Repeated cocaine administration upregulates CB_(2) receptor expression in striatal medium-spiny neurons that express dopamine D_(1) receptors in mice  

作　　者：Hai-Ying Zhang Lindsay De Biase Ramesh Chandra Hui Shen Qing-Rong Liu Eliot Gardner Mary Kay Lobo Zheng-Xiong Xi 

机构地区：[1]Intramural Research Program,National Institute on Drug Abuse,Baltimore,MD,USA [2]Section on Molecular Neuroscience,National Institute of Mental Health,Bethesda,MD,USA [3]Department of Physiology,David Geffen School of Medicine at University of California,Los Angeles,Los Angeles,CA,USA [4]Department of Anatomy and Neurobiology,University of Maryland School of Medicine,Baltimore,MD,USA [5]Laboratory of Clinical Investigation,Intramural Research Program,National Institute on Aging,Baltimore,MD,USA

出　　处：《Acta Pharmacologica Sinica》2022年第4期876-888,共13页中国药理学报（英文版）

基　　金：This research was supported by the Intramural Research Program(IRP)of the National Institute on Drug Abuse(NIDA)(DA000633-01);National Institutes of Health(NIH);grant support for MKL in UMB(NIH grant R01DA038613).

摘　　要：Cannabinoid CB2 receptors(CB2R)are importantly involved in drug reward and addiction.However,the cellular mechanisms underlying CB2R action remain unclear.We have previously reported that cocaine self-administration upregulates CB2R expression in midbrain dopamine(DA)neurons.In the present study,we investigated whether cocaine or heroin also alters CB2R expression in striatal medium-spiny neurons that express dopamine D1 or D2 receptors(D1-MSNs,D2-MSNs)and microglia.Due to the concern of CB2R antibody specificity,we developed three mouse CB2-specific probes to detect CB2R mRNA using quantitative RT-PCR and RNAscope in situ hybridization(ISH)assays.We found that a single injection of cocaine failed to alter,while repeated cocaine injections or self-administration dose-dependently upregulated CB2R gene expression in both brain(cortex and striatum)and periphery(spleen).In contrast,repeated administration of heroin produced a dose-dependent reduction in striatal CB2 mRNA expression.RNAscope ISH assays detected CB2R mRNA in striatal D1-and D2-MSNs,not in microglia.We then used transgenic CX3CR1eGFP/+microglia reporter mice and D1-or D2-Cre-RiboTag mice to purify striatal microglia or ribosome-associated mRNAs from CX3CR1eGFP/+,D1-MSNs,or D2-MSNs,respectively.We found that CB2R upregulation occurred mainly in D1-MSNs,not in D2-MSNs or microglia,in the nucleus accumbens rather than the dorsal striatum.These findings indicate that repeated cocaine exposure may upregulate CB2R expression in both brain and spleen,with regional and cell type-specific profiles.In the striatum,CB2R upregulation occurs mainly in D1-MSNs in the nucleus accumbens.Given the important role of D1-MSNs in brain reward function,the present findings provide new insight into mechanisms by which brain CB2Rs modulate cocaine action.

关 键 词：COCAINE CANNABINOID CB_(2)receptor MICROGLIA SELF-ADMINISTRATION D_(1)-MSNs 

分 类 号：R96[医药卫生—药理学]