title: Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking.
abstract: Cocaine self-administration induces dysfunctional neuroadaptations in the prefrontal cortex that underlie relapse to cocaine-seeking. Cocaine self-administration disturbs glutamatergic transmission in the nucleus accumbens that is prevented by infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic area of the prefrontal cortex. Intra-prelimbic infusion of BDNF decreases cocaine-seeking in a TrkB-ERK MAP kinase-dependent manner. Neuronal activity triggers an interaction between TrkB receptors and NMDA receptors, leading to ERK activation. In the present study, infusion of the GluN2A-containing NMDA receptor antagonist, TCN-201, or the GluN2B-containing NMDA receptor antagonist, Ro-25-6981, into the prelimbic cortex of rats blocked the suppressive effect of BDNF on cocaine-seeking. During early withdrawal from cocaine self-administration, tyrosine phosphorylation of ERK, GluN2A, and GluN2B in the prelimbic cortex was reduced and this reduction of phospho-proteins was prevented by intra-prelimbic BDNF infusion. TCN-201 infusion into the prelimbic cortex inhibited the BDNF-mediated increase in pERK and pGluN2A whereas Ro-25-6981 infusion into the prelimbic cortex blocked BDNF-induced elevation of pERK and pGluN2B, indicating that both GluN2A- and GluN2B-containing NMDA receptors underlie BDNF-induced ERK activation. These data demonstrate that BDNF-mediated activation of GluN2A- and GluN2B-containing NMDA receptors underlies ERK activation in the prelimbic cortex during early withdrawal, preventing subsequent relapse to cocaine-seeking.
authors.affiliation: Department of Neuroscience and Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Bok Soon
authors.initials: BS
authors.lastname: Go
authors.affiliation: Department of Neuroscience and Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Barry
authors.affiliation: Department of Neuroscience and Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: mcginty@musc.edu.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: McGinty
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology* / Q000523:psychology*; D018698:Glutamic Acid; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008845:Microinjections; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000523:psychology; D013449:Sulfonamides / Q000494:pharmacology; D009435:Synaptic Transmission; D006834:Hydrazines; D000096926:Benzenesulfonamides
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018698:Glutamic Acid; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; C121001:NR2B NMDA receptor; C109643:Ro 25-6981; C574512:TCN 201; D006834:Hydrazines; D000096926:Benzenesulfonamides
keywords: Addiction; Brain-derived neurotrophic factor; Extracellular signal-regulated kinase; NMDA receptors; Prefrontal cortex; Reinstatement