{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T05:06:29Z","timestamp":1770354389035,"version":"3.49.0"},"reference-count":68,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["DA036157; DA044586; DA043138;"],"award-info":[{"award-number":["DA036157; DA044586; DA043138;"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Microglia, the primary immunocompetent cells of the brain, are suggested to play a role in the development of drug addiction. Previous studies have identified the microglia-derived pro-inflammatory factor IL1\u03b2 can promote the progression of cocaine addiction. Additionally, the activation status of microglia and \u201ctwo-hit hypothesis\u201d have been proposed in the field of drug addiction to explain how early life stress (ELS) could significantly increase the incidence of drug addiction in later life. However, the mechanisms underlying microglia prime and full activation and their roles in drug addiction remain greatly unexplored. Here, we employed CX3CR1-GFP mice (CX3CR1 functional deficiency, CX3CR1\u2212\/\u2212) to explore whether primed microglia could potentiate cocaine-mediated behavioral changes and the possible underlying mechanisms. CX3CR1\u2212\/\u2212 mice revealed higher hyperlocomotion activity and conditional place preference than wild-type (WT) mice did under cocaine administration. In parallel, CX3CR1\u2212\/\u2212 mice showed higher activity of NLR family pyrin domain-containing 3 (NLRP3) inflammasome than WT mice. Interestingly, CX3CR1 deficiency itself could prime NLRP3 signaling by increasing the expression of NLPR3 and affect lysosome biogenesis under basal conditions. Taken together, our findings demonstrated that the functional status of microglia could have an impact on cocaine-mediated reward effects, and NLRP3 inflammasome activity was associated with this phenomenon. This study was consistent with the two-hit hypothesis and provided solid evidence to support the involvement of microglia in drug addiction. Targeting the NLRP3 inflammasome may represent a novel therapeutic approach for ameliorating or blocking the development of drug addiction.<\/jats:p>","DOI":"10.3390\/jpm11100963","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T10:39:20Z","timestamp":1632739160000},"page":"963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["NLRP3 Inflammasome Is Involved in Cocaine-Mediated Potentiation on Behavioral Changes in CX3CR1-Deficient Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Ming-Lei","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA 23507, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernest T.","family":"Chivero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon E.","family":"Callen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shilpa","family":"Buch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12974-016-0501-2","article-title":"Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis","volume":"13","author":"Liao","year":"2016","journal-title":"J. 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