Targeting dysregulated kappa-opioid receptors reduces working memory deficits in alcohol use disorders

As heavy or frequent drinking escalates, some people continue to drink despite increasingly negative consequences such as poor performance at work or school, deteriorating family or personal relationships, and declining physical health.

Impaired working memory, a common problem in people with alcohol use disorder (AUD), can interfere with disease recovery and management, and contribute to the risk of relapse. Working memory is one of the processes of executive function, a set of high-level mental skills (also encompassing flexible thinking and self-control) needed to learn and manage daily life.

“People with severe alcohol dependence have a reduced ability to make wise decisions or make good choices,” said Brendan Walker, PhD, professor of psychiatry and behavioral neuroscience at the University of South Florida Health (USF Health) Morsani College of Medicine. “They ignore the problems created by excessive drinking and give up important things to satisfy their urge to drink more.”

Dr. Walker studies the biological brain changes that lead to addictive behaviors with the goal of finding ways to improve treatment outcomes. A major obstacle to recovery, even months or years after rehabilitation and prolonged abstinence, appears to be physical changes in neurotransmitters and their target receptors as the brain adapts to abuse of alcohol or other drugs.

Dr. Walker’s lab and others focused on the interaction of alcohol-induced brain peptides (neurotransmitters) known as dynorphins that bind to kappa opioid receptors (KORs), natural opioid receptors in brain cells.

Now, for the first time, a preclinical study led by Dr. Walker shows that dysregulated KORs in the midline prefrontal cortex region of the brain (part of the frontal lobe) contribute to working memory impairments in alcohol addiction. . Additionally, researchers found that a compound used to block KORs (an antagonist) alleviated these working memory deficits and may help restore “normal” executive function in people with severe AUD, the report said. Dr Walker.

USF Health’s findings were published January 20, 2022 in Addiction Biology.

“Collectively, our research helps establish that targeting the dynorphin-KOR system may be a viable treatment strategy to simultaneously manage the hallmark symptoms of alcohol dependence – increased motivation to drink, increased negative emotional states, and executive function. compromised (decision-making),” said Dr. Walker, the study’s principal investigator.

Previous preclinical studies have examined how abnormal regulation of the dynorphin-KOR system in another brain region called the amygdala increases both motivation for alcohol consumption and negative emotional states like depression and anxiety that are amplified upon sudden cessation of alcohol consumption.

In a series of experiments, USF Health researchers used a rat model that mimicked severe human AUD, induced by cycles of intoxication (long-term intermittent exposure to ethanol vapor) and alcohol withdrawal (exposure to air only). This group of alcohol-dependent rats was compared to two other groups: non-dependent rats (a model mimicking social drinking in humans) and alcohol-naive rats (a control group never exposed to ethanol vapor) . All were trained and tested in working memory. task (non-sample matched delayed task) involving a T-maze.

Among the main results:

  • The alcohol-dependent rat model developed by the researchers proved to be very effective in measuring working memory deficits.
  • Medial prefrontal cortex KORs in alcohol-dependent rats were overactivated (abnormally increased) in dependence, compared to the same opioid receptors in non-dependent and alcohol-naive rats. This dysregulation of the dynorphin-KOR system in a brain region critical for the control of working memory was correlated with poorer working memory performance in alcohol-dependent rats during acute withdrawal.
  • When the researchers stimulated the KORs in the medial prefrontal cortex of not dependent rats with a dynorphin-mimicking KOR agonist, they were able to produce profound working memory deficits like those seen in alcohol-dependent rats.
  • Conversely, administration of KOR antagonist norbinaltophimine (nor-BNI) to block brain activation KORs significantly reduced alcohol-induced impaired working memory. Alcohol-dependent rats showed working memory performance comparable to non-dependent rats.

More studies are needed, including in humans, but previous laboratory research has already shown that KOR antagonists curb the desire for excessive alcohol consumption and negative emotions that can lead to self-medication with alcohol. This latest study from USF Health suggests that such a compound also has promise for restoring the executive function needed for people to make better decisions about their drinking and improve their quality of life, Dr. Walker said.

There is “no magic bullet” for AUD, Dr Walker stressed, but identifying and developing a drug that alleviates multiple symptoms could allow patients to cut down or stop drinking more easily when combined with cognitive behavioral therapy.

The USF Health study was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Alcohol is one of the most common forms of addiction and a leading cause of preventable death and disease, killing nearly 100,000 Americans each year. In 2019, nearly 15 million people ages 12 and older in the United States suffered from alcohol use disorders, according to the NIAAA.

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