Reln haploinsufficiency enhances fentanyl-induced locomotion and striatal activity without affecting opioid reinforcement and relapse-like behavior

The <i>Reln</i> gene encodes the extracellular glycoprotein Reelin that regulates synaptic plasticity and activity-dependent gene expression with implications in several neuropsychiatric disorders, including substance use disorder. While reduced <i>Reln</i> expression alters responses to psychostimulants and cannabinoid, its role in opioid-related behaviors remains unknown. Here, we examined whether <i>Reln</i> haploinsufficiency modifies behavioral and molecular responses to the synthetic opioid fentanyl. Heterozygous Reeler ( <i>Reln</i> +/-) mice and wild-type littermates were assessed using using complementary contingent and non-contingent models of fentanyl exposure, including multi-phase fentanyl intravenous self-administration paradigm, conditioned place preference paradigm, locomotor assay, and dorsal striatal immediate early gene expression. <i>Reln</i> haploinsufficiency did not alter acquisition, extinction, or cue-induced reinstatement during self-administration, indicating stable opioid reinforcement and relapse-like behavior. Progressive ratio testing revealed a sex-dependent effect in which male <i>Reln</i> +/- mice showed reduced motivation for fentanyl compared to male wild-type mice. In contrast, following passive fentanyl exposure, <i>Reln</i> +/- mice exhibited enhanced fentanyl-induced locomotion and increased Fos immunoreactivity in the dorsal striatum, while CPP remained unchanged. Together, these findings demonstrate that <i>Reln</i> haploinsufficiency does not substantially modify opioid reinforcement or cue-driven drug seeking but enhances acute pharmacological sensitivity to fentanyl. These results identify <i>Reln</i> as a modulatory factor in opioid-responsive neural circuits that preferentially influences acute drug-evoked neuronal activation rather than the associative learning processes underlying opioid reinforcement.