Brain region-specific and sex-dependent roles of 2-arachidonoylglycerol in the retrieval of contextual fear memory in mice

Neuropharmacology. 2026 Aug 19:111153. doi: 10.1016/j.neuropharm.2026.111153. Online ahead of print.

ABSTRACT

2-Arachidonoylglycerol (2-AG), an endocannabinoid, is known to regulate fear memory. However, it remains unclear whether its contribution to fear memory retrieval varies across brain regions and between sexes. Given known sex differences in 2-AG levels and cannabinoid receptor expression depend on the brain regions, we investigated whether elevating 2-AG levels in the fear-related brain regions differentially affects contextual fear memory retrieval in male and female mice. To this end, we locally injected JZL184, a selective monoacylglycerol lipase inhibitor, into three brain regions: the dorsal and ventral hippocampus and the periaqueductal gray (PAG). We found that the injection of JZL184 into the dorsal hippocampus significantly suppressed the retrieval in males but not in females. In contrast, injection of JZL184 into the ventral hippocampus showed a nonsignificant trend toward suppressing the retrieval of contextual fear memory in males but not in females. Injection of JZL184 into the PAG did not affect the retrieval in either sex. These findings reveal a region-specific and sex-dependent contribution of 2-AG signaling to fear memory retrieval, indicating the importance of considering both sex and brain region when evaluating endocannabinoid modulation of fear memory.

PMID:42617969 | DOI:10.1016/j.neuropharm.2026.111153