Bucknell Study Identifies Initial Rewarding Effects of Alcohol on Abuse Risk

About 20% of all people who consume alcohol develop an unhealthy use, accounting for over 5% of worldwide deaths. Bucknell University Professor Judy Grisel, psychology and neuroscience, was among those who developed an unhealthy relationship with these substances.

Since beating her own addictions more than 30 years ago, Grisel has gone on to study the underlying reasons for addiction and now contends that her initial reaction to her first drink of wine when she was 12 had a lot to do with her eventually wanting more. She has theorized that her brain's positive reaction to that initial drink may have put her at more risk for later drug addictions — a struggle she chronicled in her New York Times best-selling book Never Enough, the Neuroscience and Experience of Addiction.

The problem had been that there was no experimental way to study the brain’s reaction to an initial encounter with alcohol — until now. After decades of tinkering in the laboratory, Grisel's research team developed a way to carry out experiments in mice to assess individual differences in how much an individual likes alcohol or another drug, the first time they get it.

Grisel; former Bucknell psychology graduate students Madison Waldron M'21 and Holly Jones M'23; and Susquehanna University Professor of Biology Erin Rhinehart have now authored a recent paper on that study. Entitled Sensitivity to the Initial Rewarding Effects of Alcohol: Influence of Age, Sex, and β-endorphin, the study was published last month in the journal Alcohol: Clinical & Experimental Research. It's the first research to examine brain activity associated with pleasurable effects from a single exposure to alcohol, and demonstrates that just one exposure to a moderate dose of alcohol initiates brain activity that stimulates drug-seeking behavior in potentially higher-risk groups.

"Everyone doesn't feel the same reward from their initial encounter with alcohol," says Grisel, now one of the world's leading experts on addiction who was an invited panelist to the 2020 World Economic Forum. "In certain individuals, like myself, they experience the kind of positive response where they want to feel that way again and are drawn to more. And the reaction to that drug — in this case, alcohol — could put them at higher risk of disordered use."

The testing methodology the researchers devised involved a three-chambered apparatus with distinct floor tile patterns in the two opposing conditioning chambers. The floor on one side consisted of circles of various sizes, and the other, of uniform square tiles. Both floors were painted the same color red, and there was a smaller center chamber intended to be stimulus-neutral, with a smooth white floor.

On the first day of testing, half of the mice received alcohol associated with the circular floor tile, while the other half received saline, and then the protocol was reversed with the mice on the third day. On Day 5, mice were placed in the center stimulus neutral chamber immediately following a saline injection, with access to all three areas of the apparatus. The researchers recorded which mice were drawn to the alcohol chamber and those drawn to the saline chamber. They also compared the brain activity of the two groups.

"We found that natural endorphin activity in the brains of mice influenced how much they liked the feeling of alcohol," Grisel says. "Learning the mechanisms underlying why someone would be drawn to drug-seeking behavior is critical for understanding what may lead to abuse."

The researchers also found, in general, that adult mice were more sensitive to the effects of alcohol than adolescents, and outcomes depended on sex as well as the presence of endorphins. Among females, adolescents were stimulated by the drug, but insensitive to locomotor effects as adults, while among males, adolescents were insensitive and adults sedated.

"Reduced sensitivity to alcohol's reward may reflect increased risk for alcohol use disorders, as organisms tend to increase self-medication in the absence of reward," Grisel says. "Reduced sensitivity to sedation and reward in adolescents may increase susceptibility for addiction, in line with current understanding that young people have exaggerated risk for developing drug use disorders."

Grisel will discuss addiction research during a presentation at Seton Hill College in Greensburg, Pa., on Thursday, April 25, at 4 p.m.