Abstract
Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B−/− mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories.
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Acknowledgements
We thank Marina E Wolf and Yan Dong for helpful comments on the manuscript. This study was supported by the National Institute on Drug Abuse R00DA031699 (to BAG). The floxed Grin2b mouse was generated by the Gene-Targeted Mouse Core of the Integrative Neuroscience Initiative on Alcoholism (INIA)-stress consortium. The Gene-Targeted Mouse Core is supported by NIH grant U01 AA013514 (to ED). Use of these mice requires a MTA from Eric Delpire (eric.delpire@vanderbilt.edu).
Author contributions
MEJ and BDT conducted the experiments; MEJ and BAG designed the experiments; ED provided the floxed Grin2b mouse; and MEJ, BDT, and BAG wrote the paper.
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Joffe, M.E., Turner, B.D., Delpire, E. et al. Genetic loss of GluN2B in D1-expressing cell types enhances long-term cocaine reward and potentiation of thalamo-accumbens synapses. Neuropsychopharmacol 43, 2383–2389 (2018). https://doi.org/10.1038/s41386-018-0131-8
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DOI: https://doi.org/10.1038/s41386-018-0131-8
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