TY - JOUR
T1 - Cocaine-Induced Synaptic Redistribution of NMDARs in Striatal Neurons Alters NMDAR-Dependent Signal Transduction
AU - Delint-Ramirez, Ilse
AU - Segev, Amir
AU - Pavuluri, Asha
AU - Self, David W.
AU - Kourrich, Saïd
N1 - Publisher Copyright:
© Copyright © 2020 Delint-Ramirez, Segev, Pavuluri, Self and Kourrich.
PY - 2020/7/14
Y1 - 2020/7/14
N2 - The consequence of repeated cocaine exposure and prolonged abstinence on glutamate receptor expression in the nucleus accumbens has been extensively studied. However, the early effects of cocaine on NMDAR signaling remain unknown. NMDAR signaling depends on the subunit composition, subcellular localization, and the interaction with proteins at the postsynaptic density (PSD), where NMDARs and other proteins form supercomplexes that are responsible for the signaling pathways activated by NMDAR-induced Ca2+ influx. Here, we investigated the effect of cocaine on NMDAR subunit composition and subcellular localization after both intraperitoneal non-contingent cocaine and response-contingent intravenous cocaine self-administration in mice. We found that repeated cocaine exposure, regardless of the route or contingency of drug administration, decreases NMDAR interactions with the PSD and synaptic lipid rafts in the accumbens shell and dorsal striatum. We provide evidence that cocaine triggers an early redistribution of NMDARs from synaptic to extrasynaptic sites, and that this adaptation has implications in the activation of downstream signaling pathways. Thus, consistent with a loss of NMDAR function, cocaine-induced ERK phosphorylation is attenuated. Because early NMDAR activity contributes to the initiation of lasting addiction-relevant neuroadaptations, these data may hold clues into cellular mechanisms responsible for the development of cocaine addiction.
AB - The consequence of repeated cocaine exposure and prolonged abstinence on glutamate receptor expression in the nucleus accumbens has been extensively studied. However, the early effects of cocaine on NMDAR signaling remain unknown. NMDAR signaling depends on the subunit composition, subcellular localization, and the interaction with proteins at the postsynaptic density (PSD), where NMDARs and other proteins form supercomplexes that are responsible for the signaling pathways activated by NMDAR-induced Ca2+ influx. Here, we investigated the effect of cocaine on NMDAR subunit composition and subcellular localization after both intraperitoneal non-contingent cocaine and response-contingent intravenous cocaine self-administration in mice. We found that repeated cocaine exposure, regardless of the route or contingency of drug administration, decreases NMDAR interactions with the PSD and synaptic lipid rafts in the accumbens shell and dorsal striatum. We provide evidence that cocaine triggers an early redistribution of NMDARs from synaptic to extrasynaptic sites, and that this adaptation has implications in the activation of downstream signaling pathways. Thus, consistent with a loss of NMDAR function, cocaine-induced ERK phosphorylation is attenuated. Because early NMDAR activity contributes to the initiation of lasting addiction-relevant neuroadaptations, these data may hold clues into cellular mechanisms responsible for the development of cocaine addiction.
KW - ERK signaling
KW - NMDA receptor
KW - cocaine
KW - extrasynaptic
KW - postsynaptic density
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U2 - 10.3389/fnins.2020.00698
DO - 10.3389/fnins.2020.00698
M3 - Article
C2 - 32760242
AN - SCOPUS:85088801453
SN - 1662-4548
VL - 14
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
M1 - 698
ER -