title: Sensitizing exposure to amphetamine increases AMPA receptor phosphorylation without increasing cell surface expression in the rat nucleus accumbens.
abstract: Exposure to psychostimulants like cocaine or amphetamine leads to long-lasting sensitization of their behavioral and neurochemical effects. Here we characterized changes in AMPA receptor distribution and phosphorylation state in the rat nucleus accumbens (NAcc) weeks after amphetamine exposure to assess their potential contribution to sensitization by this drug. Using protein cross-linking, biochemical, subcellular fractionation, and slice electrophysiological approaches in the NAcc, we found that, unlike cocaine, previous exposure to amphetamine did not increase cell surface levels of either GluA1 or GluA2 AMPA receptor subunits, redistribution of these subunits to the synaptic or perisynaptic cellular membrane domains, protein-protein associations required to support the accumulation and retention of AMPA receptors in the PSD, or the peak amplitude of AMPA receptor mediated mEPSCs recorded in NAcc slices. On the other hand, exposure to amphetamine significantly slowed mEPSC decay times and increased levels in the PSD of PKA and CaMKII as well as phosphorylation by these kinases of the GluA1 S845 and S831 residues selectively in this cellular compartment. As the latter effects are known to respectively regulate channel open probability and duration as well as conductance, they provide a novel mechanism that could contribute to the long-lasting AMPA receptor dependent expression of sensitization by amphetamine. Rather than increase the number of surface and synaptic AMPA receptors as with cocaine, this mechanism could increase NAcc medium spiny neuron reactivity to glutamate afferents by increasing the phosphorylation state of critical regulatory sites in the AMPA receptor GluA1 subunit in the PSD.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, United States.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, United States.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bubula
authors.affiliation: Gladstone Institutes of Neurological Disease, San Francisco, CA 94158, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Campioni
authors.affiliation: Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL 60637, United States.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: McGehee
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, United States. Electronic address: pvezina@uchicago.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Vezina
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D057907:Post-Synaptic Density / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D000697:Central Nervous System Stimulants; D018091:Receptors, AMPA; D000661:Amphetamine; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: CaMKII; GluA1; GluA2; PKA; PSD; Receptor trafficking