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Although reduction of\n                    <jats:italic>Reln<\/jats:italic>\n                    expression has been associated with altered responses to psychostimulants and cannabinoids, its role in opioid\u2010evoked behaviors has not been investigated. Here, we tested whether\n                    <jats:italic>Reln<\/jats:italic>\n                    haploinsufficiency alters behavioral and molecular responses to the synthetic opioid fentanyl. Heterozygous Reeler (\n                    <jats:italic>Reln<\/jats:italic>\n                    +\/\u2212) mice and wild\u2010type littermates were assessed using complementary contingent and non\u2010contingent models of fentanyl exposure, including multi\u2010phase fentanyl intravenous self\u2010administration paradigm, conditioned place preference paradigm, locomotor assays, and dorsal striatal immediate early gene expression.\n                    <jats:italic>Reln<\/jats:italic>\n                    haploinsufficiency did not alter acquisition, extinction, or cue\u2010induced fentanyl seeking during self\u2010administration, indicating stable opioid reinforcement and relapse\u2010like behavior. Following acute, passive fentanyl exposure,\n                    <jats:italic>Reln<\/jats:italic>\n                    +\/\u2212 mice exhibited enhanced fentanyl\u2010induced locomotion and Fos immunoreactivity in the dorsal striatum, while fentanyl conditioned place preference remained unchanged. Together, these findings demonstrate that\n                    <jats:italic>Reln<\/jats:italic>\n                    haploinsufficiency does not modify opioid reinforcement or cue\u2010driven drug seeking but enhances acute drug\u2010evoked neuronal activation in the dorsal striatum. These results identify\n                    <jats:italic>Reln<\/jats:italic>\n                    as a modulatory factor in opioid\u2010responsive neural circuits rather than in the associative learning processes underlying opioid reinforcement.\n                  <\/jats:p>","DOI":"10.1111\/gbb.70072","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:46:01Z","timestamp":1791333961000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reln Haploinsufficiency Enhances Fentanyl\u2010Induced Locomotion and Dorsal Striatal Activity Without Affecting Opioid Reinforcement and Relapse\u2010Like Behavior"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9291-0104","authenticated-orcid":false,"given":"Carl","family":"Litif","sequence":"first","affiliation":[{"name":"Department of Psychiatry, School of Medicine University of California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avraham M.","family":"Libster","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine University of California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1229-732X","authenticated-orcid":false,"given":"Shane","family":"Desfor","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine University of California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5996-5354","authenticated-orcid":false,"given":"Tanieng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine University of California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0639-8645","authenticated-orcid":false,"given":"Leanne","family":"Liaw","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine University of California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5456-3214","authenticated-orcid":false,"given":"Annika","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine University of California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3877-0628","authenticated-orcid":false,"given":"Francesca","family":"Telese","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine University of California  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"issue":"10208","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1016\/S0140-6736(19)32229-9","article-title":"Global Patterns of Opioid Use and Dependence: Population Harms, Interventions, and Future Action","volume":"394","author":"Degenhardt L.","year":"2019","journal-title":"Lancet"},{"issue":"5","key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1001\/archpsyc.58.5.503","article-title":"A 33\u2010Year Follow\u2010Up of Narcotics Addicts","volume":"58","author":"Hser Y. 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J.","year":"2005","journal-title":"Nature Neuroscience"},{"key":"e_1_2_11_5_1","volume-title":"New Opioid Receptor Modulators and Agonists","author":"Cucinello\u2010Ragland J.","year":"2026"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.neuint.2018.12.004","article-title":"Expression of Immediate Early Genes in Brain Reward Circuitries: Differential Regulation by Psychostimulant and Opioid Drugs","volume":"124","author":"Bisagno V.","year":"2019","journal-title":"Neurochemistry International"},{"issue":"1","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1523\/JNEUROSCI.17-01-00023.1997","article-title":"Reelin Is a Secreted Glycoprotein Recognized by the CR\u201050 Monoclonal Antibody","volume":"17","author":"D'Arcangelo G.","year":"1997","journal-title":"Journal of Neuroscience"},{"issue":"2","key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/(SICI)1097-0177(199710)210:2<157::AID-AJA8>3.0.CO;2-F","article-title":"Expression of Reelin, the Gene Responsible for the Reeler Mutation, in Embryonic Development and Adulthood in the Mouse","volume":"210","author":"Ikeda Y.","year":"1997","journal-title":"Developmental Dynamics"},{"issue":"29","key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"20307","DOI":"10.1074\/jbc.M114.576249","article-title":"Reelin Induces Erk1\/2 Signaling in Cortical Neurons Through a Non\u2010Canonical Pathway","volume":"289","author":"Lee G. H.","year":"2014","journal-title":"Journal of Biological Chemistry"},{"issue":"3","key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.neuron.2015.03.033","article-title":"LRP8\u2010Reelin\u2010Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation","volume":"86","author":"Telese F.","year":"2015","journal-title":"Neuron"},{"issue":"11","key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"4282","DOI":"10.1093\/cercor\/bhw216","article-title":"Reelin Regulates the Maturation of Dendritic Spines, Synaptogenesis and Glial Ensheathment of Newborn Granule Cells","volume":"26","author":"Bosch C.","year":"2016","journal-title":"Cerebral Cortex"},{"issue":"1","key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.5607\/en22044","article-title":"Reelin and APP Cooperatively Modulate Dendritic Spine Formation In\u00a0Vitro and In\u00a0Vivo","volume":"32","author":"Lee H.\u2010J.","year":"2023","journal-title":"Experimental Neurobiology"},{"issue":"41","key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"10339","DOI":"10.1523\/JNEUROSCI.1917-08.2008","article-title":"The Reelin Signaling Pathway Promotes Dendritic Spine Development in Hippocampal Neurons","volume":"28","author":"Niu S.","year":"2008","journal-title":"Journal of Neuroscience"},{"issue":"9","key":"e_1_2_11_14_1","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1101\/lm.2153511","article-title":"Reelin Supplementation Enhances Cognitive Ability, Synaptic Plasticity, and Dendritic Spine Density","volume":"18","author":"Rogers J. T.","year":"2011","journal-title":"Learning & Memory (Cold Spring Harbor, N.Y.)"},{"issue":"4","key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.neuron.2005.07.007","article-title":"Modulation of Synaptic Plasticity and Memory by Reelin Involves Differential Splicing of the Lipoprotein Receptor Apoer2","volume":"47","author":"Beffert U.","year":"2005","journal-title":"Neuron"},{"issue":"50","key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"12943","DOI":"10.1523\/JNEUROSCI.2561-06.2006","article-title":"Differential Reelin\u2010Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus","volume":"26","author":"Qiu S.","year":"2006","journal-title":"Journal of Neuroscience: The Official Journal of the Society for Neuroscience"},{"issue":"6","key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/sj.mp.4000783","article-title":"Reduction in Reelin Immunoreactivity in Hippocampus of Subjects With Schizophrenia, Bipolar Disorder and Major Depression","volume":"5","author":"Fatemi S. 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J.","year":"2024","journal-title":"Biological Psychiatry: Global Open Science"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.04.03.646846"},{"issue":"13","key":"e_1_2_11_28_1","doi-asserted-by":"crossref","first-page":"eads4441","DOI":"10.1126\/sciadv.ads4441","article-title":"Reelin Marks Cocaine\u2010Activated Striatal Neurons, Promotes Neuronal Excitability, and Regulates Cocaine Reward","volume":"11","author":"Brida K. L.","year":"2025","journal-title":"Science Advances"},{"issue":"7","key":"e_1_2_11_29_1","doi-asserted-by":"crossref","first-page":"e12828","DOI":"10.1111\/gbb.12828","article-title":"Reelin Deficiency Exacerbates Cocaine\u2010Induced Hyperlocomotion by Enhancing Neuronal Activity in the Dorsomedial Striatum","volume":"21","author":"Guglielmo G.","year":"2022","journal-title":"Genes, Brain, and Behavior"},{"issue":"11","key":"e_1_2_11_30_1","doi-asserted-by":"crossref","first-page":"3376","DOI":"10.1111\/j.1460-9568.2007.05564.x","article-title":"Disruption of Reelin Signaling Attenuates Methamphetamine\u2010Induced Hyperlocomotion","volume":"25","author":"Matsuzaki H.","year":"2007","journal-title":"European Journal of Neuroscience"},{"issue":"8","key":"e_1_2_11_31_1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1093\/ijnp\/pyad034","article-title":"Reelin Plasma Levels Identify Cognitive Decline in Alcohol Use Disorder Patients During Early Abstinence: The Influence of APOE4 Expression","volume":"26","author":"Escudero B.","year":"2023","journal-title":"International Journal of Neuropsychopharmacology"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252111349"},{"issue":"4","key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1152\/physrev.00005.2009","article-title":"Reward Processing by the Opioid System in the Brain","volume":"89","author":"Le Merrer J.","year":"2009","journal-title":"Physiological Reviews"},{"issue":"6524","key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/374719a0","article-title":"A Protein Related to Extracellular Matrix Proteins Deleted in the Mouse Mutant Reeler","volume":"374","author":"D'Arcangelo G.","year":"1995","journal-title":"Nature"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0063\u201023.2023"},{"issue":"10","key":"e_1_2_11_36_1","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1007\/s00213-022-06191-9","article-title":"Adolescent Self\u2010Administration of the Synthetic Cannabinoid Receptor Agonist JWH\u2010018 Induces Neurobiological and Behavioral Alterations in Adult Male Mice","volume":"239","author":"Margiani G.","year":"2022","journal-title":"Psychopharmacology"},{"key":"e_1_2_11_37_1","doi-asserted-by":"crossref","first-page":"880845","DOI":"10.3389\/fnbeh.2022.880845","article-title":"Jugular Vein Catheter Design and Cocaine Self\u2010Administration Using Mice: A Comprehensive Method","volume":"16","author":"Valles G.","year":"2022","journal-title":"Frontiers in Behavioral Neuroscience"},{"issue":"4","key":"e_1_2_11_38_1","doi-asserted-by":"crossref","first-page":"463","DOI":"10.3758\/BF03196042","article-title":"Sign\u2010Tracking (Autoshaping) in Rats: A Comparison of Cocaine and Food as Unconditioned Stimuli","volume":"32","author":"Kearns D. 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