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Our study was designed to assess (i) whether the long-term use of benzodiazepines, at two different doses, has an irreversible effect on cognition, (ii) and whether there is an age-dependent effect. One hundred and five C57Bl\/6 male mice were randomly assigned to the 15\u2009mg\/kg\/day, the 30\u2009mg\/kg\/day diazepam-supplemented pellets, or the control group. Each group comprised mice aged 6 or 12 months at the beginning of the experiments and treated for 16 weeks. Two sessions of behavioral assessment were conducted: after 8 weeks of treatment and after treatment completion following a 1-week wash-out period. The mid-treatment test battery included the elevated plus maze test, the Y maze spontaneous alternation test, and the open field test. The post-treatment battery was upgraded with three additional tests: the novel object recognition task, the Barnes maze test, and the touchscreen-based paired-associated learning task. At mid-treatment, working memory was impaired in the 15\u2009mg\/kg diazepam group compared to the control group (<jats:italic>p<\/jats:italic>\u2009=\u20090.005). No age effect was evidenced. The post-treatment assessment of cognitive functions (working memory, visual recognition memory, spatial reference learning and memory, and visuospatial memory) did not significantly differ between groups. Despite a cognitive impact during treatment, the lack of cognitive impairment after long-term treatment discontinuation suggests that benzodiazepines alone do not cause irreversible deleterious effects on cognitive functions and supports the interest of discontinuation in chronically treated patients.<\/jats:p>","DOI":"10.1038\/s41398-021-01718-8","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T03:02:43Z","timestamp":1638500563000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Lack of direct involvement of a diazepam long-term treatment in the occurrence of irreversible cognitive impairment: a pre-clinical approach"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1523-7372","authenticated-orcid":false,"given":"Louise","family":"Carton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candice","family":"Niot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u00e9va","family":"Kyheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud","family":"Petrault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Laloux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Potey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8301-857X","authenticated-orcid":false,"given":"Marie","family":"Lenski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9gis","family":"Bordet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Deguil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,3]]},"reference":[{"key":"1718_CR1","unstructured":"Bordet R, Carton L, Deguil J, Dondaine T. 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