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

Date:
March 9, 2022
Source:
University of South Florida (USF Health)
Summary:
A preclinical study led by a neuroscientist shows that dysregulated
kappa-opioid receptors (KORs) in the brain's medial prefrontal
cortex region (part of the frontal lobe) contribute to working
memory deficits in severe alcohol dependence. The researchers
discovered that an antagonist compound used to block KORs
alleviated these working memory deficits and may help restore
'normal' executive function needed to make better decisions about
alcohol consumption.



FULL STORY ==========================================================================
As heavy or frequent alcohol use escalates, some people continue to drink despite increasingly negative consequences such as poor job or school performance, unraveling family or personal relationships and declining
physical health.


========================================================================== Impaired working memory, a common problem for those with alcohol use
disorder (AUD), can interfere with recovery and disease 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 to
manage daily life.

"People with severe alcohol dependence have reduced ability to make sound decisions, or good choices," said Brendan Walker, PhD, a professor of psychiatry and behavioral neurosciences at the University of South Florida Health (USF Health) Morsani College of Medicine. "They ignore the problems created by excessive drinking and give up things of importance to satisfy
their craving to drink more." Dr. Walker studies the biological brain
changes that drive addictive behaviors with the aim 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 receptor targets as the
brain adapts to abuse of alcohol or other drugs.

Dr. Walker's laboratory and others have focused on the interaction of
alcohol- induced "feel bad" brain peptides (neurotransmitters) known
as dynorphins that bind with kappa-opioid receptors (KORs), naturally
occurring receptors for opioids in brain cells.

Now, for the first time, a preclinical study led by Dr. Walker shows
that dysregulated KORs in the brain's medial prefrontal cortex region
(part of the frontal lobe) contribute to working memory deficiencies in
alcohol dependence.

Furthermore, the researchers discovered that a compound used to block
KORs (an antagonist) alleviated these working memory deficits and may
help restore "normal" executive function in those with severe AUD,
Dr. Walker said.



==========================================================================
The USF Health findings were reported Jan. 20, 2022, in Addiction Biology.

"Collectively, our research is helping establish that targeting
the dynorphin- KOR system could be a viable treatment strategy for simultaneously managing the hallmark symptoms of alcohol dependence -- increased motivation for drinking, increased negative emotional states
and compromised executive function (decision-making)," said Dr. Walker,
the study's principal investigator.

Earlier preclinical studies looked at 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 during sudden
withdrawal from drinking.

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

Among the key findings:
* The alcohol-dependent rat model the researchers developed proved
very
effective for measuring working memory deficits.

* Medial prefrontal cortex KORs in the alcohol-dependent rats were
overactivated (abnormally increased) in dependence, compared to
those same opioid receptors in the nondependent and alcohol-nai"ve
rats. This dysregulation of the dynorphin-KOR system in a brain
region critical for the control of working memory correlated with
worse working memory performance by the alcohol-dependent rats
during acute withdrawal.

* When researchers stimulated KORs in the medial prefrontal cortex of
nondependent rats with a KOR agonist mimicking dynorphin, they
were able to produce profound working memory deficits like those
observed in alcohol-dependent rats.

* Conversely, administering KOR antagonist norbinaltophimine
(nor-BNI) to
block activation of the brain KORs significantly reduced
alcohol-induced impaired working memory. Alcohol-dependent rats
showed working memory performance comparable to the nondependent
rats.

More studies are needed, including in humans, but previous laboratory
research has already shown that KOR antagonists curb the desire to
excessively consume alcohol and the negative emotions that can drive self-medication with alcohol.

This latest USF Health study suggests such a compound also holds promise
for restoring executive function needed for people to make better
decisions about their alcohol intake and improve their quality of life,
Dr. Walker said.

There is "no magic bullet" for AUD, Dr. Walker emphasized, but identifying
and developing one medication that alleviates multiple symptoms could
make it easier for patients to cut back or quit drinking when combined
with cognitive behavioral therapy.

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

Alcohol is one of the most common forms of substance abuse and a leading
cause of preventable deaths and disease, killing nearly 100,000 Americans yearly. In 2019, almost 15 million people ages 12 and older in the U.S
had alcohol use disorder, according to the NIAAA.


========================================================================== Story Source: Materials provided by
University_of_South_Florida_(USF_Health). Original written by Anne
DeLotto Baier. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Gengze Wei, Sunil Sirohi, Brendan M. Walker. Dysregulated
kappa‐opioid receptors in the medial prefrontal
cortex contribute to working memory deficits in alcohol
dependence. Addiction Biology, 2022; 27 (2) DOI: 10.1111/adb.13138 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220309090804.htm

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