Currently, the treatments for alcohol use disorder (AUD) work in one of two ways, explains Joseph Schacht , PhD, associate professor of psychiatry at the University of Colorado Anschutz School of Medicine — they either make the effects of alcohol less pleasurable, or they reduce cravings for alcohol.
"Those are important things for alcohol and substance use disorders — reducing how good the drug makes you feel or how much you want to use it," Schacht says.
But is there another mechanism a drug could target to help people with alcohol use disorder? Schacht and his colleague Drew Winters, PhD, research associate in the CU Anschutz Department of Psychiatry , hypothesized that there could be — and their research published recently in the journal Biological Psychiatry: Cognitive Neuroscience and Neuroimaging shows that their theory may be correct.
Targeting the prefrontal cortex
"The current medications for AUD target the neurotransmitter dopamine in the reward-related parts of the brain," Schacht says. "But we were interested in understanding how dopamine might act in a different part of the brain — the prefrontal cortex — and how its action there might affect a different behavior, which is behavioral control."
Because AUD and addiction are diseases of the "gas" — wanting to feel good by using the substance — as well as the "brakes," or the inability to control one's behavior when a craving arises, a medication that increases the amount of control one has over their behavior could be another way to treat them, the researchers hypothesized.
Enter tolcapone
To test the theory, they turned to a drug called tolcapone, an FDA-approved medication, originally designed to treat Parkinson's disease, that increases dopamine in the prefrontal cortex by suppressing the action of an enzyme that degrades dopamine. In the CU randomized study, participants with AUD who took the medication instead of a placebo performed better on a computer-based test called a "stop signal task," in which they must stop themselves from pressing the space bar when a certain signal comes up on the screen.
"You have a greater number of trials where you just press the space bar," Winters says. "You're already primed to hit the space bar, then when a different signal comes up, you have to stop yourself and not press anything. We were measuring if they can stop, and we also want to see, when they make an error, are they making corrections afterward?"
Reduction in use
MRI images taken during the stop signal task showed that the drug increased activation in the prefrontal cortex when people were trying to control their behavior, which is consistent with tolcapone increasing dopamine in the prefrontal cortex. The researchers also asked participants about their alcohol use during the seven days they were taking the drug.
"They came in, we gave them the medication, they came back a week later, and we said, 'How much did you drink during the last week?'" Schacht says. "Greater prefrontal cortex activation was associated with less drinking during that week, suggesting that the mechanism of increased control was having an effect on their behavior in the real world."
"It was very gratifying to see that this medication is working in the ways that we expected it to, and that there were actually changes in the brain that associate with behavior," Winters adds. "That connection is really important."
Next steps
Schacht, who also has conducted research on the effects of GLP-1 agonist drugs like Ozempic on AUD, is now conducting a study on the effects of tolcapone on people with AUD who also have attention-deficit/hyperactivity disorder (ADHD).
"Those patients are the ones who might especially benefit from being able to control their behavior more, because they have not only AUD, which is impairing the 'brakes,' but also this disorder related to difficulties with controlling impulsivity," he says.
Because tolcapone is no longer used to treat Parkinson's, the researchers say, it's unlikely that it would be repurposed to treat AUD. But their research sets the stage for a pharmaceutical company to develop a drug that works similarly to treat AUD and substance use disorders.
"I've worked in AUD medication development for a long time, and I've tested many medications with different mechanisms of action," Schacht says. "It was very fulfilling to see that one that works in a different way could also be effective. It suggests that we might be able to broaden the space for what medications might be useful in this condition."
