Researcher makes strides in alcohol addiction research

It’s not unusual for a person to grab a beer after work or the occasional bag of M&Ms at the Target register. But what is happening in the brain when one beer, or even five, is not enough, or someone mindlessly polishes off a 12-ounce bag of M&Ms, not the single-serving size?

That is the problem Jacqueline Barker, Ph.D., is tackling in her research, and she recently received an NIH National Institute on Alcohol Abuse and Alcoholism Research Career Program grant to do so.

“We need to be able to restore cognitive control," she said, “restore the ability to regulate drug seeking and taking. That is the angle from which I come at this problem. We are focused on what goes wrong in the brain that results in uncontrolled, inflexible behaviors.”

Barker’s research looks at addiction as a disorder of learning and memory rather than a disorder of reward seeking, whether that addiction is drugs, alcohol or sugar or a disorder such as depression, obsessive-compulsive disorder or obesity.

She explained, “You and I can probably have one glass of wine and enjoy it and then stop drinking. Then, if we need not to drink, we are able to control our behavior — in other words, we can flexibly regulate our drug seeking and taking. That is not the case with some people.”

Take, for instance, when beer drinking becomes a habit rather than a goal-directed behavior. “You’re reaching for the next beer, you crack it open, there’s a very salient process when you open it,” she said. “There’s a stimulus when you hear it click and you pour it in your glass. It becomes almost a ritual — one stimulus leads to the next step to the next step — so you find yourself going through this whole process without thinking about any of it and reaching for beer after beer.”

Most routines, or habits, are driven by the unconscious mind. Everyone relies on habits in their daily lives. Habits, which are created through a learning process and by repetition, are the routine things people do when they’re not thinking about it. The way they drive to work every day is one such habit. People drink their coffee at the same time every day out of habit. Most of the time these habits are good, as they free up the brain to think about other things, to process information.

“If every day you had to think, ‘I have to turn right at John Street, then a left on King Street,’ you’d never be able to get anywhere, you’d never get anything done,” she said.

But there are behaviors, she said, that have become uncontrolled that need to be brought back into check — behaviors such as addiction to alcohol, drugs and sugar. Restoring the ability to flexibly control a person’s alcohol or drug seeking and taking is critical.

“Often when I say we want to make alcohol seeking goal-directed again, people mistakenly ask if we want to make addicts like alcohol again. No — that is not the goal. We want to restore the ability to use goals to drive behavior, so that they’re actually thinking about an action, and it’s not just an automatic response, like mindlessly grabbing beer after beer after beer.”

A good example of that would be the ability to change up your daily routine. While taking the same route to work every day is a useful habit, the brain needs to be able to update its behavior when necessary. For instance, today you need to pick up dry cleaning on the way home from work. Normally it’s great that you don’t have to think about that drive home: You follow your same route, you arrive at your home, you prepare dinner. But today, you needed to change that routine, and instead, it wasn’t until you arrived at home that you realized you forgot to grab the dry cleaning, and now you have to go back out and get it. The habit dictated the outcome. Whenever goals change, the brain needs to be able to update your behavior.

“If you have cognitive control over your actions,” Barker said, “you’re going to update your behavior and accomplish what you need to get done. So that’s what we mean when we’re talking about restoring flexibility and cognitive control in addiction.”

But if a person is not properly understanding how those contingencies have changed or integrating that information in a way that allows them to recognize, “Hey wait. I’m being punished. My family is upset with me. I’ve lost my job. I’m living in poverty. I can’t drive my car anymore because of my behavior.” What’s going wrong that he or she isn’t able to take that in and update that information, allowing the brain to update its goals and restore goal-directed behaviors that will allow it to take that new information in and change its behavior?

Goal-directed behavior, like intentionally eating only 20 M&Ms and putting the rest of the bag away, is handled in part by the brain’s prefrontal cortex. Habits, on the other hand, are thought to be largely mediated by the dorsal striatum. The nucleus accumbens is a separate component of the ventral part of the striatum and is thought to be the key player involved in controlling motivational and emotional processes, as well as psychiatric disorders such as addiction, depression, obesity and OCD.

“The accumbens is a nucleus in the striatum that integrates a lot of inputs from other brain regions. In my research, I rely on what is called the actor-critic model type of behavior. The idea is that the accumbens takes in a lot of information, and it acts as a critic. It finds out what happens when I perform a particular behavior: Did a reward happen? Did a punishment happen? Is it good or bad? Do I like it?  What was the outcome? What’s the context in which this happens?”

All that information about contingency and reward comes into the accumbens, which integrates these inputs and functions like a critic. That neural information comes onto cells in the accumbens, and what those cells do is going to determine what information is sent to the dorsal striatum. Then, the accumbens is going to provide that feedback to the actor — the dorsal striatum region of the brain. It tells the actor what to do.

“If the actor says, ‘Push the lever,’ and the lever used to give me sucrose, but now it’s giving me a foot shock, the critic is going to say, ‘Hey, change your behavior!’ But in habits, what we think happens is that the critic becomes impaired and is unable to accurately update the information. It can’t tell the actor, the striatum, what to do properly. So, the actor keeps going and keeps performing behaviors that are maladaptive like binge eating M&Ms or drinking an entire bottle of wine.”

Whenever our critic goes offline, the actor goes awry, Barker said.

If an addict says I don’t want to drink anymore, but they have an automatic prepotent response, they walk by the refrigerator, and without thinking, open the door, grab a beer and sit down and drink it.

“Once they begin drinking,” Barker said, “they can have these continued automatic seeking- and taking-behaviors. If we can restore cognitive control over that action, we may be able to restore the ability to stop drinking or control the drinking so that person only has a beer instead of five.”

That’s where the learning and memory component comes in, she said. “At the beginning, almost all behaviors we perform, we are doing because of the outcome. When you first learned to eat M&Ms, it was because they are delicious, and you were thinking about them — you knew they were going to taste great.”

The same happens with drinking, she continued. “Whether it’s, ‘I started drinking because I think red wine is delicious, or I needed a social lubricant, or I was stressed out at the end of the day and thought it would calm my nerves,’ as you repeatedly perform these behaviors, the neural circuits that control them, change. And so once you’ve acquired and repeatedly performed these actions, there are transitions in these circuits that underlie the behaviors.

“So the idea is, these processes are co-occurring. You have goal-directed behavior and you have habits at the same time in your brain. And, one of these strategies is going to dominate the other.

Some people have a predisposition to form habits, but if a person is chronically exposed to alcohol or stress, they, too, can acquire a bias toward habits. They develop these impairments in the ability to regulate their behavior.

Barker said a lot of the brain circuitry is common between drug-seeking habits, alcohol-seeking habits, sugar-seeking habits, even driving habits. The underlying brain regions that control them appear to be largely overlapping. They expect to know more about that after this study.

The grant itself concentrates on identifying some specific circuits and projections that regulate behavioral flexibility and how alcohol might impact those circuits to promote loss of cognitive control.

“We are characterizing the circuits that mediate this behavior, and then, we are looking at if manipulation of these circuits can restore behavioral flexibility.”

Her work is focused in a couple different directions. The first is pharmacology.

“So we are looking at targets that we know are impacted by chronic alcohol exposure. For example, there are lower levels of mGluR2 in the nucleus accumbens after chronic alcohol exposure, and our findings suggest that by pharmacologically regulating mGluR2/3, we can restore cognitive control over behavior.

“In the short term,” she continued, “figuring out targets that are impacted by chronic alcohol exposure will be critical in treating alcohol use disorders. I think once we have a really thorough understanding of what the brain is doing, we can develop a deeper and better prevention and treatment strategy for addiction and other mental illnesses,” Barker said.

They are also looking at neural activity, using in vivo electrophysiology. “We want to see how the neurons are actually responding during the task, so we can determine if a cell population is encoding a specific part of a habit, and, if we put on our pharmacological target that restores goal-directed behavior, we can fix that aberrant activity.”

While experts are very confident that habitual behavior is involved in addiction, they don’t yet know enough about all of the underlying neural circuits that are driving the development of addiction and how drugs like alcohol act on those circuits to promote addiction.

“We’re in early stages of the grant, but we are confident that being able to restore cognitive control is going to be critical for treating addiction and alcohol use disorders — whether or not these specific pharmacological targets will work in humans is still to be determined and precisely how alcohol acts on these circuits to drive the acquisition of habits and to disrupt cognitive control, we don’t know. We do know it acts on some of these targets, and it’s pointing toward novel treatment strategies, but we don’t know yet how these circuits are going to be involved.” 

According to the Closing the Addiction Treatment Gap initiative, 23.5 million Americans are addicted to alcohol and drugs. Barker believes that when you get right down to it, a great deal of addiction and mental illness is a result of drugs and alcohol hijacking learning and memory circuits.

“I think that if we can get a better understanding of learning and memory in general, we’re going to facilitate better performance in schools. We can identify who is at risk for future development of addiction, and we can potentially prevent that. We can identify how stress during adolescence or drug exposure during adolescence can drive future cognitive impairments. We can really get at the root of some of these questions,rather than waiting until the end and asking, can we make you drink less.” 

She is optimistic that the results of her work will provide hope to people. “Learning and understanding how the brain functions and what it does is really what drives me. I think a better understanding of a lot of these basic mechanisms is not just going to apply to addictions or depression, it’s going to be able to open up doors for potential treatment strategies across the board in neuroscience research.”