PMID- 25268928 OWN - NLM STAT- MEDLINE DCOM- 20160927 LR - 20211021 IS - 1872-6240 (Electronic) IS - 0006-8993 (Print) IS - 0006-8993 (Linking) VI - 1628 IP - Pt A DP - 2015 Dec 2 TI - Cocaine self-administration causes signaling deficits in corticostriatal circuitry that are reversed by BDNF in early withdrawal. PG - 82-7 LID - S0006-8993(14)01299-2 [pii] LID - 10.1016/j.brainres.2014.09.050 [doi] AB - 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. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - McGinty, Jacqueline F AU - McGinty JF AD - Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: mcginty@musc.edu. FAU - Zelek-Molik, Agnieska AU - Zelek-Molik A AD - Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. FAU - Sun, Wei-Lun AU - Sun WL AD - Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA. LA - eng GR - P50 DA015369/DA/NIDA NIH HHS/United States GR - R01 DA033479/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20140928 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Central Nervous System Agents) RN - I5Y540LHVR (Cocaine) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*administration & dosage MH - Central Nervous System Agents/*administration & dosage MH - Cerebral Cortex/*drug effects/physiopathology MH - Cocaine/administration & dosage MH - Cocaine-Related Disorders/*drug therapy/physiopathology MH - Corpus Striatum/*drug effects/physiopathology MH - Humans MH - Neural Pathways/drug effects/physiopathology MH - Self Administration MH - Substance Withdrawal Syndrome/*drug therapy/physiopathology PMC - PMC4377116 MID - NIHMS633444 OTO - NOTNLM OT - BDNF OT - ERK MAP kinase OT - Glutamate OT - Nucleus accumbens OT - Prefrontal cortex OT - Reinstatement EDAT- 2014/10/01 06:00 MHDA- 2016/09/28 06:00 PMCR- 2016/12/02 CRDT- 2014/10/01 06:00 PHST- 2014/08/15 00:00 [received] PHST- 2014/09/16 00:00 [revised] PHST- 2014/09/20 00:00 [accepted] PHST- 2014/10/01 06:00 [entrez] PHST- 2014/10/01 06:00 [pubmed] PHST- 2016/09/28 06:00 [medline] PHST- 2016/12/02 00:00 [pmc-release] AID - S0006-8993(14)01299-2 [pii] AID - 10.1016/j.brainres.2014.09.050 [doi] PST - ppublish SO - Brain Res. 2015 Dec 2;1628(Pt A):82-7. doi: 10.1016/j.brainres.2014.09.050. Epub 2014 Sep 28.