Region-specific alterations in glutamate receptor expression  and subcellular distribution following extinction of  cocaine self-administration.
A role for glutamatergic signaling in the nucleus accumbens (NA) in both the expression and extinction of cocaine seeking has been suggested. The effects of extinction following cocaine self-administration on the expression and synaptosomal distribution of GluR1 and NMDAR1 glutamate receptor subunits in the NA shell and core and the dorsolateral striatum were examined. Rats self-administered cocaine or had access to saline for 14 days followed by a period of extinction training, home-cage exposure, or placement in the self-administration chambers with levers retracted in the absence of discrete cues. Self-administration followed by home-cage exposure reduced GluR1 expression in the NA shell and NMDAR1 expression in the dorsolateral striatum without affecting expression in the NA core. These effects were not observed following extinction. Extinction training increased synaptosomal GluR1 in the NA shell and core and NMDAR1 in the dorsolateral striatum while decreasing synaptosomal NMDAR1 in the shell. Extinction but not home-cage exposure was associated with altered expression and synaptosomal content of the scaffolding proteins PICK1 and PSD95.Following extinction, synaptosomal PICK1 decreased in the dorsolateral striatum while total PICK1 expression was increased in the shell. The synaptosomal PSD95 was decreased in the NA shell, while total PSD95 expression was increased in the core. These data suggest that extinguished cocaine seeking is associated with changes in GluR1 and NMDAR1 expression and subcellular distribution that are region-specific and consist of both a reversal of cocaine-induced adaptations and emergent extinction-related alterations that include receptor subunit redistribution and may involve alterations in scaffolding proteins.
Department of Biomedical Sciences, Integrative Neuroscience Research Center, Marquette University, Milwaukee, WI 53201, USA.
M Behnam
MB
Ghasemzadeh
Preethi
P
Vasudevan
Christopher R
CR
Mueller
Chad
C
Seubert
John R
JR
Mantsch
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003598:Cytoskeletal Proteins; D000076122:Disks Large Homolog 4 Protein; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012646:Self Administration
D002352:Carrier Proteins; D003042:Cocaine; D003598:Cytoskeletal Proteins; D000076122:Disks Large Homolog 4 Protein; D018765:Dopamine Uptake Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C501449:Dlg4 protein, rat; C498298:PICK1 protein, rat