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Int J Neuropsychopharmacol. 2014 Oct 31;18(1). pii: pyu033. doi: 10.1093/ijnp/pyu033.

BDNF release is required for the behavioral actions of ketamine.

Author information

1
Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).
2
Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman). ronald.duman@yale.edu.

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.

KEYWORDS:

BDNF; L-type VDCC; depression; glutamate; ketamine

PMID:
25539510
PMCID:
PMC4368871
DOI:
10.1093/ijnp/pyu033
[Indexed for MEDLINE]
Free PMC Article

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