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A profuse literature on transgenic mouse lines points out the deleterious effects of Cre expression in various cell types and tissues, presumably by acting on illegitimate loxP\u2010like sites present in the genome. However, most studies reporting the consequences of Cre\u2010lox gene invalidation often omit adequate controls to exclude the potential toxic effects of Cre, compromising the interpretation of data. In this study, we report the anatomical, neurochemical, and behavioral consequences in mice of adeno\u2010associated virus (<jats:styled-content style=\"fixed-case\">AAV<\/jats:styled-content>)\u2010mediated Cre expression in the dopaminergic nuclei substantia nigra, at commonly used viral titers (3\u00a0\u00d7\u00a010<jats:sup>9<\/jats:sup> genome copies\/0.3\u00a0\u03bcL or 2\u00a0\u00d7\u00a010<jats:sup>9<\/jats:sup> genome copies\/0.6\u00a0\u03bcL). We found that injecting <jats:styled-content style=\"fixed-case\">AAV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">eGFP<\/jats:styled-content>\u2010Cre into the <jats:styled-content style=\"fixed-case\">SN<\/jats:styled-content> engendered drastic and reproducible modifications of behavior, with increased basal locomotor activity as well as impaired locomotor response to cocaine compared to <jats:styled-content style=\"fixed-case\">AAV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">eGFP<\/jats:styled-content>\u2010injected controls. Cre expression in the <jats:styled-content style=\"fixed-case\">SN<\/jats:styled-content> induced a massive decrease in neuronal populations of both pars compacta and pars reticulata and dopamine depletion in the nigrostriatal pathway. This anatomical injury was associated with typical features of programmed cell death, including an increase in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> break markers, evidence of apoptosis, and disrupted macroautophagy. These observations underscore the need for careful control of Cre toxicity in the brain and the reassessment of previous studies. In addition, our findings suggest that Cre\u2010mediated ablation may constitute an efficient tool to explore the function of specific cell populations and areas in the brain, and the impact of neurodegeneration in these populations.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14684-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14684","type":"journal-article","created":{"date-parts":[[2019,2,12]],"date-time":"2019-02-12T16:39:27Z","timestamp":1549989567000},"page":"330-340","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Viral vector\u2010mediated Cre recombinase expression in substantia nigra induces lesions of the nigrostriatal pathway associated with perturbations of dopamine\u2010related behaviors and hallmarks of programmed cell death"],"prefix":"10.1111","volume":"150","author":[{"given":"Sara","family":"Rezai Amin","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9 INSERM CNRS Neuroscience Paris Seine Institut de Biologie Paris Seine Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Gruszczynski","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9 INSERM CNRS Neuroscience Paris Seine Institut de Biologie Paris Seine Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno P.","family":"Guiard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Toulouse CNRS Centre de Recherches sur la Cognition Animale Centre de Biologie Int\u00e9grative Toulouse 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