Researchers carrying out functional magnetic resonance imaging (fMRI) studies in different areas of the human brain have discovered how cocaine addiction disrupts the dopamine neurons that govern how we perceive and learn from rewards. Their findings indicate that while individuals with cocaine addiction have similar expectations of rewards, compared with healthy control individuals, their dopamine neurons send out much weaker signals when these rewards are actually received. This dysregulation could make it more difficult for people with cocaine addiction to learn from their experiences and change addictive behavior.

Understanding the mechanisms behind addictive behavior could inform treatment strategies, the researchers suggested. “Our results support the medical model of addiction as a disorder of the brain that deserves treatment,” said Rita Goldstein, PhD, a neuroscientist and addiction expert at the Icahn School of Medicine at Mount Sinai. “Addiction is a disorder and not a choice or a moral weakness …. Our findings suggest that interventions that boost the perception of received rewards might be a valuable component of addiction treatment. Understanding the brain mechanisms behind addiction is also extremely valuable for the public and for the person experiencing addiction.”

Goldstein is senior author of the team’s published paper in Neuron, which is titled “Reduced neural encoding of utility prediction errors in cocaine addiction,” and in which the authors noted that their findings could be used to develop, “timely prevention and intervention efforts.”

Addiction encompasses a core difficulty in adaptive decision making, the authors wrote. “Adaptive behavior requires learning from experience.” It is  well documented from both animal and human studies that cocaine addiction impacts multiple aspects of dopamine signaling in the brain. However, it’s unclear whether certain parts of the dopamine signaling pathway are more important than others.

Rather than general errors with dopamine signaling, addictive behavior is thought to be due to disruptions to the reward prediction error (PE), a system that calibrates future expectations based on past experiences by comparing expected rewards to actual rewards as encoded by dopamine neurons in the midbrain. “Influential accounts of addiction posit alterations in adaptive behavior driven by deficient dopaminergic prediction errors (PEs), signaling the discrepancy between actual and expected reward,” the scientists noted. First author Anna Konova, PhD, a neuroscientist at Rutgers University, explained further, “If you’re not tracking the reward signal appropriately, it makes it much harder to disengage from something that’s no longer rewarding.”

However, few studies have directly demonstrated the impact of cocaine use on reward prediction error in humans. “People with chronic cocaine addiction have well-documented alterations in dopamine transporters, receptors, and transmission,” the team continued, “however, it is not yet known if these changes functionally dysregulate PE signals.”

To examine the role of prediction error in cocaine addiction the research team carried out fMRI scanning to examine neural activity in people with cocaine addiction and in healthy comparison controls, while the participants were performing a simple decision-making task. This task was to choose between a “safe” monetary reward and a “risky” reward that carried a chance of being either much higher or lower in value than the safe option. The researchers compared brain activity during the two phases of the prediction error calculation, first during the expectation phase (while participants were making their decision and anticipating the resulting reward), and then during the actual reward phase (when participants were presented with the outcome).

Their findings, consistent with those from animal studies, showed that people with cocaine addiction had reduced prediction error responses. And when the team broke the prediction error response down into its component parts, they found that while signals of reward expectation were similar for both groups, the signal for received reward was weaker for people with cocaine addiction. This weakened reward signal was visible in the ventral striatum, the brain region where prediction error is processed, and there was also reduced activity in the orbitofrontal cortex, a brain region involved in integrating the prediction error signal to inform future behavior. “Relative to control participants, people with chronic cocaine addiction demonstrate reduced utility PEs in the dopaminoceptive ventral striatum, with similar trends in orbitofrontal cortex,” the scientists wrote. Dissecting this PE signal into its subcomponent terms attributed these reductions to weaker striatal responses to received reward/utility, whereas suppression of activity with reward expectation was unchanged.”

“We found evidence that people with chronic cocaine addiction have reduced prediction error responses, and this difference seems to be caused by differences in the subjective perception of received reward,” said Konova. “The reduced reward signal seems to propagate to other regions of the brain that would receive this information to then update your expectations for the next time you encounter this same situation.” The investigators further stated, “Thus, for the first time in the human brain, this analysis allowed us to test whether alterations in one or both PE subcomponents are found in people with cocaine addiction, further informing a broader circuit-level understanding of our findings,” the investigators stated. “These findings support the notion that cocaine addiction may disrupt the PE computations that are at the core of human learning from experience and adaptive behavior.”

The team showed that people with cocaine addiction were more likely to choose risky options compared with controls, and this risk tolerance was more apparent in people who had begun using cocaine at an earlier age, pointing to potential predisposing factors for developing addiction. “Taken together, these results raise the possibility that risk preferences are an early predisposing factor for addiction,” the team stated.

Understanding the mechanisms behind addictive behavior could inform treatment strategies for addiction, the researchers said. “The documentation of such a preferential deficit in response to received reward here in people with cocaine addiction is significant because it may provide a computationally specific translational target for intervention.,” they noted. Goldstein added, “Our findings suggest that interventions that boost the perception of received rewards might be a valuable component of addiction treatment. Understanding the brain mechanisms behind addiction is also extremely valuable for the public and for the person experiencing addiction.”

Next, the team wants to understand how this dysregulation of reward signaling changes during different stages of addiction and recovery and whether reward perception is involved in other types of substance disorder, for example in addiction to opioids such as heroin. “We want to understand how this signal changes through the progression of recovery, or as a function of different stages of addiction to understand whether it’s really driven by chronic cocaine exposure or something that comes on earlier, maybe even before you start substance use,” says Goldstein.

An important direction for future work will be to isolate the developmental trajectory of how risk preferences, cocaine exposure, and utility PEs intersect to confirm the vulnerability hypothesis suggested by our data,” the investigators further stated. “Such future work promises to advance our understanding of how early dopamine signaling abnormalities eventually culminate in the resolute drug seeking and use that characterizes addiction.”

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