Selective GRAB sensors reveal distinct endocannabinoid dynamics in vivo

Authors

Cai, R., Yang, Y., Cai, S., Silva de Sousa, A. I., Todd, K., Wang, L., Teo, W., Dong, A., Chen, S., Dong, H., Wang, H., Wu, Z., Qiao, Y., Xu, P., Song, C., Cragg, S. J., Li, Y.

Abstract

The endocannabinoid system modulates diverse physiological processes via two endogenous lipid ligands, 2-arachidonoylglycerol (2-AG) and anandamide (AEA); however, their specific spatiotemporal dynamics remain poorly understood owing to the lack of selective probes. Here, we developed GRAB2-AG2.0 and GRABAEA2.0, two genetically encoded fluorescent sensors that selectively detect 2-AG and AEA, respectively. Both sensors exhibited high apparent affinity and molecular specificity for their respective ligands, enabling the real-time detection of 2-AG and AEA release evoked by electrical stimulation in cultured neurons and acute brain slices. In freely behaving mice, these sensors revealed ligand- and context-specific eCB dynamics: aversive stimulation preferentially evoked 2-AG, whereas psychoactive drugs produced distinct 2-AG and AEA responses. Notably, {Delta}9-THC elicited a sustained 2-AG signal in the nucleus accumbens shell, and local deletion of Dagla markedly attenuated both this signal and {Delta}9-THC-induced hypolocomotion. These sensors therefore enable detecting 2-AG and AEA signaling seperately and reveal an endogenous 2-AG component of the behavioral response to {Delta}9-THC.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 13 Aug 2026.

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