How Do GLP-1 Drugs Quiet the Brain’s Reward Circuits?

Glucagon-like peptide-1 receptor agonist (GLP-1RA) drugs like semaglutide and liraglutide have gained substantial popularity due to their efficacy for weight loss and glycemic control (Box 9-3, Principles of Neurobiology, 3ed). While initially developed to treat type 2 diabetes, they are now also being used for a broader range of conditions, including obesity, heart disease, and non-medical, cosmetic purposes. Interestingly, as more people take GLP-1RAs and share their experiences, an unexpected pattern has emerged: in addition to weight loss, users also report reductions in their desire for a wide variety of addictive behaviors and substances such as gambling, shopping and alcohol. Indeed, a recent paper that studied this phenomenon in a cohort of approximately two million U.S. veterans with diabetes found that GLP-1RA users had lower risk for substance use disorders compared to non-users and users of other antidiabetic medication (Xie et al., 2025). Together, these data raise the possibility that GLP1-RAs act on neural circuitry shared across many appetitive substances and behaviors rather than on food intake alone.

One likely site of convergence is the brain's dopaminergic reward circuitry. As discussed in Section 11.25, midbrain dopaminergic projections play a key role in reward-based learning (see Figure 11-44). GLP-1 signaling is already known to interact with this system, as GLP-1RAs have been shown to dampen mesolimbic dopamine and reduce drug-seeking behavior in a variety of behavioral paradigms. Other brain regions, such as the amygdala, are thought to feed into this reward circuitry as well, though the specific pathways involved are not fully mapped.

New evidence from Godschall et al. (2026) sheds light on this system. Since many small-molecule GLP-1RAs are unable to activate the rodent GLP-1 receptor due to a single amino acid difference at position 33 (tryptophan in humans, serine in mice), the researchers began by using CRISPR–Cas9 technology (see Box 14-1) to generate knock-in point mutation Glp1rS33W mice. This allowed them to test the effect(s) of small-molecule GLP-1RAs in vivo.

Using their model, they surveyed several GLP-1 receptor-expressing brain regions to see where the drugs act and what each region's role in feeding behavior might be. GLP-1 receptor activation in the hypothalamus and hindbrain suppressed food intake, consistent with these regions' established roles in homeostatic feeding. Interestingly however, the central amygdala (CeA) suppressed high-fat food intake but not standard chow intake. Since high-fat food is eaten largely for pleasure rather than caloric need, this finding suggests that GLP-1 acts on the CeA to selectively dampen hedonic, rather than homeostatic, feeding. The researchers validated the functional role of these GLP-1 receptor-expressing CeA neurons in regulating behavior through multiple approaches: optogenetic stimulation was sufficient to reduce high-fat food intake, whereas selective deletion of GLP-1 receptors impaired liraglutide's ability to attenuate it. Neurochemically, these GLP-1 receptor-expressing cells were found to be broadly GABAergic, but belonged to a diverse array of neuronal subtypes.

To begin situating the CeA within broader reward circuitry, Godschall et al. performed multiple tracing experiments. They show that GLP-1 receptor-expressing CeA neurons receive direct input from GLP-1 releasing neurons in the nucleus tractus solitarius (NTS) — the brain’s main store of endogenous GLP-1 — and that they project directly onto dopamine neurons in the VTA. These connections were also shown to be functionally relevant for GLP-1RA mediated reductions in high-fat food intake via optogenetic manipulations, suggesting that the CeA is directly involved in both pharmacological and endogenous GLP-1 signalling, as well as dopamine reward signalling.

Finally, given the established CeA→VTA connection and the importance of VTA dopamine release into the nucleus accumbens (NAc) for reward-based learning, the authors hypothesized that GLP-1RAs reduce dopamine release in the NAc. Indeed, administration of the drugs during high-fat food consumption in mice with humanized GLP-1 receptors (Glp1rS33W) in the CeA was sufficient to blunt peak and consumption-associated dopamine transients. Furthermore, danuglipron and orforglipron — two small-molecule GLP-1RAs — both replicated this effect, indicating that it is a general property of GLP-1 receptor activation rather than the result of one particular compound. All together, these findings support a distinct CeA→VTA→NAc circuit that works in tandem with other established midbrain circuits to curb hedonic feeding.

Overall, these data offer a potential mechanistic explanation for the changes in reward processing revealed by anecdotal reports and epidemiological examinations in humans. That is, if the CeA→VTA→NAc pathway is also involved in reward responses to non-food substances/behaviors, then it could help to explain why GLP-1RA users report attenuated drive for a wide variety of addictive substances/behaviors. Testing whether this pathway modulates non-food rewards will, thus, be an important next step, and could help to position GLP-1RAs as a promising new treatment for substance use disorders.

References

Godschall, E. N., Gungul, T. B., Sajonia, I. R., Buyukaksakal, A. K., Li, O., Ogilvie, S., Keeler, A. B., Tian, G., Shi, Y., Koita, O., Guo, C. X., Deutsch, T. C., Steacy, E. J., Crook, M., Zhang, Y., Conley, N. J., Memi, G., Webster, A. N., Yipkin Calhan, O., … Güler, A. D. (2026). A brain reward circuit inhibited by next-generation weight-loss drugs in mice. Nature, 654(8120), 1055–1064. https://doi.org/10.1038/s41586-026-10444-4

Xie, Y., Choi, T., & Al-Aly, Z. (2025). Mapping the effectiveness and risks of GLP-1 receptor agonists. Nature Medicine, 31(3), 951–962. https://doi.org/10.1038/s41591-024-03412-w