title: BDNF release is required for the behavioral actions of ketamine.
abstract: BACKGROUND
  Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC).
  
  
  METHODS
  Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine.
  
  
  RESULTS
  The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs.
  
  
  CONCLUSIONS
  Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Lepack
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).
authors.forename: Manabu
authors.initials: M
authors.lastname: Fuchikami
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).
authors.forename: Mounira
authors.initials: M
authors.lastname: Banasr
authors.affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman). ronald.duman@yale.edu.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018091:Receptors, AMPA; D007649:Ketamine; D014700:Verapamil; D009543:Nifedipine
keywords: BDNF; L-type VDCC; depression; glutamate; ketamine