Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking.
Learning to inhibit drug seeking can be an important strategy for inhibiting relapse, and this can be modeled by extinguishing drug seeking in response to a drug-paired context. Rats were either extinguished or withdrawn without extinction training (abstinence) from cocaine self-administration, and measurements of postsynaptic density proteins in the core and shell subcompartments of the nucleus accumbens were compared with yoked-saline controls. Only extinguished rats had elevations of PSD-95, Homer1b/c, and Narp in the postsynaptic density of the core, whereas no proteins measured were altered in the postsynaptic density of the shell in either extinguished or abstinent rats. Using a biotinylation strategy, it was found that surface expression of mGluR5 was reduced only in the core of extinguished animals. Although both extinguished and abstinent animals showed a reduction in long-term potentiation elicited in the core by stimulating prefrontal cortex, blunted long-term depression was observed only in extinguished rats. These data indicate that the elevation in Homer1b/c in the core may have sequestered mGluR5 away from the membrane surface and that the loss of surface mGluR5 inhibits long-term depression. Accordingly, when Homer1c was overexpressed in the core of cocaine-naive rats with an adenoassociated virus, long-term depression was inhibited. This mechanism may contribute to the inhibition of cocaine seeking by extinction training because overexpression of Homer1c in the core also inhibited cue-induced reinstatement of cocaine seeking. These data identify a cellular mechanism that may contribute to extinction-induced inhibition of cocaine seeking.
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. knackst@musc.edu
Lori A
LA
Knackstedt
Khaled
K
Moussawi
Ryan
R
Lalumiere
Marek
M
Schwendt
Matthias
M
Klugmann
Peter W
PW
Kalivas
D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology / Q000523:psychology*; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology / Q000523:psychology*; D000076122:Disks Large Homolog 4 Protein; D004594:Electrophysiology; D005108:Extinction, Psychological; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012646:Self Administration / Q000379:methods; D009435:Synaptic Transmission / Q000187:drug effects; D000099153:Pentraxins
D002097:C-Reactive Protein; D002352:Carrier Proteins; D003042:Cocaine; D000076122:Disks Large Homolog 4 Protein; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000099153:Pentraxins; C501449:Dlg4 protein, rat; C578937:Grm5 protein, rat