Neuroadaptations in the cellular and postsynaptic group 1 metabotropic glutamate receptor mGluR5 and Homer proteins following extinction of cocaine self-administration.
This study examined the role of group1 metabotropic glutamate receptor mGluR5 and associated postsynaptic scaffolding protein Homer1b/c in behavioral plasticity after three withdrawal treatments from cocaine self-administration. Rats self-administered cocaine or saline for 14 days followed by a withdrawal period during which rats underwent extinction training, remained in their home cages, or were placed in the self-administration chambers in the absence of extinction. Subsequently, the tissue level and distribution of proteins in the synaptosomal fraction associated with the postsynaptic density were examined. Cocaine self-administration followed by home cage exposure reduced the mGluR5 protein in nucleus accumbens (NA) shell and dorsolateral striatum. While extinction training reduced mGluR5 protein in NAshell, NAcore and dorsolateral striatum did not display any change. The scaffolding protein PSD95 increased in NAcore of the extinguished animals. Extinction of drug seeking was associated with a significant decrease in the synaptosomal mGluR5 protein in NAshell and an increase in dorsolateral striatum, while that of NAcore was not modified. Interestingly, both Homer1b/c and PSD95 scaffolding proteins were decreased in the synaptosomal fraction after extinction training in NAshell but not NAcore. Extinguished drug-seeking behavior was also associated with an increase in the synaptosomal actin proteins in dorsolateral striatum. Therefore, extinction of cocaine seeking is associated with neuroadaptations in mGluR5 expression and distribution that are region-specific and consist of extinction-induced reversal of cocaine-induced adaptations as well as emergent extinction-induced alterations. Concurrent plasticity in the scaffolding proteins further suggests that mGluR5 receptor neuroadaptations may have implications for synaptic function.
Ghasemzadeh
M Behnam
MB
Department of Biomedical Sciences, Integrative Neuroscience Research Center, Marquette University, Milwaukee, WI 53201, United States. behnam.ghasemzadeh@marquette.edu
Vasudevan
Preethi
P
Mueller
Christopher
C
Seubert
Chad
C
Mantsch
John R
JR
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000199:Actins; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018765:Dopamine Uptake Inhibitors; C578937:Grm5 protein, rat; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D003042:Cocaine