The FDA-approved diabetes drug semaglutide reduces alcohol drinking in mice and rats, suggesting it could be repurposed as an effective medication for alcohol use disorder (AUD).
Key findings include:
- Semaglutide dose-dependently decreased binge-like drinking in both male and female mice.
- In rats, semaglutide reduced binge-like and dependence-induced alcohol drinking.
- Semaglutide also decreased consumption of caloric and non-caloric solutions in mice, indicating effects on appetite and thirst beyond alcohol specifically.
- No interactions were found between semaglutide and alcohol on motor coordination or blood alcohol levels in mice.
- In the central amygdala and infralimbic cortex, brain regions involved in alcohol drinking, semaglutide increased GABA transmission in alcohol-naive rats but had mixed effects in dependent rats.
Source: JCI Insight 2023
Overview of Alcohol Use Disorder
Alcohol use disorder (AUD) is a chronic relapsing condition characterized by uncontrolled alcohol use despite negative consequences.
AUD is a leading cause of preventable death worldwide.
Only a few medications are approved for AUD treatment, highlighting the need for additional pharmacotherapies.
Binge drinking is an alarming pattern of alcohol misuse that increases AUD risk.
Chronic drinking can lead to physical alcohol dependence.
Brain changes drive compulsive drinking in AUD, even once dependence develops.
Two involved regions are the central amygdala (CeA), regulating stress and motivation, and the infralimbic cortex (ILC), regulating inhibition and decision-making.
Targeting Systems That Control Appetite and Reward
Growing evidence shows overlap between brain systems governing pathological overeating and addictive behaviors.
Appetite-regulating systems are now being studied as potential AUD treatment targets.
An example is glucagon-like peptide-1 (GLP-1), a hormone that curbs appetite and food intake. GLP-1 analogues treat diabetes and obesity.
Studies in animals show GLP-1 analogues also reduce addictive drug effects, including alcohol.
This suggests GLP-1 medications could treat AUD.
Semaglutide is a new, highly potent GLP-1 analogue approved for diabetes and obesity.
Compared to other GLP-1 drugs, semaglutide has superior efficacy for weight loss and glucose control.
This study provides the first detailed investigation of semaglutide’s behavioral and neuronal effects related to alcohol use.
Testing Semaglutide’s Impact on Alcohol Drinking and Brain Signaling
This research examined semaglutide in mouse and rat models using a comprehensive experimental approach.
Binge-like and dependence-induced alcohol drinking were measured to model different facets of AUD.
Male and female animals were included to assess sex differences.
Effects of semaglutide on consuming other solutions were tested for specificity.
Possible interactions with alcohol sedation and metabolism were evaluated.
Lastly, electrophysiology experiments probed semaglutide’s effects on GABA signaling in the CeA and ILC of alcohol-naive versus dependent rats.
Semaglutide Reduces Binge Drinking in Mice & Rats
Binge drinking was modeled using a 4-hour “drinking in the dark” test.
This procedure measures rapid, excessive alcohol intake by rodents.
In both mice and rats, semaglutide dose-dependently decreased binge-like alcohol consumption.
The effective doses were similar between species and sexes.
These findings suggest semaglutide reduces alcohol reward circuitry activation to curb binge intake.
Lower Doses Effective in Rat Model of Dependence
Rats were made physically dependent on alcohol via chronic intermittent alcohol vapor exposure.
This well-established model reproduces escalated drinking during alcohol withdrawal.
In dependent rats, semaglutide decreased alcohol self-administration at doses 10 times lower than the binge drinking tests.
Alcohol dependence alters many brain systems.
The lower effective doses suggest added sensitivity to semaglutide in the dependent state.
Behaviors Beyond Alcohol Change with Semaglutide
GLP-1 analogues treat obesity by reducing appetite and calories.
To examine specificity of semaglutide for alcohol, mice were tested on consuming solutions not containing alcohol.
Intake of water, non-caloric sweet (saccharin), unsweet carbohydrate, and unsweet fat emulsions were measured.
Semaglutide broadly reduced drinking of non-alcohol caloric and non-caloric fluids.
Total calories and chow intake were also decreased.
These results suggest semaglutide has wide effects on consummatory behaviors beyond alcohol specifically.
Reduced appetite, thirst, taste reward, and metabolic need likely all contribute.
Importantly, many current AUD medications influence weight and appetite.
Also, alcohol is often consumed in combination with foods.
Thus, semaglutide reducing other consumptive behaviors could provide a dual benefit in treating AUD patients.
No Evidence of Sedative Interactions with Alcohol
Preclinical research on potential AUD medications requires testing for unintended interactions with alcohol.
If a drug alters alcohol absorption or metabolism, this could dangerously impact motor impairment and sedation.
Mice were injected with a high alcohol dose after semaglutide pretreatment.
Motor coordination impairment on a rotarod test was unaltered by semaglutide.
Likewise, blood alcohol levels did not differ.
Open field tests also showed semaglutide does not sedate rats.
Together these results indicate semaglutide itself does not cause sedation or interact with alcohol sedating effects.
Neurotransmitter Systems: Semaglutide Effects on GABA Signaling
Chronic alcohol exposure dysregulates brain signaling, causing neuroadaptations that drive continued drinking.
Preclinical research provides invaluable opportunities to investigate AUD medication effects on these adaptations at the neuronal level.
The CeA and ILC show heightened GABA system activation after chronic alcohol exposure in animals and humans.
Compounds that restore GABA balance in these regions reduce alcohol drinking.
Thus, researchers tested if semaglutide normalizes GABA signaling disrupted by alcohol dependence.
Electrophysiology recordings in brain slices showed semaglutide increased GABA release onto CeA and ILC neurons in alcohol-naive rats.
However in dependent rats, semaglutide had mixed effects, increasing GABA transmission in some neurons while inhibiting it in others.
Though inconclusive, these findings reveal semaglutide can rapidly modulate GABA synapses in key addiction-related brain regions.
Semaglutide May Treat Alcohol Addiction
Overall, this comprehensive preclinical investigation demonstrates semaglutide reduces alcohol drinking across models, species, and sexes.
Efficacy at low doses in dependent rats is particularly promising clinically.
Appetite and reward brain systems appear implicated in semaglutide’s effects.
Despite influencing consummatory behaviors broadly, semaglutide did not negatively interact with alcohol.
The mixed results on GABA signaling warrant further study but suggest functional neuroadaptations with alcohol dependence.
These novel data provide strong support for testing semaglutide in AUD patients.
As an approved medication with minimal drug interactions, semaglutide has advantages for potential therapeutic repurposing.
Given the obesity epidemic, semaglutide’s weight loss effects could provide additional benefits in treating AUD.
These findings open exciting new avenues for developing improved pharmacological treatments to combat alcohol misuse and dependence.
References
- Study: The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission
- Authors: Vicky Chuong et al. (2023)
