期刊
CELL
卷 154, 期 3, 页码 637-650出版社
CELL PRESS
DOI: 10.1016/j.cell.2013.07.001
关键词
-
资金
- NIH [DA011742, DA010309, MH084020, MH51106, NS050274, CA110940]
- Howard Hughes Medical Institute
- Office of Basic Energy Sciences, Catalysis Science Program
- U.S. Department of Energy [DE-FG02-05ER15699]
- U.S. Department of Energy (DOE) [DE-FG02-05ER15699] Funding Source: U.S. Department of Energy (DOE)
Synaptic plasticity induced by cocaine and other drugs underlies addiction. Here we elucidate molecular events at synapses that cause this plasticity and the resulting behavioral response to cocaine in mice. In response to D1-dopamine-receptor signaling that is induced by drug administration, the glutamate-receptor protein metabotropic glutamate receptor 5 (mGluR5) is phosphorylated by microtubule-associated protein kinase (MAPK), which we show potentiates Pin1-mediated prolyl-isomerization of mGluR5 in instances where the product of an activity-dependent gene, Homer1a, is present to enable Pin1-mGluR5 interaction. These biochemical events potentiate N-methyl-D-aspartate receptor (NMDAR)-mediated currents that underlie synaptic plasticity and cocaine-evoked motor sensitization as tested in mice with relevant mutations. The findings elucidate how a coincidence of signals from the nucleus and the synapse can render mGluR5 accessible to activation with consequences for drug-induced dopamine responses and point to depotentiation at corticostriatal synapses as a possible therapeutic target for treating addiction.
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