Vozella_2023_Br.J.Pharmacol__

BACKGROUND AND PURPOSE: Stress-related disorders are often intertwined with alcohol use disorder (AUD). The endocannabinoid (eCB) system, which comprises the lipid mediators anandamide (AEA) and 2-arachidonoylglycerol (2-AG), plays an important homeostatic role in the regulation of stress circuits and has emerged as a therapeutic target to treat stress disorders and AUD. Extensive research has elucidated the role of AEA, but less is known about 2-AG-mediated signaling. EXPERIMENTAL APPROACH: We pharmacologically enhanced the eCB signaling by inhibiting the 2-AG metabolizing enzyme, monoacylglycerol lipase (MAGL), in male and female Marchigian-Sardinian alcohol preferring (msP) rats, a model of innate alcohol preference and stress hypersensitivity, and control Wistar rats. We tested the acute effect of the selective MAGL inhibitor MJN110 in alleviating symptoms of alcohol drinking, anxiety, irritability, and fear in both male and female rats. KEY RESULTS: A single systemic administration of MJN110 increased 2-AG levels in the central amygdala, prelimbic, and infralimbic cortex, but did not acutely alter alcohol drinking. MAGL inhibition reduced aggressive behaviors in female msPs and increased defensive behaviors in male msPs, during the irritability test. Moreover, in the novelty-induced hypophagia test, MJN110 selectively enhanced palatable food consumption in females, mitigating stress-induced food suppression. Lastly, msP rats showed increased conditioned fear behavior compared to Wistar rats, and MJN110 reduced context-associated conditioned fear responses, but not cue-probed fear expression, in male msPs. CONCLUSION AND IMPLICATIONS: Acute inhibition of MAGL attenuated some stress-related responses in msP rats but not voluntary alcohol drinking. Our results provide new insights into the sex dimorphism documented in stress-induced responses and suggest that sex-specific endocannabinoid-based approaches should be considered in the clinical development of therapeutics.