PMID- 25522393 OWN - NLM STAT- MEDLINE DCOM- 20150930 LR - 20181113 IS - 1469-5111 (Electronic) IS - 1461-1457 (Print) IS - 1461-1457 (Linking) VI - 18 IP - 1 DP - 2014 Dec 5 TI - A single brain-derived neurotrophic factor infusion into the dorsomedial prefrontal cortex attenuates cocaine self-administration-induced phosphorylation of synapsin in the nucleus accumbens during early withdrawal. LID - pyu049 [pii] LID - 10.1093/ijnp/pyu049 [doi] AB - BACKGROUND: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. METHODS: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. RESULTS: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. CONCLUSIONS: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration-induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal. CI - (c) The Author 2015. Published by Oxford University Press on behalf of CINP. FAU - Sun, Wei-Lun AU - Sun WL AD - Department of Neurosciences and Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina, (Drs Sun and McGinty); Department of Psychiatry, Washington University, St Louis, MO (Dr Eisenstein); Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (Dr Zelek-Molik). FAU - Eisenstein, Sarah A AU - Eisenstein SA AD - Department of Neurosciences and Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina, (Drs Sun and McGinty); Department of Psychiatry, Washington University, St Louis, MO (Dr Eisenstein); Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (Dr Zelek-Molik). FAU - Zelek-Molik, Agnieszka AU - Zelek-Molik A AD - Department of Neurosciences and Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina, (Drs Sun and McGinty); Department of Psychiatry, Washington University, St Louis, MO (Dr Eisenstein); Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (Dr Zelek-Molik). FAU - McGinty, Jacqueline F AU - McGinty JF AD - Department of Neurosciences and Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina, (Drs Sun and McGinty); Department of Psychiatry, Washington University, St Louis, MO (Dr Eisenstein); Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (Dr Zelek-Molik). mcginty@musc.edu. LA - eng GR - P50 DA015369/DA/NIDA NIH HHS/United States GR - T32 DA007288/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141205 PL - England TA - Int J Neuropsychopharmacol JT - The international journal of neuropsychopharmacology JID - 9815893 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Central Nervous System Agents) RN - 0 (Dopamine Uptake Inhibitors) RN - 0 (Synapsins) RN - I5Y540LHVR (Cocaine) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*administration & dosage MH - Central Nervous System Agents/*administration & dosage MH - Cocaine/administration & dosage MH - Cocaine-Related Disorders/*drug therapy/metabolism MH - Disease Models, Animal MH - Dopamine Uptake Inhibitors/administration & dosage MH - Male MH - Nucleus Accumbens/drug effects/*metabolism MH - Phosphorylation/drug effects MH - Prefrontal Cortex/drug effects/metabolism MH - Rats, Sprague-Dawley MH - Self Administration MH - Substance Withdrawal Syndrome/*drug therapy/metabolism MH - Synapsins/*metabolism PMC - PMC4368877 OTO - NOTNLM OT - cocaine self-administration OT - immunoblotting OT - nucleus accumbens OT - phosphatase OT - synapsin EDAT- 2014/12/19 06:00 MHDA- 2015/10/01 06:00 PMCR- 2015/01/02 CRDT- 2014/12/19 06:00 PHST- 2014/12/19 06:00 [entrez] PHST- 2014/12/19 06:00 [pubmed] PHST- 2015/10/01 06:00 [medline] PHST- 2015/01/02 00:00 [pmc-release] AID - pyu049 [pii] AID - 10.1093/ijnp/pyu049 [doi] PST - epublish SO - Int J Neuropsychopharmacol. 2014 Dec 5;18(1):pyu049. doi: 10.1093/ijnp/pyu049.