title: Cocaine self-administration causes signaling deficits in corticostriatal circuitry that are reversed by BDNF in early withdrawal.
abstract: Cocaine self-administration disturbs intracellular signaling in prefrontal cortical neurons that regulate neurotransmission in the nucleus accumbens. The deficits in dorsomedial prefrontal cortex (dmPFC) signaling change over time, resulting in different neuroadaptations during early withdrawal from cocaine self-administration than after one or more weeks of abstinence. Within the first few hours of withdrawal, there is a marked decrease in tyrosine phosphorylation of critical intracellular and membrane-bound proteins in the dmPFC that include ERK/MAP kinase and the NMDA receptor subunits, GluN1 and GluN2B. These changes are accompanied by a marked increase in STEP tyrosine phosphatase activation. Simultaneously, ERK and PKA-dependent synapsin phosphorylation in presynaptic terminals of the nucleus accumbens is increased that may have a destabilizing impact on glutamatergic transmission. Infusion of brain-derived neurotrophic factor (BDNF) into the dmPFC immediately following a final session of cocaine self-administration blocks the cocaine-induced changes in phosphorylation and attenuates relapse to cocaine seeking for as long as three weeks. The intra-dmPFC BDNF infusion also prevents cocaine-induced deficits in prefronto-accumbens glutamatergic transmission that are implicated in cocaine seeking. Thus, intervention with BDNF in the dmPFC during early withdrawal has local and distal effects in target areas that are critical to mediating cocaine-induced neuroadaptations that lead to cocaine seeking.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: mcginty@musc.edu.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: McGinty
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Agnieska
authors.initials: A
authors.lastname: Zelek-Molik
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Sun
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage*; D002491:Central Nervous System Agents / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002491:Central Nervous System Agents; D003042:Cocaine
keywords: BDNF; ERK MAP kinase; Glutamate; Nucleus accumbens; Prefrontal cortex; Reinstatement