GluN3-Containing NMDA Receptors in the Rat Nucleus Accumbens Core Contribute to Incubation of Cocaine Craving

Cue-induced cocaine craving progressively intensifies (incubates) after withdrawal from cocaine self-administration in rats and humans. In rats, the expression of incubation ultimately depends on Ca -permeable AMPARs that accumulate in synapses onto medium spiny neurons (MSNs) in the NAc core. Howev...

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Bibliographic Details
Published in:The Journal of neuroscience 2021-09, Vol.41 (39), p.8262-8277
Main Authors: Christian, Daniel T, Stefanik, Michael T, Bean, Linda A, Loweth, Jessica A, Wunsch, Amanda M, Funke, Jonathan R, Briggs, Clark A, Lyons, Joseph, Neal, Demetria, Milovanovic, Mike, D'Souza, Gary X, Stutzmann, Grace E, Nicholson, Daniel A, Tseng, Kuei Y, Wolf, Marina E
Format: Article
Language:English
Subjects:
Adaptation
Animals
Biotinylation
Calcium - metabolism
Calcium influx
Calcium ions
Calcium permeability
Cocaine
Cocaine - administration & dosage
Craving - drug effects
Dendritic spines
Dopamine Uptake Inhibitors - administration & dosage
Drug self-administration
Drug-Seeking Behavior - drug effects
Drug-Seeking Behavior - physiology
Glutamatergic transmission
Glutamic acid receptors
Glutamic acid receptors (ionotropic)
Magnesium
Male
Membrane Glycoproteins - metabolism
N-Methyl-D-aspartic acid receptors
Nucleus accumbens
Nucleus Accumbens - drug effects
Nucleus Accumbens - metabolism
Patch-Clamp Techniques
Permeability
Plastic properties
Plasticity
Rats
Rats, Sprague-Dawley
Rodents
Self Administration
Spiny neurons
Synapses
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
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Summary:Cue-induced cocaine craving progressively intensifies (incubates) after withdrawal from cocaine self-administration in rats and humans. In rats, the expression of incubation ultimately depends on Ca -permeable AMPARs that accumulate in synapses onto medium spiny neurons (MSNs) in the NAc core. However, the delay in their accumulation (∼1 month after drug self-administration ceases) suggests earlier waves of plasticity. This prompted us to conduct the first study of NMDAR transmission in NAc core during incubation, focusing on the GluN3 subunit, which confers atypical properties when incorporated into NMDARs, including insensitivity to Mg block and Ca impermeability. Whole-cell patch-clamp recordings were conducted in MSNs of adult male rats 1-68 d after discontinuing extended-access saline or cocaine self-administration. NMDAR transmission was enhanced after 5 d of cocaine withdrawal, and this persisted for at least 68 d of withdrawal. The earliest functional alterations were mediated through increased contributions of GluN2B-containing NMDARs, followed by increased contributions of GluN3-containing NMDARs. As predicted by GluN3-NMDAR incorporation, fewer MSN spines exhibited NMDAR-mediated Ca entry. GluN3A knockdown in NAc core was sufficient to prevent incubation of craving, consistent with biotinylation studies showing increased GluN3A surface expression, although array tomography studies suggested that adaptations involving GluN3B also occur. Collectively, our data show that a complex cascade of NMDAR and AMPAR plasticity occurs in NAc core, potentially through a homeostatic mechanism, leading to persistent increases in cocaine cue reactivity and relapse vulnerability. This is a remarkable example of experience-dependent glutamatergic plasticity evolving over a protracted window in the adult brain. "Incubation of craving" is an animal model for the persistence of vulnerability to cue-induced relapse after prolonged drug abstinence. Incubation also occurs in human drug users. AMPAR plasticity in medium spiny neurons (MSNs) of the NAc core is critical for incubation of cocaine craving but occurs only after a delay. Here we found that AMPAR plasticity is preceded by NMDAR plasticity that is essential for incubation and involves GluN3, an atypical NMDAR subunit that markedly alters NMDAR transmission. Together with AMPAR plasticity, this represents profound remodeling of excitatory synaptic transmission onto MSNs. Given the importance of MSNs for translati
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0406-21.2021