Reln Haploinsufficiency Enhances Fentanyl-Induced Locomotion and Dorsal Striatal Activity Without Affecting Opioid Reinforcement and Relapse-Like Behavior.

The Reln gene encodes the extracellular glycoprotein Reelin that regulates synaptic plasticity and activity-dependent gene expression with implication in several neuropsychiatric disorders, including substance use disorder. Although reduction of Reln expression has been associated with altered responses to psychostimulants and cannabinoids, its role in opioid-evoked behaviors has not been investigated. Here, we tested whether Reln haploinsufficiency alters behavioral and molecular responses to the synthetic opioid fentanyl. Heterozygous Reeler (Reln+/-) mice and wild-type littermates were assessed using complementary contingent and non-contingent models of fentanyl exposure, including multi-phase fentanyl intravenous self-administration paradigm, conditioned place preference paradigm, locomotor assays, and dorsal striatal immediate early gene expression. Reln haploinsufficiency did not alter acquisition, extinction, or cue-induced fentanyl seeking during self-administration, indicating stable opioid reinforcement and relapse-like behavior. Following acute, passive fentanyl exposure, Reln+/- mice exhibited enhanced fentanyl-induced locomotion and Fos immunoreactivity in the dorsal striatum, while fentanyl conditioned place preference remained unchanged. Together, these findings demonstrate that Reln haploinsufficiency does not modify opioid reinforcement or cue-driven drug seeking but enhances acute drug-evoked neuronal activation in the dorsal striatum. These results identify Reln as a modulatory factor in opioid-responsive neural circuits rather than in the associative learning processes underlying opioid reinforcement.