European Journal of Neuroscience
December 6, 2019
Ronald S. Duman, Satoshi Deyama, Manoela V. Fogaça
319 citations
Stress and depression cause neuron atrophy and reduced synaptic connectivity in the hippocampus and prefrontal cortex, contributing to depressive behaviors. Antidepressant treatment can reverse these deficits. Brain-derived neurotrophic factor (BDNF) is key: stress decreases BDNF expression in these regions, while antidepressants up-regulate it. Rapid-acting antidepressants like ketamine produce fast synaptic and behavioral effects dependent on activity-dependent BDNF release, unlike typical monoaminergic agents that require chronic administration for slow BDNF induction. Other rapid-acting agents also require BDNF release, indicating a convergent downstream mechanism. Ketamine's actions also depend on vascular endothelial growth factor (VEGF) and its interplay with BDNF.
Pharmacology, Biochemistry and Behavior
December 9, 2019
Satoshi Deyama, R. Duman
181 citations
Depression is linked to reduced levels of neurotrophic factors like BDNF and VEGF, which contribute to neuronal atrophy in brain regions such as the prefrontal cortex and hippocampus, and to decreased adult neurogenesis. Conventional antidepressants partially reverse these deficits by inducing BDNF or VEGF but have limitations, including a delayed therapeutic response and low efficacy. Ketamine, an NMDA receptor antagonist, produces rapid (within hours) and sustained (up to a week) antidepressant effects in treatment-resistant depression and rodent models. In rodents, ketamine quickly increases BDNF and VEGF release in the medial prefrontal cortex and hippocampus, boosting spine synapses and hippocampal neurogenesis. These neurotrophic actions appear to underlie ketamine's rapid and sustained antidepressant effects, pointing toward development of faster-acting antidepressants with fewer side effects.
American Journal of Psychiatry
January 4, 2019
Satoshi Deyama, Eunyoung Bang, Eric S. Wohleb et al.
100 citations
The antidepressant effects of ketamine require vascular endothelial growth factor (VEGF) signaling through its receptor Flk-1 in excitatory neurons of the medial prefrontal cortex (mPFC). Deleting VEGF or Flk-1 from forebrain excitatory neurons, or blocking VEGF in the mPFC, prevented ketamine's behavioral effects in mice. Infusing VEGF directly into the mPFC produced rapid antidepressant-like actions similar to ketamine, but these were blocked by Flk-1 deletion. Local knockdown of Flk-1 in adult mPFC excitatory neurons also blocked ketamine's effects. Additionally, blocking neuronal VEGF signaling prevented the neurotrophic and synaptogenic actions of ketamine. Neuronal VEGF-Flk-1 signaling in the mPFC is essential for ketamine's rapid antidepressant actions.
European Journal of Pharmacology
October 25, 2025
Satoshi Deyama, Kenji Mishiro, Munetaka Kunishima et al.
A single injection of (R)-ketamine at 30 mg/kg, but not 10 mg/kg, reduced marble burying—a measure of compulsive-like behavior—in male mice at 2 hours, 24 hours, and 7 days after treatment, without affecting general movement. (S)-ketamine at 10 mg/kg also reduced burying. Blocking L-type voltage-dependent calcium channels (L-VDCCs) with verapamil prevented the effect of (S)-ketamine but not of (R)-ketamine. Infusing verapamil directly into the ventromedial orbitofrontal cortex or ventromedial prefrontal cortex also blocked (S)-ketamine's effect. These findings suggest (R)-ketamine produces anticompulsive-like effects comparable to a 3-fold lower dose of (S)-ketamine, and that L-VDCC activation in those brain regions mediates the effects of (S)-ketamine but not (R)-ketamine.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
January 1, 2018
Satoshi Deyama, Eunyoung Baing, T. Kato et al.
Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the medial prefrontal cortex (mPFC) work together to produce antidepressant effects. In cultured cortical neurons, BDNF stimulates VEGF release and VEGF stimulates BDNF release. BDNF increases dendritic complexity, but this effect is blocked by inhibiting the VEGF receptor Flk-1; similarly, VEGF's effect on dendrites is blocked by inhibiting the BDNF receptor TrkB. A single infusion of either BDNF or VEGF into the mPFC of mice produces antidepressant effects lasting at least 5 days in three behavioral tests. These effects are blocked by neutralizing the other factor, indicating that mutual signaling between BDNF and VEGF is required for rapid and sustained antidepressant responses.
Translational Psychiatry
May 17, 2022
Satoshi Deyama, M. Kondo, Shoichi Shimada et al.
Ketamine's rapid antidepressant effects depend on the sustained release of insulin-like growth factor 1 (IGF-1) in the medial prefrontal cortex (mPFC) of male mice. Blocking IGF-1 in the mPFC before or after ketamine injection prevented its antidepressant-like effects in behavioral tests. IGF-1 acted independently of brain-derived neurotrophic factor (BDNF). Infusing IGF-1 into the mPFC produced antidepressant-like effects even in mice with lipopolysaccharide-induced depression, via activation of mTORC1. The findings indicate that persistent intra-mPFC IGF-1 signaling is essential for ketamine's antidepressant actions.
Psychopharmacology
July 1, 2019
Shiho Ito, Satoshi Deyama, Masaki Domoto et al.
The synthetic cannabinoid 5F-AMB, when injected into the brain of mice, reduces anxiety and impairs the acquisition of recognition memory by activating CB1 receptors. Systemic injection severely reduces movement, an effect partially blocked by a CB1 antagonist. Infusion into the medial prefrontal cortex impairs memory acquisition but does not affect anxiety, suggesting other brain regions mediate the anxiolytic effect.
Psychopharmacology
August 1, 2018
Masaki Domoto, Hitoki Sasase, Shintaro Wada et al.
5F-AMB, a synthetic cannabinoid abused worldwide, reduces both excitatory and inhibitory signaling in layer V pyramidal neurons of the medial prefrontal cortex by activating CB1 receptors on presynaptic terminals. Bath application of 5F-AMB decreased the frequency of spontaneous and miniature excitatory and inhibitory postsynaptic currents, an effect blocked by the CB1 antagonist AM251. The suppression of excitatory transmission was greater than that of inhibitory transmission, shifting the balance toward net inhibition of these neurons. This inhibitory effect may contribute to the memory and consciousness impairments observed after inhalation of 5F-AMB.