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We recently discovered that cannabinoid use promotes two PTSD-like symptoms: avoidance coping behaviors and the generalization of stress-coping responses to a neutral stimulus. Here, we used in vivo zymography and confocal microscopy to examine how stress and cannabinoid use influence multipartite synaptic plasticity. Specifically, we assessed astroglial plasticity, Synapsin-I density, and matrix metalloproteinases (MMP-2,9) activity, in the nucleus accumbens core (NAcore). For this purpose, rats were restrained for 2\u2009h and simultaneously exposed to an odor; the stress-conditioned stimulus (stress-CS). Three weeks later, rats were exposed to cannabinoid vapor (delta9-tetrahydrocannabinol+cannabidiol; THC\u2009+\u2009CBD) for 5 days, self-administered THC\u2009+\u2009CBD (i.v.) for 10 days, followed by 10 days of abstinence. We then evaluated the effect of stress-CS or neutral odor (NS) on coping strategies in a defensive burying task. We found that THC\u2009+\u2009CBD generalized stress responses to the NS, associated with astrocyte retraction from synapses and a decrease in Synapsin-I density. THC\u2009+\u2009CBD pretreatment promoted avoidant coping during stress-CS exposure, activated MMP-2,9, re-associated astrocytes with synapses, increased Synapsin-I density, and caused astrocyte atrophy. By inhibiting MMP-2,9, we found that stress-CS-induced plasticity required MMP-2,9 activation. MMP-2 inhibition also restored active coping behaviors during stress-CS exposure. Surprisingly, these neuroadaptations only occurred in males. Overall, these findings suggest a potential role for MMPs and astrocytes in the changes produced by THC\u2009+\u2009CBD use in responding to a stress-CS.<\/jats:p>","DOI":"10.1038\/s41380-026-03687-0","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T10:34:11Z","timestamp":1781174051000},"page":"5979-5992","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cannabinoid use generalizes stress responses: involvement of astrocyte plasticity and activation of matrix metalloproteinases in the nucleus accumbens core"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3998-6116","authenticated-orcid":false,"given":"Ritchy","family":"Hodebourg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Dereschewitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9487-0119","authenticated-orcid":false,"given":"Peter","family":"Kalivas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"3687_CR1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association., Diagnostic and statistical manual of mental disorders : DSM-5. 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