title: Disruption of glutamate receptor-interacting protein in nucleus accumbens enhances vulnerability to cocaine relapse.
abstract: Trafficking and stabilization of AMPA receptors at synapses in response to cocaine exposure is thought to be critical for expression of cocaine addiction and relapse. Glutamate receptor-interacting protein (GRIP) is a neuronal scaffolding protein that stabilizes GluA2 AMPARs at synapses but its role in cocaine addiction has not been examined. The current study demonstrates that conditional deletion of GRIP within the nucleus accumbens potentiates cue-induced reinstatement of cocaine seeking without affecting operant learning, locomotor activity, or reinstatement of natural reward seeking. This is the first study to demonstrate a role for accumbal GRIP in behavior. Electrophysiological recordings revealed increased rectification of AMPAR-mediated currents in the nucleus accumbens and increased AMPAR sensitivity to the GluA2-lacking AMPAR antagonist, 1-naphthylacetyl spermine, indicative of an increased contribution of GluA2-lacking calcium-permeable AMPARs. In addition, accumbal GRIP deletion was associated with blunted long-term depression, similar to what is seen following cocaine self-administration. Taken together, these results indicate that GRIP may modulate addictive phenotypes through its regulation of synaptic AMPARs by controlling their subunit composition and susceptibility to LTD. These effects are associated with changes in vulnerability to cocaine relapse and highlight GRIP as a novel target for the development of cocaine addiction therapeutics.
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Briand
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Blake A
authors.initials: BA
authors.lastname: Kimmey
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Ortinski
authors.affiliation: 1] Howard Hughes Medical Institute, Baltimore, MD, USA [2] Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, 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 / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018765:Dopamine Uptake Inhibitors; C491309:Grip1 protein, mouse; C485567:Grip2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; D013395:Sucrose; D003042:Cocaine