Abstract
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.
Highlights
Previous studies have demonstrated an important role for glutamate transmission within the nucleus accumbens in drug addiction, a critical structure involved in reward and motivation
Using an electrophysiological approach in the accumbens shell, an earlier study provided indirect evidence that extrasynaptic NMDARs are increased 24 h after the last cocaine selfadministration session or after direct stimulation of D1 receptors in vitro (Ortinski et al, 2013). These findings suggest that NMDARs redistribute from synaptic to extrasynaptic sites
These results indicate that repeated cocaine exposure, regardless of the route of administration and the contingency of drug exposure, decreases the interaction of the NMDAR with the postsynaptic density (PSD), suggesting reduced recruitment of NMDARs at the postsynaptic membrane
Summary
Previous studies have demonstrated an important role for glutamate transmission within the nucleus accumbens in drug addiction, a critical structure involved in reward and motivation. Much of the work in this area has focused on slowly developing changes in AMPAR-mediated currents after prolonged withdrawal (Wolf and Tseng, 2012). Only a few studies have shown that activity of NMDARs during cocaine administration is critically involved in the subsequent development of changes in AMPAR activity (Sun et al, 2008; Zweifel et al, 2008; Ferrario et al, 2010; Brown et al, 2011; Mameli et al, 2011). NMDAR-mediated Ca2+ currents can activate calmodulin that triggers several signaling pathways involved in drug addiction, including CaMKII, MAPK, CREB, and PKA pathways (Licata et al, 2004; DiRocco et al, 2009; Sarantis et al, 2009; Besnard et al, 2011; Pascoli et al, 2011a). The temporospatial properties and magnitude of the Ca2+ rise, and signaling pathways engaged, are strongly controlled by NMDAR subunit composition and subcellular localization (Petralia et al, 2009)
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