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Endocannabinoid signaling has been associated with drug\u2010induced neuroadaptations, but the role of lipases that mediate endocannabinoid biosynthesis and metabolism in regulating relapse behaviors following prolonged periods of drug abstinence has not been examined. Here, we investigated how pharmacological manipulation of lipases involved in regulating the expression of the endocannabinoid 2\u2010AG in the nucleus accumbens (NAc) influence cocaine relapse via discrete neuroadaptations. At prolonged abstinence (30\u00a0days) from cocaine self\u2010administration, there is an increase in the NAc levels of diacylglycerol lipase (DAGL), the enzyme responsible for the synthesis of the endocannabinoid 2\u2010AG, along with decreased levels of monoacylglycerol lipase (MAGL), which hydrolyzes 2\u2010AG. Since endocannabinoid\u2010mediated behavioral plasticity involves phosphatase dysregulation, we examined the phosphatase calcineurin after 30\u00a0days of abstinence and found decreased expression in the NAc, which we demonstrate is regulated through the transcription factor EGR1. Intra\u2010NAc pharmacological manipulation of DAGL and MAGL with inhibitors DO\u201034 and URB\u2010602, respectively, bidirectionally regulated cue\u2010induced cocaine seeking and altered the phosphostatus of translational initiation factor, eIF2\u03b1. Finally, we found that cocaine seeking 30\u00a0days after abstinence leads to decreased phosphorylation of eIF2\u03b1 and reduced expression of its downstream target NPAS4, a protein involved in experience\u2010dependent neuronal plasticity. Together, our findings demonstrate that lipases that regulate 2\u2010AG expression influence transcriptional and translational changes in the NAc related to drug relapse vulnerability.<\/jats:p>","DOI":"10.1111\/adb.13007","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T02:39:23Z","timestamp":1611628763000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue\u2010induced cocaine craving following prolonged abstinence"],"prefix":"10.1111","volume":"26","author":[{"given":"Swarup","family":"Mitra","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Program in Neuroscience The State University of New York at Buffalo  Buffalo NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro 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