Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking

Eur Neuropsychopharmacol. 2016 Dec;26(12):1989-1999. doi: 10.1016/j.euroneuro.2016.10.002. Epub 2016 Oct 17.


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.

Keywords: Addiction; Brain-derived neurotrophic factor; Extracellular signal-regulated kinase; NMDA receptors; Prefrontal cortex; Reinstatement.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / administration & dosage
  • Brain-Derived Neurotrophic Factor / antagonists & inhibitors
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Cocaine-Related Disorders / physiopathology*
  • Cocaine-Related Disorders / psychology*
  • Glutamic Acid*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Microinjections
  • Phenols / pharmacology
  • Piperidines / pharmacology
  • Prefrontal Cortex / physiopathology*
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Self Administration
  • Substance Withdrawal Syndrome / drug therapy
  • Substance Withdrawal Syndrome / psychology
  • Sulfonamides / pharmacology
  • Synaptic Transmission*


  • Brain-Derived Neurotrophic Factor
  • NR2B NMDA receptor
  • Phenols
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Ro 25-6981
  • Sulfonamides
  • TCN 201
  • Glutamic Acid
  • N-methyl D-aspartate receptor subtype 2A