Inhibition of fatty acid amide hydrolase (FAAH) by URB597 counteracts cognitive deficit and alters neuroendocrine stress responses in male and female rats

Cognitive deficits are hallmark features of several neuropsychiatric disorders, yet therapeutic options remain scarce. Modulation of the endocannabinoid system through inhibition of fatty acid amide hydrolase (FAAH) represents a promising target that may influence both cognitive functions and the neuroendocrine system. However, mechanisms linking FAAH inhibition to these outcomes remain poorly understood. In this study, we hypothesised that FAAH inhibition by URB597 counteracts scopolamine-induced memory deficits and modulates neuroendocrine reactivity differently in males and females. We tested the effects of URB597 (0.3 mg/kg, i.p.) in Sprague Dawley rats at baseline and during a scopolamine challenge (0.5 mg/kg, i.p.). Recognition memory was assessed in the novel object recognition (NOR) task, which also served as a mild stressor. Plasma concentrations of adrenocorticotropic hormone (ACTH), corticosterone, vasopressin, aldosterone, and plasma renin activity (PRA) were measured. URB597 pretreatment counteracted the cognitive impairment induced by scopolamine, showing greater efficacy in males. FAAH inhibition reduced ACTH, corticosterone, vasopressin, and aldosterone concentrations, while PRA remained unaffected. Correlation analyses revealed sex-specific associations. In males, better recognition performance was associated with lower ACTH, corticosterone, and vasopressin, whereas in females, cognition correlated negatively with aldosterone and positively with PRA. These findings demonstrate that FAAH inhibition elicits cognitive protection, associated with the attenuation of neuroendocrine stress responses, and this effect is distinct in males and females. By linking behavioural and endocrine outcomes, this study identifies dual actions of FAAH inhibition and underscores the importance of sex as a biological variable in endocannabinoid-based therapeutic strategies.