Addiction: Neurological Basis
Guest: Dr. Peter Kalivas – Neurosciences/Neuroscience Research
Host: Dr. Linda Austin – Psychiatry
Dr. Linda Austin: I’m Dr. Linda Austin. I’m interviewing, today, Dr. Peter Kalivas who is Director of the Department of Neurosciences here at the Medical University of South Carolina. Dr. Kalivas, in other podcasts, you’ve given us an overview of all of the exciting research that’s going on in your department, but let’s talk about your own research now. Tell us what you do.
Dr. Peter Kalivas: Well, I’m interested, and have been for the last 20 years, in discovering the neurobiological basis of addiction to drugs. And the drugs we’ve focused on primarily are cocaine, a little less so on heroin, methamphetamine, and even less on nicotine. So, we’ve kept ourselves to those drugs. We haven’t done any research per se on alcohol, although, here at MUSC, there’s a very large and internationally recognized group working on alcohol research.
For my own research, we’re interested in, as I mentioned, the biological basis of addiction. So, what we start with are animals, rats, primarily, although we use mice at times as well. They become addicted to the drug, so they will administer the drugs themselves, and it becomes a daily habit just like it would in a human addict.
Dr. Linda Austin: Okay, now, slow down. How do they do this? I’m kind of picturing, you know, some little druggie rats.
Dr. Peter Kalivas: They are. It’s intravenous.
Dr. Linda Austin: Pulling out their tourniquets.
Dr. Peter Kalivas: We do a little surgery on them and they have a jugular catheter that’s externalized on their back so that everyday they can come in and we can hook the catheter up to a syringe pump and there’s a lever so that every time they hit the lever, they’ll receive an infusion of drug. So, we bring them in, typically, for a couple of hours everyday and, depending on the drug, nicotine is a little harder to teach them, but cocaine or heroin, they learn the first day, usually, that this lever is a good thing and that they’re going to get drugged. And, they develop what we call a drug-seeking habit or drug-seeking behavior within the first couple of days.
So, we let them do that for anywhere from a couple of weeks to a month and then we do one of two things with them. We take their brain out at that point and look to see what’s been changed at a gene expression level, a protein level, or a level, really, of how the neurons have organized themselves. So, what we find is that the organization of neurons within the brain is actually altered in the addicted animals compared to the control animals.
From that discovery, we can then proceed to the other thing that we would do with the rats, which is, basically, once we find a protein or even a morphological change in the brain that seems to be tied to the addiction, in other words, we find that only in the addicted animals, not in the control animals, we then try to develop ways that we can restore the brain back to normal. When we think we’ve got those, we then take our addicted animals and we, of course, treat the animals with that procedure, whether it’s a training procedure or a new drug, and see if we can prevent the animal from going after the cocaine or the heroin. And, in doing this kind of thing, we’ve come up with, over the years, a couple of compounds, one, in particular, that’s very deep into clinical trials right now.
And, being a basic scientist, we get together with our colleagues in the Department of Psychiatry, here, where they have a large clinical trials engine for addiction. Our main partner in crime there would be Robert Malcolm. He’s helped us set up a number of trials for these compounds. And, you know, so far, so good. We’ve got one compound that seems to work in decreasing the craving for cocaine and nicotine, and they’re now in larger trials in the interim. Since we published those papers, the same compound was tried by another group and seemed to work in gambling as well.
Dr. Linda Austin: Now, is that in Phase I, the earliest?
Dr. Peter Kalivas: They’ve been through Phase I. The trials we’re running now are Phase II. The first trials were absolutely correct, part toxicology trials and trials to see if it had an impact on drug craving, for example. They were still double-blind studies, but the ends were low, the number of patients or subjects involved was low. There were anywhere from 15 to 20 in a group. We’re now engaged in a much larger trial which involves a total of nearly 300 subjects. That’ll really be the trial that tells us for sure how effective this compound is.
Dr. Linda Austin: Now, going back to the changes that you see in the brains of these addicted mammals, rodents, you mentioned that there could be a couple different kinds of changes, that they could be morphological, which means, actually, that you could see a change in the shape of the structures within the brain, or functional, that is, chemical, I believe. Can you describe a little bit more about that? What do you actually see in the brains of these addicted rodents?
Dr. Peter Kalivas: Okay, let’s back up, Linda, just for a second, and think about what happens in daily life. Basically, to be alive and to experience things in daily life, to make decisions, to develop new behaviors, like learning to drive a car, involves changing the brain. So, the brain changing is how we adapt to the world around us, just like, if you exercise, your muscles change, your brain changes. So, a changing brain, by itself, is a good thing. It’s not pathological. What we find is that because of the strong rewarding qualities of addictive drugs, the changes in the parts of the brain that actually process rewarding information, ultimately allow you to develop behavior that would lead you to obtain the rewards. So, of course, getting rewards in life, whether it’s food or sex, or whatever, is a good thing, and you develop behaviors to achieve those goals. But, those are natural rewards.
The drug rewards are induced pharmacologically. They go to the same parts of the brain that we would normally use to seek out and find rewards, natural rewards, and they produce changes that are extensions, pathological extensions, of what would normally occur. So, for example, something as simple as food, if you want to learn where to get food, you would learn that if you go down to a meadow and find mushrooms there, that’s the meadow you would go to. You would learn the trail that would take you down there, and you would remember that, so that the next time you were hungry, you could go down to the meadow and find the food more efficiently, and it becomes a learned behavior.
With addictive drugs, it’s the same thing. You learn where to go to get your cocaine. But, every time you get the reward for cocaine, it reinforces that learning, whereas once you learned how to get the food down in the meadow, a natural reward, you’ve learned it and the changes in the brain are done. Every time you learn to get the cocaine, even if it’s the same thing you’ve done before, then you get the cocaine at the end, that big release of chemicals that reinforce that learning happens again. That’s essentially what the drugs of abuse do. They keep seeking that drug-reinforcing behavior to the point where it becomes a habit that is almost impossible to break.
What that translates to in the brain is the release of certain chemicals, and the structure of the way the neurons communicate with each other actually become more rigid. So, it becomes fixed so that it can’t change as easily as it otherwise would. So, for example, take the meadow analogy. Once you’ve gotten all the mushrooms out of one meadow, you’d have to develop a new behavior and find them somewhere else, and you can do that very easily. If you take an addict, they, in a sense, have over learned their drug seeking, so now when society tells them, this is a bad thing, let’s say, they’re losing their job, their family is breaking up because of their addiction, they can’t change their behavior very easily because the drugs have hardwired this drug-seeking behavior.
They can have every intention of, say, well, I’m going home to do homework with my daughter tonight instead of going to the bar, but as soon as their friend calls them up, on the way home, they forget all about their other agenda, their natural reward, and they engage immediately in the drug-seeking behavior. The next thing they know, they find themselves at the bar drinking some beers. So, it’s that inflexibility that we’re really trying to break up. And, we, of course, see that same inflexibility in our animal models. Animals will go through stressful behaviors to get their drug once they’re addicted, and that would be, more our less, how we [humans] would model it.
What we’ve found with the treatment that I described earlier, that we’ve taken into the clinic, is that it restores flexibility to the contacts, the synaptic contacts, that neurons make with each other. So, instead of being stuck and giving only a range of information, it opens them back up so that they can now give a full range of information between the neurons. And we believe that, then, allows the animal to change their behavior, or the human being to change their behavior and assess the world around them more effectively, to modify their habitual behavior.
Dr. Linda Austin: Once those changes have occurred and time passes, does it ever go back to the way it would have been had that addiction never happened?
Dr. Peter Kalivas: That’s a really good question. I would say, in most cases, the answer is, to a large extent, yes, it can go back. It takes years and years. There’s always the memory of the addiction. So, in as much as a memory never goes away, it is always there. But, I think the clinical literature is pretty clear that while you can induce craving 20 years later, when somebody hasn’t had a cigarette, in general, the number of craving events begins to diminish as you develop alternate behaviors to associate with that event. So, for example, every time after I finish a meal, I smoke a cigarette, so it becomes difficult not to smoke a cigarette because you associate it with a meal. But, over time, if you’ve forced yourself not to smoke a cigarette with the meal, eventually the meal becomes associated with other things, so the eating-induced craving begins to fade away.
It doesn’t mean that somewhere, out of the blue, you find yourself at a baseball game, maybe, where you always smoked, and you just get a set of cues you haven’t extinguished that response to, and you can get just as strong a craving as you had the day you tried to quit smoking. So, in some ways it’s there, at a permanent level, but, in fact, as people go through their lives and re-engage in normal reward-seeking behaviors, and just life in general, without the drugs, the number of craving events would seem to diminish. What I would say, as near as we can tell from the biology, is that the susceptibility to relapse or to take the drug remains higher than it was before you ever took the drugs, if you’ve been an addict. I think there’s no question about that. But, most addicts, if they’re going to be successful, start reorganizing their life such that there’s less opportunity in their life to activate that circuitry and cause a relapsing event.
Dr. Linda Austin: I have one final question that I’ve wondered about as a psychiatrist. I have been struck by seeing people become alcoholic or drug addicted, most often, alcohol, at age 50, 60, 70, and often times what people will say is that it’s during a period of stress, which has made me wonder, biologically, about the role of stress hormones somehow priming the pump and making the person more susceptible to addiction. Any research in that area?
Dr. Peter Kalivas: There is. The research I’m most familiar with is more with an animal or an individual who’s already developed some addictive behaviors, maybe not to the point where it’s really disrupting their life too much, but they definitely have developed a habit, and stress can precipitate drug seeking. There’s no question about that. In terms of stress initiating drug seeking, the way I would think about it is you would be seeking the drug initially for self-medication purposes. So, alcohol, in particular, as you mentioned, and I think the demographics would support that, is about the only drug that a significant number of people become addicted to in the 40s, 50s and 60s. The vast majority, especially in regards to illicit drugs, if they tend to encounter them and use them, experiment with them, when they’re adolescents is usually when the addiction begins to emerge, to things like cocaine or heroin. It’s drugs like alcohol that you start seeing the later addictive behavior.
I’ve always thought that, I’m not a psychiatrist, has more to do with the initiation, anyway, with self-medicating because of the anxiolytic qualities of the drug. Then, of course, once you develop a habit of drug seeking, it’s very clear that a stressful event can precipitate a relapse. That happens all the time.
Dr. Linda Austin: Dr. Kalivas, thanks so much for talking with us.
Dr. Peter Kalivas: Sure.
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