Enhancement of 2-arachidonoylglycerol but not anandamide signaling in the ventral tegmental area selectively increases the choice to respond to reward-predictive incentive cues in male rats

Neuropharmacology. 2026 Aug 26:111154. doi: 10.1016/j.neuropharm.2026.111154. Online ahead of print.

ABSTRACT

Mesolimbic endocannabinoid (eCB) signaling impacts reward-seeking behaviors that rely on incentive salience. We previously showed that systemic enhancement of 2-arachidonoylglycerol (2-AG) using the monoacylglycerol lipase (MAGL) inhibitor MJN110 robustly decreased the latency of responding to reward-predictive incentive cues (ICs) and collecting the reward, as well as the choice to respond to the IC. Here we sought to determine the contribution of the endocannabinoids 2-AG and anandamide in the ventral tegmental area (VTA) in mediating incentive salience processes. We microinfused MJN110 or PF3845, a fatty acid amide hydrolase (FAAH) inhibitor, into the VTA to increase 2-AG and anandamide, respectively in male rats. These rats were trained to nosepoke during an 8-sec audiovisual IC to receive a 10% sucrose reward. We found that while intra-VTA PF3845 had little effect on responding to the IC, intra-VTA MJN110 specifically increased only the choice to respond without impacting the vigor (e.g., rapidity) of the response towards either the IC or the sucrose reward itself. This contrasts with our previous work in which systemic MJN110 treatment enhanced choice, and vigor to both the IC and reward. Further, the intra-VTA MJN110 enhancement of responding to ICs was blocked by the CB1 receptor antagonist rimonabant. Our results suggest that increasing 2-AG, but not anandamide, in the VTA selectively enhances the choice to respond to cues predicting a reward. However, the effects of systemic MJN110 in enhancing the vigor of responding cannot be attributed to VTA 2-AG signaling.

PMID:42648566 | DOI:10.1016/j.neuropharm.2026.111154