Role of Src Family Kinases in BDNF-Mediated Suppression of Cocaine-Seeking and Prevention of Cocaine-Induced ERK, GluN2A, and GluN2B Dephosphorylation in the Prelimbic Cortex

Neuropsychopharmacology. 2017 Sep;42(10):1972-1980. doi: 10.1038/npp.2017.114. Epub 2017 Jun 6.


Models of relapse have demonstrated that neuroadaptations in reward circuits following cocaine self-administration (SA) underlie reinstatement of drug-seeking. Dysregulation of the pathway from the prelimbic (PrL) cortex to the nucleus accumbens is implicated in reinstatement. A single BDNF infusion into the PrL cortex following a final cocaine SA session results in attenuation of reinstatement of cocaine-seeking. Inhibiting BDNF's receptor, TrkB, ERK/MAP kinase activation, or NMDA receptors blocks this attenuating effect, indicating that the interaction between glutamate-mediated synaptic activity and TrkB signaling is imperative to BDNF's suppressive effect on drug-seeking. Src family kinases (SFKs) are involved in both NMDA-mediated activation of TrkB- and TrkB-mediated tyrosine phosphorylation of NMDA receptors. We hypothesized that infusion of the SFK inhibitor, PP2, into the PrL cortex prior to a BDNF infusion, immediately after the end of the last cocaine SA session, would block BDNF's ability to suppress reinstatement of cocaine-seeking in rats with a cocaine SA history. PP2, but not the negative control, PP3, blocked BDNF's suppressive effect on context-induced relapse after 1 week of abstinence and cue-induced reinstatement after extinction. As previously reported, infusion of BDNF into the PrL cortex blocked cocaine SA-induced dephosphorylation of ERK, GluN2A, and GluN2B-containing receptors. Inhibition of SFKs using PP2 blocked BDNF-mediated phosphorylation of GluN2A, GluN2B, and ERK. These data indicate that SFK activity is necessary for BDNF-mediated suppression of cocaine-seeking and reversal of cocaine-induced dephosphorylation of key phosphoproteins in the prefrontal cortex related to synaptic plasticity.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Central Nervous System Agents / pharmacology*
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / enzymology
  • Drug-Seeking Behavior / drug effects*
  • Drug-Seeking Behavior / physiology
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Male
  • Phosphorylation / drug effects
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / enzymology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*


  • AG 1879
  • Brain-Derived Neurotrophic Factor
  • Central Nervous System Agents
  • NR2B NMDA receptor
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Receptors, N-Methyl-D-Aspartate
  • src-Family Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Cocaine
  • N-methyl D-aspartate receptor subtype 2A