels of dopamine D2 receptors may be a factor that makes you more vulnerable to take drugs. So that's what we hypothesized.

And in order to test the hypothesis, certainly, it would have been ideal to say, "Okay, if it is correct that it makes you more vulnerable, then it follows that if I were to be able to increase dopamine receptors in this individual, I should be able to help them stop taking drugs."

Of course, the problem is that it is not possible, non-invasively, to increase dopamine D2 receptors in the human brain except if you use a neuroleptic, but that will block the receptors so it defeats the purpose. You want receptors that are active.

You cannot do it in individuals, but you can do it in animals. You can make an animal self-administer drugs compulsively. When they self-administer it, then you can actually see: If I increase the receptors, do I change the behavior?

And this is exactly what you see here, is that study, the first study we did, we've now done four different studies with this paradigm. Three of them are in alcohol and one in cocaine, and the results are the same. This is the first study of the series in which we made animals self-administer alcohol compulsively. Once they self-administer alcohol compulsively, we inject them stereotactically with an adenovirus.

We inject them stereotactically into the nucleus accumbens with the adenovirus. And inside the adenovirus we introduce the dopamine D2 receptor gene. So this is done, the adenovirus is just used as a vector so that the D2 receptor gene can be incorporated into the cells.

And in the nucleus accumbens, this results when you do that, in a 50% increase in the expression of the dopamine D2 receptors. This expression is short lasting, and by then you see levels that are nonsignificantly different from those in baseline, this percent change in D2 receptors. But you can then increase, inject again, so you can inject your subjects again, your animals, and receptors go up again.

When you do this and you increase dopamine D2 receptors this way, which is a sort of gene therapy, what happens to the behavior? And what happens is fascinating. You dramatically reduce the compulsive alcohol intake. You don't abolish alcohol intake. You reduce, you basically abolish the consumption of large quantities of alcohol.

So in this case, alcohol drinking behavior was decreased by 70%. It was not abolished but decreased by 70%. And as the receptors went back to baseline, alcohol drinking behavior went back to its baseline state.

When we administer the adenovirus again with the gene, again drinking behavior was dramatically reduced, and in blue here are animals in whom we injected them with the adenovirus, but we did not incorporate the D2 receptor into the adenovirus. And we did that to control for nonspecific effects.

And you can see that when you just inject the adenovirus without the gene, you have no effect on the behavior of drinking. Similar findings were recently reported in the past I think three months, in cocaine-abusing animals in which again the injection of the D2 receptor gene, and the increases that follow in the expression of the receptor were associated with a dramatic reduction on the doses of cocaine consumed.

We are not able to abolish the consumption of the drug. We dramatically reduce the doses consumed. But if you think about it, that's ultimately certainly in the case of alcohol where it's easier to quantify where the alcohol is, is not for us problematic to drink glass of wine. It's when you as a female drink four or more drinks in a row, or when you as a male drink five or more drinks in a row.

So that modulation of the doses that you are consuming appears to be in part regulated by dopamine D2 receptors. So it's not the dopamine D2 receptors in bringing it up says okay no more, it appears as if it were sensitive, it's interfering with the consumption of high doses which of course would be much more potent in reinforcing.

So this is where actually in terms of where we are, and there's now data in primates to associating there are other strategies that have been used, not that it, a priority that were set up, that can produce increases in receptors in primates and similarly to what we're seeing in the rodents. These animals, as long as they have high levels of receptors, are much less likely to consume, in that case, cocaine.

Nora Volkow: What about obesity? Do we have, where you see, you see, you see, what we're having here is that compulsion, that compulsion. I mean, it's high quantities, it's compulsion. Well, what about obesity where you can have that same compulsion of eating?

And where the D2 receptors, what may be mediating here, and actually there is now data, a recent paper that was published within the past year from Trevor Robbins and his group at Cambridge, that the D2 receptors in a row then predict the compulsivity, that is to say low levels, much more likely to have an animal that becomes compulsive.

So then when you do that and you see obesity, what do you see?

Nora Volkow: We saw exactly the same thing that we had been reporting in alcoholics, in cocaine abusers, in heroin abusers, in methamphetamine abusers: significant reductions on dopamine D2 receptor availability.

Nora Volkow: Moreover, where was actually look at this data here, when you plot the dopamine D2 receptor against the body mass index, what you observe is in the obese subjects, the D2 receptor availability is associated with the body mass index, but not in controls. In obese subjects, the lower your receptors, the more severe your body mass index.

Nora Volkow: And we've actually replicated this in animal studies, and we actually take zucker animals, we food restrict them. And the zucker animal here, there's two types: the lean and the obese.

The obese is obese because the leptin receptor is not functioning properly. So this animal has become obese, and developed a metabolic syndrome just like in humans, diabetes and hypertriglyceremia.

When you food-restrict them, they are not as lean as the lean animals, but they are just not as big as these gigantic creatures. And you can actually measure dopamine D2 receptors in these four groups of animals: lean (restricted to 80% of the average diet), lean (free access of food), obese zucker (restricted to 80% of diet), and obese zucker (with free access to food).

And you can clearly see just as we saw in the human subjects, that these are the animals with the lower levels of dopamine D2 receptors. These are the animals that compulsively consume high quantities of food.

And know that in these animals, we know that the defect that originated this obesity is the leptin receptors. But it's now been translated behaviorally into a modification in the dopamine pathway.

Now, this shouldn't completely surprise us because there are leptin receptors directly sitting in dopamine cells in the ventral tegmental area.

Now, I started a D2 receptor story with a prefrontal cortex, and now I'm linking it. Compulsivity, D2 receptors, a propensity for severe compulsive behaviors. Why may that be?

Nora Volkow: Prefrontal cortex. Prefrontal cortex is what we know allows us to regulate and inhibit prepotent tendencies. So I want to do something very much, but I said, I shouldn't do it. And that motivation and that may be that the drive to eat chocolate, or the next or the drive to drink alcohol, that propensity when I see something that I like very much and I say, "Uh-uh, no," that's a prefrontal cortex. Well how does that relate to these changes that we are observing in dopamine D2 receptors?

Nora Volkow: I told you, we've been studying subjects with both of these measures, brain glucose metabolism and D2 receptors, and in this slide what you see is the summary for the studies assessing the relationship between brain glucose metabolism and dopamine D2 receptors: dopamine D2 receptors that we measure in striatum, brain glucose metabolism that we measure throughout the whole brain.

And then we inquire, this is not the priority questions that we have. At the beginning we did not know where changes in dopamine D2 receptors, how these changes were going to affect brain glucose metabolism in the rest of the brain. We did not know where that was going to be.

In fact, I thought that decreases in receptors like the ones that I've been showing you would be associated with decreases in metabolism in the striatum. But that was not what we found.

What we found was that decreases in dopamine D2 receptors were associated with decreases in metabolic activity in the prefrontal cortex. And this is the data in two very different trials. One in cocaine abusers, one in methamphetamine abusers, and were recently in the past year published exactly the same findings in alcoholic subjects.

The lower the dopamine D2 receptors, the lower the metabolic activity in the dorsal, lateral, prefrontal cortex, in the anterior cingulate gyrus, and in the orbital frontal cortex.

And here you see an image at the level of the orbital frontal cortex. It's an axial image, anterior-posterior, control subject, cocaine abuser. This is the area of the orbital frontal cortex where the reduction of dopamine D2 receptors is associated with this picture that you see here.

Decrease metabolism in the orbital frontal cortex. This of course is incredibly relevant because the lateral orbital frontal cortex, along with the anterior cingulate gyrus are the areas of the brain that allow us to exert inhibitory control.

Also, it is extraordinarily relevant, because if I damage the orbital frontal cortex in a laboratory animal, I can produce compulsive behaviors, compulsive behaviors that make no rational sense.

I can take an animal, a rat, and you can train an animal to press a lever in order to get food. And the animal presses the lever, and it gets food. But if you remove the food, the animal rapidly learns that that lever is no longer reinforcing and stops pressing.

If you damage the orbital frontal cortex, the animal learns very rapidly the association of, "I press this lever, and I get food." There's no impairment on that learning. But when you remove the food, the animal keeps on pressing again, and again, and again, despite the fact that that lever is no longer reinforcing.

The animal is unable to shift his or her behavior as a function of the changing context that has shifted the reinforcing value of stimuli into neutral. And that fixates the behavior of the animal.

And so there, you can see, then you can start to say, maybe that explains why a person that's addicted to drugs, whether it's alcohol or cocaine or methamphetamine, compulsively takes the drug even though consciously they may tell you, "I don't even know why I'm taking it. I just cannot stop."

Now, what happens with food? And this actually if you are dealing with people that are basically one of the things that impressed me very much in this respect was when you are dealing with compulsive eaters. And they will tell you, "You know, doc, it doesn't matter, what you put in front of me, when I get into that state you can put one of these bags of white bread," which in Mexico we call Bimbo, I don't know how you call them in the United States, but Bimbo. It's tasteless. It's a gigantic piece of bread.

It doesn't matter. You eat it compulsively.

Nora Volkow: Now, what happens with that? And this is data we just came out I think in the last month. Well, we did exactly the same thing that we did here. Except here, we were using methodology where we're actually preselecting the regions across the whole brain. I'm only showing those that were significant. But we draw a region here and there.

In the next study since it's very new, we use a technology where you just ask the computer to identify across the whole brain, you don't select regions, where is metabolism associated with D2 receptors? And this is where you get it, in obese subjects.

These exactly correspond to the orbital frontal cortex. These correspond to the dorsal cingulate gyrus. The lower the metabolic activity, the lower the metabolism. The lower the receptors, the lower the metabolism. In the cingulate gyrus, the lower the D2 receptors, the lower the metabolism in the orbital frontal cortex.

And since I just came across doing an explanation about what happens when you damage the orbital frontal cortex, you start to understand how in an individual where there is decrease in the function of the orbital frontal cortex, that person will have a much harder time in inhibiting the prepotent responses to keep on consuming the food or to keep on taking the drug.

Nora Volkow:So how do we take this knowledge? When Alan Leshner was director of the Institute, he did an extraordinary job in educating the public that drug addiction is a disease of the brain. And he used this eloquent metaphor. He says, "There's a switch. You cannot really equate the decision of taking the drug for pleasure and the drinking of the alcohol, one glass of wine, to what it is to be addicted. There's a switch. It's just categorically different."

And this metaphor was very good at explaining the concept that this is qualitatively different. It's not just the quantitative difference

But as we gain more knowledge, it also becomes clear that the concept of the switch is not really precise because it's not that one day you are perfectly fine and the next day you are addicted, as happens when you turn the light on and off.

What knowledge, what science is identifying, is that drug addiction, as is the case for obesity, it's not a result of one area of the brain not functioning properly. I've already given you three systems that are extraordinary important in motivating our everyday activities. Reward motivation, memory-learning-conditioning, and the third one is executive function inhibitory control.

Nora Volkow: Three circuits. Three circuits that are involved with one another to determine what is it that we're going to do. So it's not the drug addiction, it will be great. I think it'll be fantastic, that it'll be okay, we have this little area that's abnormal, we go in and repair it.

No. This disease is a disease of systems. And in fact, it's likely that many of the psychiatric diseases, in fact that's what it's believed, reflect systems pathology and not regionally localized effects as would be evident, as one would infer from the switch hypothesis.

Reward circuit, learning-memory, executive control, and motivational drive. And if you think about it, how systems work, this is important, is that in a system where there are circuits that interact with one another, this could explain why it's not that one day you are addicted and not the other.

It does explain why some people that are addicted are able to stop taking drugs for six months, are perfectly fine, and then one day they relapse. You may have damage in the reward system, but you may be able to buffer that damage through executive function.

And it is when something happens that destroys that balance that you lose the ability to buffer one system with the other, and the pathology emerges. And in fact, this is very similar to what happens with hypertension.

It's not that one day you have the disease, the blood vessels become narrow, and not the other. It's that something happens that makes you lose the ability to actually buffer the systems in order to function properly, and that loss of balance is what allows for the pathology to emerge.

This is the way it goes, and you've seen me present this circuit model which is equivalent for addiction as it is equivalent for obesity. You are an obese person; you have a compulsive drive to take a certain part of food.

You see that you are not, say, you are more or less like me, I can be compulsive with chocolate. But say, suppose, that there is that chocolate there, and I see it and I said, "Okay, It's an M&M. I like M&Ms," and I shouldn't disregard them. And I salivate, and it's a nice color, and it's a chocolate cookie with M&Ms, I like them even better than the M&Ms by themselves.

And I said, "all right, I'll eat it, yes, should I," but I'm saying in my prefrontal cortex, "No, if I eat this then I'm not going to have dinner and I'm just going to be completely stuffed and I'm going to feel lousy when" - so - but I have the drive to eat it. So we all have, I mean, we are constantly should I, should I not?

Certainly I do, I shouldn't tell everybody. But in my life, I'm constantly, I'm saying to myself, "should I do this, or should I not do that. Should I go exercise, should I go and study?" And I guess in essence, the element of, we have multiple choices in our behavior, and what we decide to do is a function of what is the balance between the motivational drive and the cognitive control of whether this is proper or not proper at this point of time. And there are other alternatives.

So there is that M&M cookie there, and I said, "no, no, uh-uh, uh-uh, uh-uh." I'm going to have dinner, and if I eat this chocolate cookie, I'm not going to have the desire to eat anything. So my prefrontal cortex says, "No, Nora, don't eat it." And I don't eat it. How is that? Okay?

But then I'm a compulsive eater. And I am coming here, and I see this display of food that you have out there, and I'm salivating, my heart is racing, I want it, I want it, I want it.

And I mean, part of it is my memory, I have sort of this, "Oh my, that's a fantastic chocolate chip cookie that I am seeing there." And I am saying to myself, "No, Nora, don't eat it," and I'm sort of saying it, "I want it, I want it," and there is an unconscious response.

We always like to think that all of the things that we do are consciously perceived and regulated. I know an enormous amount of these prepotent responses are initiated at an unconscious level.

So at my unconscious level, this is activating my whole motor. Now it's, they've actually shown, your motor cortex is activated. It's activated before you are aware that you want to do it. Your prefrontal cortex is not functioning properly. I show you that study on the obese people.

So even though they want to stop it just like in the drug person, they cannot do it. And this gets disconnected the moment that you taste it or the moment you take the drug. This leads to increases in dopamine, the classic dopamine increases, even though there may not be very potent at this point. Certainly in addicted or - hasn't - in an addicted person but it still increases dopamine, so does food.

This initiates dopamine, the signaling, and the motivation to go activate the motor systems. You take it back again, activate motor systems, you take it; back again, you activate motor system. And you get these compulsive effects. And the prefrontal cortex is disconnected. So you cannot stop it, and this is underlying a core essence of the pathology of both of these disorders.

Nora Volkow: Very important, because by delineating the systems and circuits, of course we have targets and targets that in the past we've actually been developing to strengthen the likelihood and increase the probability of someone to stop taking drugs, can be applied exactly the same type of strategy for the problem of obesity. Interfere with the drugs' reinforcing effect.

Can you interfere with food's reinforcing effects? And again, it's specific foods. It's not all of the foods. A piece of lettuce without dressing will not lead to compulsive eating. So in this case, there are one of the things that we're targeting is vaccines.

Well, there has been discussions about targeting vaccines against fats, in particular those systems are not a percent target that was interfering with our reinforcing effects, but interfere with the absorption. But if you interfere with the absorption, of course, you are not going to have the saliency value, because the ability of fat to produce those reinforcing effects are not just linked with your conscious experience. They're also associated with peripheral responses.

Executive function, inhibitory control: the ability that you have to sort of say before you actually get exposed or when you get exposed to the stimuli, "I'm not - I'm going to resist." Which relates in part in the frontal control of dopaminergic system, these are glutamatergic, dopaminergic systems, can be increased.

There is some data that through biofeedback mechanisms may strengthen this circuit, corticostriatal circuit. There is also some evidence that perhaps medications like Modafinil increase executive function.

Increasing prefrontal striatal communication, not just through inhibitory control but actually through pathways that may also relate to functions that are associated with the regulation of learned responses. Which as over here, and I always sort of said, wouldn't it be extraordinary that we could have a pill that when you start to crave something, just like you did with the nitroglycerine in patients that have cardiac chest pain, that you could take it and that inhibits the conditioned response that generates the saliency and the motivation?

There's no reason why one couldn't develop those medications, and in fact in animals, there are medications that interfere with conditioned responses. We also are targeting, not just inhibiting, but can you generate new memories that can counteract these conditioned responses?

And also extremely important, both for addiction as well as food, that one of the factors that leads to relapse and to compulsive taking of drugs in an addicted person or compulsive eating, is stress. Suffice it to say next time that you are in an airport and this is going to happen to you, and they canceled your flight, look around you. And you start to see that immediately what people start to do is eat.

And since now they have all of these very appealing food stores around the airport. It's very, actually, one of the ones I go and when they cancel my flight, I go and buy my chocolate chip cookies.

So this is biology at its best. And what we're doing now is, of course, by dissecting it, understanding it better, and hopefully we can now use this information obviously to increase the likelihood that we will succeed in helping that person, to say no to the drugs or the same thing, to say no to the compulsive patterns of eating behavior.

Nora Volkow: And with that I want to thank my colleagues at Brookhaven National Laboratory, without whom this work would not have been possible, and of course I always thank the National Institute on Drug Abuse for its general support.

And I thank you for your attention.