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Among the factors that contribute to tobacco initiation, use, and dependence, genetics may exert a strong influence. In mouse models, genetic differences between strains have been studied to investigate the potential drivers for these states. Previous reports indicate that C57BL\/6\u00a0J (B6J) and C57BL\/6N (B6N) mouse substrains show varying behavioral responses towards both natural and drug rewards. However, nicotine reward as assessed by preference for nicotine in the conditioned place preference (CPP) test has not yet been evaluated. Additionally, a point mutation in the cytoplasmic FMRP interacting protein 2 (\n                    <jats:italic>Cyfip2<\/jats:italic>\n                    ) gene has been regarded as a potential underlying factor towards these substrain differences. Here, we compare the response to nicotine between B6J and B6N mouse substrains and establish a genetic correlation between\n                    <jats:italic>Cyfip2<\/jats:italic>\n                    expression and nicotine preference in the brain. We also examine the effects of this mutation on nicotine preference between these substrains. We report reduced preference for nicotine in B6N mice compared to B6J mice and a negative correlation between nicotine CPP scores and\n                    <jats:italic>Cyfip2<\/jats:italic>\n                    expression in both the hippocampus and prefrontal cortex. In our investigation of the\n                    <jats:italic>Cyfip2<\/jats:italic>\n                    variant, we found that B6J mice carrying the B6N\n                    <jats:italic>Cyfip2<\/jats:italic>\n                    mutation showed a lower preference for nicotine while B6N mice carrying the B6J\n                    <jats:italic>Cyfip2<\/jats:italic>\n                    mutation showed increased preference. This study establishes substrain differences in preference for nicotine in the CPP test and a mutation in the\n                    <jats:italic>Cyfip2<\/jats:italic>\n                    as the causal variant for this behavior.\n                  <\/jats:p>","DOI":"10.1007\/s00213-026-07154-0","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T06:21:24Z","timestamp":1787984484000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["C57BL\/6N mutation in cytoplasmic FMRP interacting protein 2 regulates nicotine reward in the conditioned place preference test"],"prefix":"10.1007","author":[{"given":"Belle","family":"Buzzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina M.","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Baldwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alayna","family":"Palamar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda","family":"Cornes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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