BDNF Release Is Required for the Behavioral Actions of Ketamine
Ashley E. Lepack, Manabu Fuchikami, J. M. Dwyer, Mounira Banasr, Ronald S. Duman
The International Journal of Neuropsychopharmacology October 31, 2014 DOI: 10.1093/ijnp/pyu033 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats and primary cortical neurons |
| Interventions | ketamine nifedipine verapamil |
| Topics | Ketamine Esketamine |
| Keywords | Ampa receptor Glutamate receptor Pharmacology Nmda receptor Brain-derived neurotrophic factor Behavioural despair test Neurotrophic factors Antidepressant Prefrontal cortex Voltage-dependent calcium channel Hippocampus Biochemistry |
| Citations | 369 |
| Key findings | Ketamine's antidepressant effects in the forced swim test are mediated by activation of L-type voltage-dependent calcium channels and the release of BDNF in the medial prefrontal cortex. |
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.