Booze on the brain

Summary: Dysfunction in a brain pathway that usually keeps compulsive drinking in check may play a critical role in alcohol use disorder.

Source: Santa Clarita University

Compulsive drinking may be due to dysfunction in a specific brain pathway that normally helps keep drinking in check. The results are reported in the journal Biological Psychiatry.

In the United States, 14 million adults struggle with alcohol use disorder (AUD)– formerly known as alcoholism. This disorder makes individuals unable to stop drinking even when they know the potential risks to health, jobs, and relationships.

“Difficulty saying no to alcohol, even when it could clearly lead to harm, is a defining feature of alcohol use disorders,” said Andrew Holmes, PhD, senior investigator of the study and Chief of the Laboratory on Behavioral and Genomic Neuroscience at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). “This study takes us a step further in understanding the brain mechanisms underlying compulsive drinking.”

Many complex parts of behavior–emotion, reward, motivation, anxiety–are regulated by the cortex, the outer layers of the brain that are responsible for complex processes like decision-making. Unlike drugs like cocaine, alcohol has broad effects on the brain, which makes narrowing down a target for therapeutic treatment much more difficult.

“We want to understand how the brain normally regulates drinking, so we can answer questions about what happens when this regulation isn’t happening as it should,” said Lindsay Halladay, PhD, Assistant Professor of Psychology and Neuroscience at Santa Clara University, and lead author of the study.

To study how the brain regulates drinking, Halladay and colleagues trained mice in the lab to press a lever for an alcohol reward. Once trained, the mice were presented with a new, conflicting situation: press the same lever for alcohol and receive a light electric shock to their feet, or avoid that risk but forfeit the alcohol. After a short session, most mice quickly learn to avoid the shock and choose to give up the alcohol.

Halladay’s team first used surgically-implanted electrodes to measure activity in regions of the cortex during that decision.

“We found a group of neurons in the medial prefrontal cortex that became active when mice approached the lever but aborted the lever press,” said Halladay. “These neurons only responded when the mice did not press the lever, apparently deciding the risk of shock was too great, but not when mice chose alcohol over the risk of shock. This means that the neurons we identified may be responsible for putting the brakes on drinking when doing so may be dangerous.”

The medial prefrontal cortex (mPFC) plays a role in many forms of decision-making and communicates with many regions of the brain, so Halladay’s team explored those external connections.

This shows cocktails
Unlike drugs like cocaine, alcohol has broad effects on the brain, which makes narrowing down a target for therapeutic treatment much more difficult. The image is in the public domain.

The team used optogenetics, a viral engineering technique that allowed them to effectively shut down precise brain pathways by shining light in the brain. They shut down activity of cells in the mPFC that communicate with the nucleus accumbens, an area of the brain important for reward, and found that the number of risky lever presses increased.

“Shutting down this circuit restored alcohol-seeking despite the risk of shock,” said Halladay. “This raises the possibility that alcohol use disorder stems from some form of dysfunction in this pathway.”

Understanding compulsive drinking in some people relies on identifying the neural pathway that keeps drinking in check.

“Current treatments just aren’t effective enough,” said Halladay.

“Nearly half of all people treated for AUD relapse within a year of seeking treatment.”

Once scientists understand exactly how wiring in the brain is different for individuals with AUD compared to those without the disorder, more effective treatments can be developed.

Funding: This work was supported by the National Institute on Alcohol Abuse and Alcoholism. Other co-authors include Adrina Kocharian, Patrick Piantadosi, PhD, Michael Authement, PhD, Abby Lieberman, Nathen Spitz, Lucas Glover, PhD, Kendall Coden, and Veronica Alvarez, PhD at NIAAA, and Vincent Costa, PhD, at Oregon Health Sciences University.

[divider]About this neuroscience research article[/divider]

Source:
Santa Clarita University
Media Contacts:
https://www.scu.edu/ – Santa Clarita University
Image Source:
The image is in the public domain.

Original Research: Open access
“Prefrontal regulation of punished ethanol self-administration”. Andrew Holmes et al.
Biological Psychiatry doi:10.1016/j.biopsych.2019.10.030.

Abstract

Prefrontal regulation of punished ethanol self-administration

Background
A clinical hallmark of alcohol use disorder (AUD) is persistent drinking despite potential adverse consequences. The ventral (vmPFC) and dorsal (dmPFC) medial prefrontal cortex are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala (BLA), which encode positive and negative valence of EtOH-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA).

Methods
We conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1-positive MSNs receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC and dmPFC, vmPFC projections to NAcS or BLA, to punished EtOH-SA.

Results
Punishment reduced EtOH-lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in vmPFC and dmPFC exhibited phasic firing to EtOH-lever presses and aborts, but only in vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, not dmPFC, photosilencing on a post-punishment probe test negated the reduction in EtOH-lever presses but not aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1-MSNs in NAcS. Photosilencing vmPFC projections to NAcS, not BLA, partially reversed suppression of EtOH-lever presses on probe testing.

Conclusions
These findings demonstrate a key role for vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in AUDs.

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