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

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.