title: A Critical Role for the GluA1 Accessory Protein, SAP97, in Cocaine Seeking.
abstract: A growing body of evidence indicates that the transport of GluA1 subunit-containing calcium-permeable AMPA receptors (CP-AMPARs) to synapses in subregions of the nucleus accumbens promotes cocaine seeking. Consistent with these findings, the present results show that administration of the CP-AMPAR antagonist, Naspm, into the caudal lateral core or caudal medial shell of the nucleus accumbens attenuated cocaine priming-induced reinstatement of drug seeking. Moreover, viral-mediated overexpression of 'pore dead' GluA1 subunits (via herpes simplex virus (HSV) GluA1-Q582E) in the lateral core or medial shell attenuated the reinstatement of cocaine seeking. The overexpression of wild-type GluA1 subunits (via HSV GluA1-WT) in the medial shell, but not the lateral core, enhanced the reinstatement of cocaine seeking. These results indicate that activation of GluA1-containing AMPARs in subregions of the nucleus accumbens reinstates cocaine seeking. SAP97 and 4.1N are proteins involved in GluA1 trafficking to and stabilization in synapses; SAP97-GluA1 interactions also influence dendritic growth. We next examined potential roles of SAP97 and 4.1N in cocaine seeking. Viral-mediated expression of a microRNA that reduces SAP97 protein expression (HSV miSAP97) in the medial accumbens shell attenuated cocaine seeking. In contrast, a virus that overexpressed a dominant-negative form of a 4.1N C-terminal domain (HSV 4.1N-CTD), which prevents endogenous 4.1N binding to GluA1 subunits, had no effect on cocaine seeking. These results indicate that the GluA1 subunit accessory protein SAP97 may represent a novel target for pharmacotherapeutic intervention in the treatment of cocaine craving.
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: White
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Ortinski
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Shayna H
authors.initials: SH
authors.lastname: Friedman
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center 814, Philadelphia, PA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research at the Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center 814, Philadelphia, PA, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kalb
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Heath D
authors.initials: HD
authors.lastname: Schmidt
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R Christopher
authors.initials: RC
authors.lastname: Pierce
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D019422:Dietary Sucrose / Q000008:administration & dosage; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012646:Self Administration; D046509:Tissue Culture Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003042:Cocaine; D019422:Dietary Sucrose; D018765:Dopamine Uptake Inhibitors; D008565:Membrane Proteins; D018091:Receptors, AMPA; C501119:Dlg1 protein, rat