Department of Psychiatry, University of California, San Diego, La Jolla, California, USA.
Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Genes Brain Behav. 2022 Sep;21(7):e12828. doi: 10.1111/gbb.12828. Epub 2022 Jul 29.
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 whether Reelin signaling contributes to the hyperlocomotor and rewarding effects of cocaine. After a single or repeated cocaine injections, HR mice showed enhanced cocaine-induced 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-induced 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 Reln was highly co-expressed with the Drd1 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.
Reln 基因编码细胞外糖蛋白 Reelin，它从发育到成年调节多种大脑功能，包括神经元迁移、树突生长和分支以及突触形成和可塑性。人类研究表明 Reelin 信号在几种神经发育和精神疾病中起作用。使用杂合型 Reeler（HR）小鼠的小鼠研究表明，Reln 表达水平降低与学习和记忆缺陷以及抑制增加有关。尽管这些特征与物质使用障碍有关，但 Reelin 在细胞和行为对成瘾药物的反应中的作用在很大程度上仍然未知。在这里，我们将 HR 小鼠与野生型（WT）同窝对照进行比较，以研究 Reelin 信号是否有助于可卡因的过度运动和奖赏效应。在单次或重复可卡因注射后，HR 小鼠与 WT 对照相比表现出增强的可卡因诱导的运动活动。这种效应在戒断后仍然存在。相比之下，Reelin 缺乏不会诱导可卡因敏化，也不会影响条件性位置偏爱测定中可卡因的奖赏效应。与 WT 相比，HR 小鼠中可卡因诱导的过度运动与背内侧纹状体（DMS）中蛋白 Fos 表达增加有关。最后，我们进行了 RNA 荧光原位杂交实验，发现 Reln 与编码多巴胺受体 D1 的 Drd1 基因高度共表达在 DMS 中。这些发现表明 Reelin 信号有助于可卡因的运动效应，并提高了我们对可卡因细胞和行为效应的神经生物学机制的理解。
