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Human studies have implicated Reelin signaling in several neurodevelopmental and psychiatric disorders. Mouse studies using the heterozygous Reeler (HR) mice have shown that reduced levels of\n                    <jats:italic>Reln<\/jats:italic>\n                    expression are associated with deficits in learning and memory and increased disinhibition. Although these traits are relevant to substance use disorders, the role of Reelin in cellular and behavioral responses to addictive drugs remains largely unknown. Here, we compared HR mice to wild\u2010type (WT) littermate controls to investigate whether Reelin signaling contributes to the hyperlocomotor and rewarding effects of cocaine. After a single or repeated cocaine injections, HR mice showed enhanced cocaine\u2010induced locomotor activity compared with WT controls. This effect persisted after withdrawal. In contrast, Reelin deficiency did not induce cocaine sensitization, and did not affect the rewarding effects of cocaine measured in the conditioned place preference assay. The elevated cocaine\u2010induced hyperlocomotion in HR mice was associated with increased protein Fos expression in the dorsal medial striatum (DMS) compared with WT. Lastly, we performed an RNA fluorescent in situ hybridization experiment and found that\n                    <jats:italic>Reln<\/jats:italic>\n                    was highly co\u2010expressed with the\n                    <jats:italic>Drd1<\/jats:italic>\n                    gene, which encodes for the dopamine receptor D1, in the DMS. These findings show that Reelin signaling contributes to the locomotor effects of cocaine and improve our understanding of the neurobiological mechanisms underlying the cellular and behavioral effects of cocaine.\n                  <\/jats:p>","DOI":"10.1111\/gbb.12828","type":"journal-article","created":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T01:20:23Z","timestamp":1659144023000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Reelin deficiency exacerbates cocaine\u2010induced hyperlocomotion by enhancing neuronal activity in the dorsomedial striatum"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4782-7430","authenticated-orcid":false,"given":"Giordano","family":"de Guglielmo","sequence":"first","affiliation":[{"name":"Department of Psychiatry University of California, San Diego  La Jolla California 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