Kang Lai, Class of 2026

Ghrelin, a hormone secreted by the stomach, increases appetite through the activation of growth hormone secretagogue receptors (GHSR), primarily in the hypothalamus and ventral tegmental area (VTA). These are key regions of the brain responsible for reward and motivation due to an abundance of dopamine-releasing neurons. Another player in the food reward system is a family of lipid molecules called endogenous cannabinoids. Similar to the effects of cannabis, endogenous cannabinoids influence stimuli such as stress, pain, and appetite. While ghrelin and endocannabinoids have been independently proven to promote orexigenic effects, stimulating appetite and increasing food intake, their interaction remains underexplored. Researchers hypothesized that ghrelin enhances food motivation through endocannabinoid signaling, stimulating dopamine cells in the VTA. 

Through in situ hybridization and immunohistochemistry, researchers led by Dr. Alexander Edwards confirmed the presence of GHSR in both dopamine neurons and dopamine-negative neurons and the expression of the CB-1R (an endocannabinoid receptor) in primarily non-dopamine neurons. Mice given either ghrelin or endocannabinoids showed no increases in food intake, suggesting a crosslink between the two signaling pathways. 

Endocannabinoids such as 2-AG (2-arachidonoylglycerol) and AEA (anandamide) are synthesized through hydrolysis of diacylglycerol via diacylglycerol lipase ɑ (DAGLɑ). GHSR then translocates DAG to the membrane, where DAGLɑ converts it to 2-AG. Rats genetically modified with GHSR signaling deficits displayed significantly lower levels of 2-AG as shown by molecular and biochemical analyses, supporting the model of a signaling crosslink between the endocannabinoid and ghrelin pathways. 

Electrophysiological data revealed that ghrelin activation of dopamine neurons in the VTA is independent of endocannabinoids, but endocannabinoids enhance excitatory drive, ultimately indirectly increasing dopamine levels. This amplifies reward-seeking behaviors. When 2-AG degradation is inhibited, rats displayed greater motivation for food, suggesting endocannabinoids enhance ghrelin-induced food-seeking behavior.

The mechanism that interlinks the hormone ghrelin, the endocannabinoid system, and dopamine provides critical insights into reward circuitry, food motivation, and rewarding behavior. Ghrelin activates dopamine neurons in the VTA and, in turn, modulates the release of endocannabinoid levels that further enhance the excitatory effect of dopamine levels. Moreover, these findings support the notion that cannabinoid and ghrelin signaling pathways may act as potential interventions for eating disorders and obesity, adding significant depth to the fields of neuroscience and nutrition.

Figure 1: Brain showing signaling

Works Cited: 

[1] Edwards, Alexander (2025). Ghrelin Recruits the Endocannabinoid System to Modulate Food Reward. Journal of Neuroscience, 45 (9) e1620242024; https://doi.org/10.1523/JNEUROSCI.1620-24.2024

[2] Image: https://unsplash.com/photos/a-computer-generated-image-of-a-human-brain-SAnbBfME5Q8