title: 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.
abstract: 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.
authors.affiliation: 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).
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Sun
authors.affiliation: 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).
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Eisenstein
authors.affiliation: 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).
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zelek-Molik
authors.affiliation: 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.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: McGinty
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage*; D002491:Central Nervous System Agents / Q000008:administration & dosage*; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002491:Central Nervous System Agents; D018765:Dopamine Uptake Inhibitors; D016704:Synapsins; D003042:Cocaine
keywords: cocaine self-administration; immunoblotting; nucleus accumbens; phosphatase; synapsin