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One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma\u2010associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear and measured both passive (freezing) and active (darting) conditioned responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2\u2010arachidonoyl glycerol (2\u2010AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2\u2010AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid<jats:sub>1<\/jats:sub> (CB<jats:sub>1<\/jats:sub>) receptors. Measurement of AEA and 2\u2010AG levels after extinction training revealed sex\u2010 and brain region\u2010specific changes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>We provide the first evidence that AEA and 2\u2010AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex\u2010specific therapeutics to treat trauma\u2010related disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15341","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T04:32:53Z","timestamp":1607920373000},"page":"983-996","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Sex\u2010dependent effects of endocannabinoid modulation of conditioned fear extinction in rats"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6590-8130","authenticated-orcid":false,"given":"Maria","family":"Morena","sequence":"first","affiliation":[{"name":"Hotchkiss Brain Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Mathison Centre for Mental Health Research, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Department of Cell Biology and Anatomy &amp; Psychiatry, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3320-6887","authenticated-orcid":false,"given":"Andrei S.","family":"Nastase","sequence":"additional","affiliation":[{"name":"Hotchkiss Brain Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Mathison Centre for Mental Health Research, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Neuroscience Program, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Santori","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin F.","family":"Cravatt","sequence":"additional","affiliation":[{"name":"The Skaggs Institute for Chemical Biology and Department of Chemistry The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca M.","family":"Shansky","sequence":"additional","affiliation":[{"name":"Department of Psychology Northeastern University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew N.","family":"Hill","sequence":"additional","affiliation":[{"name":"Hotchkiss Brain Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Mathison Centre for Mental Health Research, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Department of Cell Biology and Anatomy &amp; Psychiatry, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,13]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"S57","article-title":"the Concise Guide to PHARMACOLOGY 2019\/20: G protein\u2010coupled receptors","volume":"176","author":"Alexander S. 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