Behavioral sensitization to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens.
Regulation of AMPA receptor trafficking is important for many forms of neuronal plasticity. In this study, a protein cross-linking assay was used to evaluate the contribution of AMPA receptor trafficking to plasticity associated with behavioral sensitization, an animal model of drug addiction. Cross-linking was used to distinguish between cell surface and intracellular AMPA receptors in nucleus accumbens (NAc) tissue obtained from rats treated repeatedly with saline or cocaine. Surface/intracellular (S/I) ratios for glutamate receptor 1 (GluR1) and GluR2/3 subunits were increased 21 d after the last injection in cocaine-sensitized rats but not rats that failed to sensitize, and the magnitude of the S/I ratio for cocaine-sensitized rats was positively correlated with the magnitude of behavioral sensitization. At the 1 d withdrawal time, cocaine did not alter S/I ratios, and there was no correlation between S/I ratios and behavioral sensitization. The majority of surface-expressed GluR1 detected with this assay was associated with synapses, based on coimmunoprecipitation with postsynaptic density protein of 95 kDa. These findings suggest that behavioral sensitization to cocaine is associated with a slowly developing redistribution of AMPA receptors to the surface of NAc neurons. Motor execution of drug-seeking responses depends on activation of AMPA receptors on NAc neurons by glutamate afferents originating in cortical and limbic regions. We propose that drug-seeking responses are more effectively triggered in cocaine-sensitized rats because of increased cell surface expression of AMPA receptors.
Boudreau
Amy C
AC
Department of Neuroscience, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064-3095, USA.
Wolf
Marina E
ME
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D003042:Cocaine / Q000008:administration & dosage*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013997:Time Factors
D003432:Cross-Linking Reagents; D018765:Dopamine Uptake Inhibitors; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C033652:postsynaptic density proteins; D003042:Cocaine