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However, the underlying mechanisms remain inadequately understood. In this study, we show that paternal heroin self-administration (SA) increased heroin-seeking behavior in the F1 generation, when compared with offspring sired by yoke-infused control males, indicating cross-generational impact of paternal voluntary heroin seeking behavior. Notably, the increase of heroin seeking behavior in offspring was replicated by zygotic microinjection of sperm RNAs derived from sperm of heroin-SA-experienced rats. Analysis of non-coding RNAs in spermatozoa revealed coordinated changes in miRNA content between the nucleus accumbens and spermatozoa. We validated that restoration of miR-19b downregulation in sperm RNA from self-administration-experienced rats, in parallel with its overexpression in the nucleus accumbens of F1 offspring sired by heroin-SA-experienced fathers, reversed the increased heroin SA observed in these F1 offspring. Taken together, our findings suggest in rats that paternal heroin self-administration induces epigenetic changes in both brain and sperm miRNA, with miR-19b downregulation playing a critical role in mediating the epigenetic inheritance of increased heroin self-administration behavior in the F1 generation.<\/jats:p>","DOI":"10.1038\/s41386-025-02081-8","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T09:11:48Z","timestamp":1741425108000},"page":"1027-1038","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Paternal heroin self-administration in rats increases drug-seeking behavior in male offspring via miR-19b downregulation in the nucleus accumbens"],"prefix":"10.1038","volume":"50","author":[{"given":"Wenjing","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyuan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2157-6098","authenticated-orcid":false,"given":"Changyou","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2351-6873","authenticated-orcid":false,"given":"Feifei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9722-3109","authenticated-orcid":false,"given":"Xing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9034-5472","authenticated-orcid":false,"given":"Lan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2596-3052","authenticated-orcid":false,"given":"Qiumin","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,8]]},"reference":[{"key":"2081_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1124\/pharmrev.120.000083","volume":"73","author":"GF Koob","year":"2021","unstructured":"Koob GF. 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