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The objective of our translational study was to identify the genes and biological pathways underlying the tolerance to cocaine-induced motor effects. In a 5-day protocol measuring motor tolerance to cocaine in rats (<jats:italic>N<\/jats:italic>\u2009=\u200940), modeling the motor response to cocaine in patients, whole-genome RNA sequencing was conducted on the ventral and dorsal striatum to prioritize a genetic association study in 225 patients with severe CUD who underwent thorough phenotypic (cocaine-induced hyperlocomotion, CIH; and cocaine-induced stereotypies, CIS) and genotypic [571,000 polymorphisms (SNPs)] characterization. We provide a comprehensive description of the rat striatal transcriptomic response to cocaine in our paradigm. Repeated vs. acute cocaine binge administration elicited 27 differentially expressed genes in the ventral striatum and two in the dorsal striatum. One gene, <jats:italic>Lrp1b<\/jats:italic>, was differentially expressed in both regions. In patients, <jats:italic>LRP1B<\/jats:italic> was significantly associated with both CIS and CIH. CIH was also associated with <jats:italic>VPS13A<\/jats:italic>, a gene involved in a severe neurological disorder characterized by hyperkinetic movements. The <jats:italic>LRP1B<\/jats:italic> minor allele rs7568970 had a significant protective effect against CIS (558 SNPs, Bonferroni-corrected <jats:italic>p<\/jats:italic>\u2009=\u20090.02) that resisted adjustment for confounding factors, including the amount of cocaine use (adjusted beta\u2009=\u2009\u22120.965 and \u22122.35 for heterozygotes and homozygotes, respectively, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Using hypothesis-free prioritization of candidate genes along with thorough methodology in both the preclinical and human analysis pipelines, we provide reliable evidence that <jats:italic>LRP1B<\/jats:italic> and <jats:italic>VPS13A<\/jats:italic> are involved in the motor tolerance to cocaine in CUD patients, in line with their known pathophysiology.<\/jats:p>","DOI":"10.1038\/s41398-020-01050-7","type":"journal-article","created":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T13:02:54Z","timestamp":1604667774000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5168-3727","authenticated-orcid":false,"given":"Florence","family":"Vorspan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5078-4048","authenticated-orcid":false,"given":"Romain","family":"Icick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nawel","family":"Mekdad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindie","family":"Courtin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Bloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Bellivier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Laplanche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Prince","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Pishalin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Firmo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Blugeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"M\u00e9garbane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2282-134X","authenticated-orcid":false,"given":"Cynthia","family":"Marie-Claire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Benturquia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,6]]},"reference":[{"key":"1050_CR1","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.drugalcdep.2010.07.026","volume":"113","author":"L Degenhardt","year":"2011","unstructured":"Degenhardt, L. et al. 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F.V. has received an honorarium from Lundbeck and Camurus AB. F.B. has received honoraria or research or educational conference grants from Bristol-Myers Squibb, Otsuka, Eli Lilly and Co., Servier, Sanofi Aventis, Lundbeck, AstraZeneca, and the European Space Agency and has received peer review research funding from French Ministry of research, Assistance Publique \u2013 Ho\u0302pitaux de Paris, the National Institute for Research (INSERM) and the NARSAD. None of the support received by R.I., F.V., and F.B. was related to the theme of the present study. V.B., N.P., J.L.L., C.M.C., and N.B. have no conflict of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"381"}}