Researchers at the University of Pennsylvania have uncovered a promising new target for combating cocaine addiction by leveraging the body's natural glucagon-like peptide-1 (GLP-1) system. In a study published in Science Advances, the team led by Riley Merkel and colleagues demonstrated that activating an endogenous GLP-1 circuit in the brain can reduce cocaine-seeking behavior in rats. Their findings could pave the way for novel pharmacological treatments for cocaine use disorder (CUD), which currently lacks FDA-approved medications.
Previous studies have shown that GLP-1 receptor (GLP-1R) agonists—drugs commonly used to treat diabetes and obesity—can reduce the rewarding effects of addictive substances. However, the precise neural mechanisms underlying this effect were not well understood. The new study sheds light on how GLP-1 signaling in the ventral tegmental area (VTA), a key brain region involved in motivation and reward, can suppress drug-seeking behavior.
The researchers found that chronic cocaine use led to a decrease in circulating GLP-1 levels in rats. To explore whether restoring GLP-1 signaling could influence addiction-related behaviors, they used a chemogenetic approach to selectively activate GLP-1–producing neurons in the nucleus tractus solitarius (NTS), a brainstem region that sends GLP-1 signals to the VTA. Their results were striking—activating these neurons significantly reduced cocaine-seeking behavior without affecting general motivation for natural rewards like food.
A key discovery was that GLP-1Rs in the VTA are primarily located on inhibitory gamma-aminobutyric acid (GABA) neurons, rather than dopamine neurons. Using fiber photometry, a technique that allows real-time monitoring of neural activity in awake animals, the researchers observed that activating the GLP-1 system increased the activity of VTA GABA neurons while simultaneously suppressing dopamine neuron activity. Since dopamine release in the brain’s reward circuits drives drug-seeking behavior, this shift in neural activity likely underlies the ability of GLP-1 activation to reduce relapse risk.
This study not only highlights the therapeutic potential of targeting GLP-1 pathways in addiction treatment but also provides crucial insights into the brain’s natural mechanisms for regulating drug-seeking behavior. The findings could inspire new clinical trials exploring the use of GLP-1R agonists, such as semaglutide or exenatide, as potential treatments for CUD.
For more details, you can access the full study here: https://www.science.org/doi/10.1126/sciadv.adr5051
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