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Extensive research has elucidated a role for the eCB anandamide (AEA), but less is known about 2\u2010arachidonoylglycerol (2\u2010AG) mediated signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We pharmacologically enhanced eCB signalling by inhibiting the 2\u2010AG metabolizing enzyme, monoacylglycerol lipase (MAGL), in male and female Marchigian Sardinian alcohol\u2010preferring (msP) rats, a model of innate alcohol preference and stress hypersensitivity, and in control Wistar rats. We tested the acute effect of the selective MAGL inhibitor MJN110 in alleviating symptoms of alcohol drinking, anxiety, irritability and fear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>A single systemic administration of MJN110 increased 2\u2010AG levels in the central amygdala, prelimbic and infralimbic cortex but did not acutely alter alcohol drinking. MAGL inhibition reduced aggressive behaviours in female msPs, and increased defensive behaviours in male msPs, during the irritability test. Moreover, in the novelty\u2010induced hypophagia test, MJN110 selectively enhanced palatable food consumption in females, mitigating stress\u2010induced food suppression. Lastly, msP rats showed increased conditioned fear behaviour compared with Wistar rats, and MJN110 reduced context\u2010associated conditioned fear responses, but not cue\u2010probed fear expression, in male msPs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Acute inhibition of MAGL attenuated some stress\u2010related responses in msP rats but not voluntary alcohol drinking. Our results provide new insights into the sex dimorphism documented in stress\u2010induced responses. Sex\u2010specific eCB\u2010based approaches should be considered in the clinical development of therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16197","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:43:57Z","timestamp":1690245837000},"page":"3130-3145","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Sexually dimorphic effects of monoacylglycerol lipase inhibitor MJN110 on stress\u2010related behaviour and drinking in Marchigian Sardinian alcohol\u2010preferring rats"],"prefix":"10.1111","volume":"180","author":[{"given":"Valentina","family":"Vozella","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Cruz","sequence":"additional","affiliation":[{"name":"Department of Molecular 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