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Mark Thomas: Research may identify relapse trigger in human brain

Relapse to drug use is common — the majority of people who have completed recovery programs eventually slide back to substance abuse one or more times.

Mark Thomas: "I think there are traces of all life experiences that are stored in the brain. ... If we knew more about how to track that in cases like addiction, we might be able to disrupt those signals so that they don’t control a person’s behavior."
Courtesy of Mark Thomas

Some addicted people say that quitting is the easy part. What’s hard is staying sober. Relapse to drug use is common — the majority of people who have completed recovery programs eventually slide back to substance abuse one or more times. A number of factors can trigger relapse, including social cues, access to drugs or life stress.

A group of researchers at the University of Minnesota Medical School’s Department of Neuroscience has identified a potential target for preventing morphine relapse in mice. By pinpointing and manipulating this target in the brain using a method called optogenetics, researchers have been able to repress relapse behaviors in mice, blocking continued morphine use.

They hope that these findings will bring them closer to a treatment that will block relapse in humans.

The group’s research was published in January in the Proceedings of the National Academy of Sciences. The senior author was Mark Thomas, Ph.D., associate professor in the departments of neuroscience and psychology.

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Thomas, a Minnesota native, has been at the University of Minnesota since 2003. His longtime interest in how the brain works led him to this field. When we met for coffee last week, he took time to explain his research and its potential application in human addiction.

MinnPost: How did you enter into this particular area of research?

Mark Thomas: I got interested in neuroscience because I am very interested in how experience shapes the brain. Initially I was interested in normal learning and how information is stored in the brain in normal, everyday memory. I was working on that as a graduate student, but it is a field that is really saturated with talent.

So I started getting interested in a very small literature that focuses on addiction as kind of a maladaptive form of learning. I began to get interested in the question of whether some of the same neural processes involved in normal learning could get corrupted and play a part in how drug experience shapes the brain in a way that leads to compulsive drug seeking. There was very little hard research on it. That seemed like a way to apply the experimental approaches I’d been using in this other field to a new field.

MP: Have you always used animals in your research?

MT: Yes. My initial interest was how the brain stores information. In order to study that, you have to land on a process where you can study individual brain cells and how the connections to other brain cells are changing, which is something that you can only do in a reduced preparation of some kind. So a lot of what we do now has to do with treating animals — mice — with drugs, and then taking the brain out, making a thin section through the brain and keeping that tissue alive for eight to 10 hours so we can study it. Then we can probe the function of neural pathways by stimulating and recording the neural responses.

MP: Why would you want to find that out? 

MT: I think there are traces of all life experiences that are stored in the brain. And so I wonder, “What is the signature of each experience?” If we knew more about how to track that in cases like addiction, we might be able to disrupt those signals so that they don’t control a person’s behavior.

MP: So you’d disrupt those signals through some kind of pharmacological means?

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MT: This is a very good question. I think it’s most likely to be a combination of pharmacology and neural stimulation that turns out to be the useful antidote to addiction-related brain plasticity. So it’s not likely to be a pill alone that does the trick.

MP: You’re searching for a treatment method?

MT: I have a long-term vision of the work that we’re doing. Right now we’ve really focused in on relapse. And that’s where it seems like the work that we’re doing in the lab could really help people in the most direct way. Because what we’re finding is that with the mice that are treated for chronic drugs, whether it’s morphine or other opioids or cocaine or amphetamines, their brains continue to respond differently to stimuli after chronic drug use, even in abstinence.

When I say “stimuli,” I mean drug exposure during abstinence or stress during abstinence or even exposure to the context or cues that were paired with the drug in the past. Those three different categories of stimuli create a brain change in the chronic-drug mice that doesn’t happen in drug-naive mice. If we could pinpoint and control the exact area of that change, we could prevent it from taking control of behavior. And that could really make a difference for people. 

So we’ve got a laser focus on the relapse part now.

MP: Can you explain how you recreate drug relapse in a mouse? Mice aren’t people, obviously, and I’m trying to imagine how a mouse would relapse to drug use.

MT: It’s amazing how the behavioral patterns of mice mirror that of people.

MP: So you’d be giving a mouse a regular does of morphine and then suddenly you cut off the morphine. And the mouse’s reaction is, “I’ll do anything for the morphine.”

MT: Initially, the mice will work for the morphine, but when they realize they can’t get it, they sort of give up. And then it is pretty difficult to tell the difference between a drug-treated mouse and a regular mouse.

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The drug-treated mice may be miserable initially, but after they are all hanging out together for a time, eventually you can’t tell the difference unless you probe them with a stimulus that was paired with the drug in the past or the drug itself or stress of some sort.

Then the drug-treated mice respond differently. If given the opportunity under of any of those trigger conditions they’ll immediately go back to looking for the drug again. So that’s the relapse in mice. That’s why we call it relapse because it really does create what we interpret as craving — hard to know for certain — but under stress, the drug-treated mice will clearly go back to seeking the drug again and the drug-naive mice won’t.

MP: How is this research applicable to human addiction?

MT: We think there is a trigger in the brain that gets switched by chronic drug use. So far what we’ve been doing in this study is changing brain activity just prior to delivering a drug again after abstinence. That has blocked the relapse response in mice.

With people, presumably, you’re not usually going to know whether you are about to be stressed in life, which could lead to a susceptible period for relapse. So we have to think of something that happens just after that. The stress/relapse trigger gets flipped and then what? Then perhaps an addicted person realizes that they’re in a vulnerable state and they need some help. If they are in AA, they call their sponsor and get them to talk them down.

We feel like if we were able to identify the exact location of the brain change then we would be able to return the brain to an abstinence-like state.

But your question is, “How do we do that?”

MP: Right.

MT: So that’s what we’re now trying to figure out. By knowing more about what the relapse brain change is that’s triggered by stress in as specific terms as we can find out, we will have a better shot at trying to flip the switch back over to the “good” side. And how do we do that? We’re hoping to use neural stimulation and pharmacology in combination. But we don’t yet know the magic combination.

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MP: There are a growing number of physicians who are interested in using pharmacological treatments for addiction.

MT: Yes. But I think the 12-step approach has its place. That, and other behavioral treatments for addiction will always play an important role. Pharmacology alone is not likely to correct everything with addiction. But it can help. No matter what we find, support networks are always going to be important for fighting addiction.

MP: Because triggers are always going to exist, and those triggers are often caused by human interaction.

MT:  Absolutely. What seems to me to be the most important or most likely opportunity that we have is this: There’s an addict who’s decided to quit. They’ve gone through treatment. They’re now clean. Those steps are always going to have to happen that way. We won’t prevent people from getting addicted in the first place. We won’t probably reverse the brain plasticity completely to the extent where they will never even have any cravings for a substance. It is probably going to be a lifelong issue.

Some people go through treatment and change their lives in a way where triggers just can’t touch them. But most people probably won’t be like that. The triggers will always be there so they can try to avoid the cues, the context they were in. But don’t get stressed? That’d be pretty hard. So having something that would be a tool to prop people up who get triggered before they go way back down and start compulsively using again, that’s where we’re headed.

MP: What about methadone? Doesn’t a drug like that work to keep people from compulsive use?

MT: From our point of view it’s not a very satisfying form of treatment, because it’s just sort of putting somebody in a holding pattern. You can taper down from addiction, which helps at that initial stage for sure. But people who taper off have the same relapse rates as those who quit cold turkey.

MP: So it’s not the greatest solution?

MT: It’s not the greatest solution. And I hear that it’s pretty common to use methadone and supplement that with other opioids.

MP: But won’t the combo you’re talking about still be a lifelong form of maintenance?  

MP: My hope is that this treatment would be time-limited. It would be a one-time deal that you would use when you’ve been triggered and you’re in a susceptible period for relapse. You could go into a clinic. At this point this is fantasy. When we’re doing research in the lab about how this would help people this is what we’re imagining.

MP: So you haven’t invented a prototype device that could deliver the electric stimulation?

MT: Not yet. Right now our study subjects are very small and they run around a lot. But the thing that makes us feel like this isn’t complete and utter fantasy is that kind of stimulation is a big deal in neuroscience these days, especially at the University of Minnesota. There is an initiative that’s funded by the state called the MnDrive Initiative on Brain Conditions. It is fostering private-public partnerships in neural stimulation. There’s a big focus on that.

I think it’s exciting to learn about the brain. I’m happy to have the opportunity to be doing that.