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Neuron‐specific deletion of VEGF or its receptor Flk‐1 occludes the antidepressant‐like effects of desipramine and fluoxetine in mice

Satoshi Deyama,Xiao-Yuan Li,Ronald S. Duman

Published 2023 in Neuropsychopharmacology Reports

ABSTRACT

Vascular endothelial growth factor (VEGF) signaling is known to be involved in the antidepressant‐like effects of conventional antidepressants, such as desipramine (DMI), a tricyclic antidepressant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor; however, the precise role of neuronal VEGF signaling in mediating these effects remains unclear. Using mice with excitatory neuron‐specific deletion of VEGF and its receptor, fetal liver kinase 1 (Flk‐1) in the forebrain, we examined the effects of forebrain excitatory neuron‐specific deletion of VEGF or Flk‐1 on the antidepressant‐like effects of repeated DMI and chronic FLX administration in the forced swim test (FST). Repeated intraperitoneal (i.p.) injections of DMI (10, 10, and 20 mg/kg at 24, 4, and 1 h before the FST, respectively) significantly decreased immobility in control mice; however, this effect was completely blocked in mice with neuron‐specific VEGF or Flk‐1 deletion. Although chronic treatment with FLX (18 mg/kg/day, i.p.) did not impact immobility in control mice 1 day after the 22nd injection, immobility was significantly reduced 1 day after the preswim and the 23rd FLX injection. However, in mice with neuron‐specific Flk‐1 deletion, chronic FLX treatment significantly increased immobility in the preswim and failed to produce antidepressant‐like effects. Collectively, these findings indicate that neuronal VEGF–Flk‐1 signaling contributes to the antidepressant‐like actions of conventional antidepressants.

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