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bioRxiv · 10.1101/2022.04.12.488105

Reelin deficiency exacerbates cocaine-induced hyperlocomotion by enhancing neuronal activity in the dorsomedial striatum.

de Guglielmo, G.·Iemolo, A.·Nur, A.·Turner, A.·Montilla-Perez, P.·Telese, F.
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Abstract

The Reln gene encodes for the extracellular glycoprotein Reelin, which regulates several brain functions from development to adulthood, including neuronal migration, dendritic growth and branching, and synapse formation and plasticity. 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 Reln 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-type (WT) littermate controls to investigate the contribution of Reelin signaling to the hyper-locomotor and rewarding effects of cocaine. After a single cocaine injection, HR mice showed enhanced cocaine-induced locomotor activity compared to WT controls. After repeated injections of cocaine, Reelin deficiency also led to increased cocaine-induced locomotor sensitization, which persisted after withdrawal. In contrast, Reelin deficiency did not affect the rewarding effects of cocaine measured in the conditioned place preference assay. The elevated cocaine-induced hyper-locomotion in HR mice resulted in increased Fos expression in the dorsal medial striatum (DMS) compared to WT. Lastly, we found that Reln was highly co-expressed with the Drd1 gene, which encodes for the dopamine receptor D1, in the DMS. These findings demonstrated that Reelin signaling contributes to the locomotory effects of cocaine and improved our understanding of the neurobiological mechanisms underlying the cellular and behavioral effects of cocaine.

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de Guglielmo, G., Iemolo, A., Nur, A., Turner, A., Montilla-Perez, P., Telese, F.. 2022-04-13. Reelin deficiency exacerbates cocaine-induced hyperlocomotion by enhancing neuronal activity in the dorsomedial striatum.. https://doi.org/10.1101/2022.04.12.488105

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