Targeting Stress Hormones to Reduce Alcohol Drinking
- Olivier George
- Jan 27
- 2 min read
Alcohol addiction doesn't just affect the brain's reward system, it fundamentally alters how our bodies handle stress. We've known for years that the stress hormone system goes haywire during alcohol dependence, but finding safe, effective medications to target this system has remained elusive. In collaboration with the Vendruscolo and Mason labs, we set out to test whether a new class of drugs that modulate stress hormone receptors could reduce alcohol consumption.
The Research Question
We wanted to know whether selective glucocorticoid receptor (GR) modulators—drugs that fine-tune how stress hormones work in the brain—could reduce alcohol self-administration in rats. Since different GR modulators recruit different molecular partners inside cells, we hypothesized they might have varying effects on drinking behavior.
What We Did
We tested four different GR modulators (CORT118335, CORT122928, CORT108297, and CORT125134) in male rats. We used two groups: alcohol-dependent rats (exposed to alcohol vapor to induce dependence) and non-dependent rats. The rats were trained to press levers to receive either alcohol or water, allowing us to measure how each drug affected their drinking.
Each compound was given at different doses 90 minutes before testing sessions. We measured not just how much alcohol the rats consumed, but also whether the drugs affected their water drinking, a way to check if the compounds were simply making the rats sick or unable to respond, rather than specifically targeting alcohol consumption.
The Surprising Findings
Three of the four compounds (CORT118335, CORT122928, and CORT125134) significantly reduced alcohol self-administration in both dependent and non-dependent rats, without generally suppressing other consumptive behaviors. CORT108297, however, had no effect on drinking at any dose tested.
This was somewhat surprising because our previous work with mifepristone (a mixed GR antagonist) and CORT113176 showed they specifically reduced drinking in alcohol-dependent rats without affecting non-dependent rats. The broader effects of these newer compounds likely reflect a larger than expected role of glucocorticoid receptor in driving alcohol drinking0.
Interestingly, the compounds generally didn't disrupt water drinking, suggesting they weren't simply making the rats feel sick. They appeared to specifically reduce the motivation to consume alcohol.
Why This Matters
Alcohol use disorder is a devastating condition with limited treatment options. The stress hormone system—particularly glucocorticoid receptors—becomes dysregulated in alcohol dependence, driving continued drinking and relapse.
These results suggest that GR modulators hold promise as potential treatments for alcohol use disorder. While mifepristone (which also blocks progesterone receptors) has shown efficacy in both animals and humans with alcohol problems, selective GR modulators might offer better side-effect profiles for long-term use.
The varying effects of these compounds also teach us something important: not all GR modulators are created equal. The molecular details of how they work—which cellular partners they recruit, which genes they turn on or off—dramatically affects their ability to reduce drinking. Understanding these molecular mechanisms will be crucial for developing the next generation of addiction medications that target the stress system more precisely and effectively.
For more information about the study see the article below.
Article: McGinn MA, Tunstall BJ, Schlosburg JE, Gregory-Flores A, George O, de Guglielmo G, Mason BJ, Hunt HJ, Koob GF, Vendruscolo LF. Glucocorticoid receptor modulators decrease alcohol self-administration in male rats. Neuropharmacology. 2021 May 01;188:108510. doi: 10.1016/j.neuropharm.2021.108510. Epub 2021 Feb 19.
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