Oleoylethanolamide modulates fear memory even after rapamycin infusion into the hippocampus of male Wistar rats.

Fear memory can become maladaptive, leading to stress disorders, which represent a significant global health challenge that requires alternative treatment approaches. Oleoylethanolamide (OEA), an endogenous lipid mediator, has demonstrated anxiolytic and pro-cognitive properties to address these conditions. This study investigated the role of OEA in fear memory attenuation and its interaction with hippocampal protein synthesis pathways during memory reconsolidation. Male Wistar rats were trained in a contextual fear conditioning paradigm. Twenty-four hours post-training, memory reactivation was induced through a 10-min context re-exposure, immediately followed by systemic intraperitoneal administration of OEA (1, 5, or 10 mg/kg) or saline. To examine downstream mechanisms, the protein synthesis inhibitor anisomycin or the mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin was microinfused into the CA1 region of the hippocampus. Freezing behavior was assessed during a retention test conducted 3 h or 24 h later. Systemic OEA at 10 mg/kg facilitated the attenuation of fear memory 24 h post-reactivation, an effect that was dependent on memory reactivation. Intra-CA1 microinfusion of anisomycin blocked the behavioral effects of OEA, while rapamycin did not reliably prevent the behavioral effects of OEA under the present conditions. These results indicate that OEA-mediated memory attenuation requires de novo protein synthesis within the hippocampus, but that the precise involvement of mTORC1 remains unresolved, implicating alternative downstream cascades. Our findings highlight the potential of OEA as a therapeutic target for fear-related disorders and emphasize the need for further research to delineate the specific neural pathways involved.